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.

SU-F-T-263: Dosimetric Characteristics of the Cine Acquisition Mode of An A-Si EPID

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

Bawazeer, O; Deb, P; Sarasanandarajah, S

2016-06-15

Purpose: To investigate the dosimetric characteristics of Varian a-Si-500 electronic portal imaging device (EPID) operated in cine mode particularly considering linearity with delivered dose, dose rate, field size, phantom thickness, MLC speed and common IMRT fields. Methods: The EPID that attached to a Varian Clinac 21iX linear accelerator, was irradiated with 6 and 18 MV using 600 MU/min. Image acquisition is controlled by the IAS3 software, Trigger delay was 6 ms, BeamOnDelay and FrameStartDelay were zero. Different frame rates were utilized. Cine mode response was calculated using MATLAB as summation of mean pixel values in a region of interest ofmore » the acquired images. The performance of cine mode was compared to integrated mode and dose measurements in water using CC13 ionization chamber. Results: Figure1 illustrates that cine mode has nonlinear response for small MU, when delivering 10 MU was about 0.5 and 0.64 for 6 and 18 MV respectively. This is because the missing acquired images that were calculated around four images missing in each delivery. With the increase MU the response became linear and comparable with integrated mode and ionization chamber within 2%. Figure 2 shows that cine mode has comparable response with integrated mode and ionization chamber within 2% with changing dose rate for 10 MU delivered. This indicates that the dose rate change has no effect on nonlinearity of cine mode response. Except nonlinearity, cine mode is well matched to integrated mode response within 2% for field size, phantom thickness, MLC speed dependences. Conclusion: Cine mode has similar dosimetric characteristics to integrated mode with open and IMRT fields, and the main limitation with cine mode is missing images. Therefore, the calibration of EPID images with this mode should be run with large MU, and when IMRT verification field has low MU, the correction for missing images are required.« less

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

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

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

2014-08-15

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

Hazard identification, dose-response and environmental characteristics of stachybotryotoxins and other health-related products from Stachybotrys.

PubMed

Lai, K M

2006-03-01

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

Dosimetric characteristics of a MOSFET dosimeter for clinical electron beams.

PubMed

Manigandan, D; Bharanidharan, G; Aruna, P; Devan, K; Elangovan, D; Patil, Vikram; Tamilarasan, R; Vasanthan, S; Ganesan, S

2009-09-01

The fundamental dosimetric characteristics of commercially available metal oxide semiconductor field effect transistor (MOSFET) detectors were studied for clinical electron beam irradiations. MOSFET showed excellent linearity against doses measured using an ion chamber in the dose range of 20-630cGy. MOSFET reproducibility is better at high doses compared to low doses. The output factors measured with the MOSFET were within +/-3% when compared with those measured with a parallel plate chamber. From 4 to 12MeV, MOSFETs showed a large angular dependence in the tilt directions and less in the axial directions. MOSFETs do not show any dose-rate dependence between 100 and 600MU/min. However, MOSFETs have shown under-response when the dose per pulse of the beam is decreased. No measurable effect in MOSFET response was observed in the temperature range of 23-40 degrees C. The energy dependence of a MOSFET dosimeter was within +/-3.0% for 6-18MeV electron beams and 5.5% for 4MeV ones. This study shows that MOSFET detectors are suitable for dosimetry of electron beams in the energy range of 4-18MeV.

Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

PubMed

Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

2009-06-01

The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test.

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

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

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

Kim, D; Chung, W; Chung, M

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

Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials.

PubMed

von Minckwitz, Gunter; Untch, Michael; Nüesch, Eveline; Loibl, Sibylle; Kaufmann, Manfred; Kümmel, Sherko; Fasching, Peter A; Eiermann, Wolfgang; Blohmer, Jens-Uwe; Costa, Serban Dan; Mehta, Keyur; Hilfrich, Jörn; Jackisch, Christian; Gerber, Bernd; du Bois, Andreas; Huober, Jens; Hanusch, Claus; Konecny, Gottfried; Fett, Werner; Stickeler, Elmar; Harbeck, Nadia; Müller, Volkmar; Jüni, Peter

2011-01-01

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.

A novel approach to multihazard modeling and simulation.

PubMed

Smith, Silas W; Portelli, Ian; Narzisi, Giuseppe; Nelson, Lewis S; Menges, Fabian; Rekow, E Dianne; Mincer, Joshua S; Mishra, Bhubaneswar; Goldfrank, Lewis R

2009-06-01

To develop and apply a novel modeling approach to support medical and public health disaster planning and response using a sarin release scenario in a metropolitan environment. An agent-based disaster simulation model was developed incorporating the principles of dose response, surge response, and psychosocial characteristics superimposed on topographically accurate geographic information system architecture. The modeling scenarios involved passive and active releases of sarin in multiple transportation hubs in a metropolitan city. Parameters evaluated included emergency medical services, hospital surge capacity (including implementation of disaster plan), and behavioral and psychosocial characteristics of the victims. In passive sarin release scenarios of 5 to 15 L, mortality increased nonlinearly from 0.13% to 8.69%, reaching 55.4% with active dispersion, reflecting higher initial doses. Cumulative mortality rates from releases in 1 to 3 major transportation hubs similarly increased nonlinearly as a function of dose and systemic stress. The increase in mortality rate was most pronounced in the 80% to 100% emergency department occupancy range, analogous to the previously observed queuing phenomenon. Effective implementation of hospital disaster plans decreased mortality and injury severity. Decreasing ambulance response time and increasing available responding units reduced mortality among potentially salvageable patients. Adverse psychosocial characteristics (excess worry and low compliance) increased demands on health care resources. Transfer to alternative urban sites was possible. An agent-based modeling approach provides a mechanism to assess complex individual and systemwide effects in rare events.

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

NASA Astrophysics Data System (ADS)

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

2006-02-01

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

Investigation of the response characteristics of OSL albedo neutron dosimeters in a 241AmBe reference neutron field

NASA Astrophysics Data System (ADS)

Liamsuwan, T.; Wonglee, S.; Channuie, J.; Esoa, J.; Monthonwattana, S.

2017-06-01

The objective of this work was to systematically investigate the response characteristics of optically stimulated luminescence Albedo neutron (OSLN) dosimeters to ensure reliable personal dosimetry service provided by Thailand Institute of Nuclear Technology (TINT). Several batches of InLight® OSLN dosimeters were irradiated in a reference neutron field generated by the in-house 241AmBe neutron irradiator. The OSL signals were typically measured 24 hours after irradiation using the InLight® Auto 200 Reader. Based on known values of delivered neutron dose equivalent, the reading correction factor to be used by the reader was evaluated. Subsequently, batch homogeneity, dose linearity, lower limit of detection and fading of the OSLN dosimeters were examined. Batch homogeneity was evaluated to be 0.12 ± 0.05. The neutron dose response exhibited a linear relationship (R2=0.9974) within the detectable neutron dose equivalent range under test (0.4-3 mSv). For this neutron field, the lower limit of detection was between 0.2 and 0.4 mSv. Over different post-irradiation storage times of up to 180 days, the readings fluctuated within ±5%. Personal dosimetry based on the investigated OSLN dosimeter is considered to be reliable under similar neutron exposure conditions, i.e. similar neutron energy spectra and dose equivalent values.

Low-dose ionizing radiation limitations to seed germination: Results from a model linking physiological characteristics and developmental-dynamics simulation strategy.

PubMed

Liu, Hui; Hu, Dawei; Dong, Chen; Fu, Yuming; Liu, Guanghui; Qin, Youcai; Sun, Yi; Liu, Dianlei; Li, Lei; Liu, Hong

2017-08-01

There is much uncertainty about the risks of seed germination after repeated or protracted environmental low-dose ionizing radiation exposure. The purpose of this study is to explore the influence mechanism of low-dose ionizing radiation on wheat seed germination using a model linking physiological characteristics and developmental-dynamics simulation. A low-dose ionizing radiation environment simulator was built to investigate wheat (Triticum aestivum L.) seeds germination process and then a kinetic model expressing the relationship between wheat seed germination dynamics and low-dose ionizing radiation intensity variations was developed by experimental data, plant physiology, relevant hypotheses and system dynamics, and sufficiently validated and accredited by computer simulation. Germination percentages were showing no differences in response to different dose rates. However, root and shoot lengths were reduced significantly. Plasma governing equations were set up and the finite element analysis demonstrated H 2 O, CO 2 , O 2 as well as the seed physiological responses to the low-dose ionizing radiation. The kinetic model was highly valid, and simultaneously the related influence mechanism of low-dose ionizing radiation on wheat seed germination proposed in the modeling process was also adequately verified. Collectively these data demonstrate that low-dose ionizing radiation has an important effect on absorbing water, consuming O 2 and releasing CO 2 , which means the risk for embryo and endosperm development was higher. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Evaluation of an Experimental Production Wireless Dose Monitoring System for Radiation Exposure Management of Medical Staff].

PubMed

Fujibuchi, Toshioh; Murazaki, Hiroo; Kuramoto, Taku; Umedzu, Yoshiyuki; Ishigaki, Yung

2015-08-01

Because of the more advanced and more complex procedures in interventional radiology, longer treatment times have become necessary. Therefore, it is important to determine the exposure doses received by operators and patients. The aim of our study was to evaluate an experimental production wireless dose monitoring system for pulse radiation in diagnostic X-ray. The energy, dose rate, and pulse fluoroscopy dependence were evaluated as the basic characteristics of this system for diagnostic X-ray using a fully digital fluoroscopy system. The error of 1 cm dose equivalent rate was less than 15% from 35.1 keV to 43.2 keV with energy correction using metal filter. It was possible to accurately measure the dose rate dependence of this system, which was highly linear until 100 μSv/h. This system showed a constant response to the pulse fluoroscopy. This system will become useful wireless dosimeter for the individual exposure management by improving the high dose rate and the energy characteristics.

Performance of finishing beef steers in response to anabolic implant dose and zilpaterol hydrochloride

USDA-ARS?s Scientific Manuscript database

British × Continental steers (n = 168; 7 pens/treatment; initial BW = 362 kg) were used to evaluate the dose of trenbolone acetate (TBA) and estradiol-17ß (E2) and feeding of zilpaterol hydrochloride (ZH) on performance and carcass characteristics. A randomized complete block design was used with a ...

DEVELOPMENT, APPLICATION AND VALIDATION OF A SHEEPSHEAD MINNOW ESTROGEN-RESPONSIVE CDNA MACROARRAY

EPA Science Inventory

This presentation provides an overview of research conducted by the Gulf Ecology Division investigating the effects of endocrine disrupting chemicals on estuarine fish species. A series of research studies were initiated to examine the comparative dose-response characteristics an...

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.

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.

Characteristic of EBT-XD and EBT3 radiochromic film dosimetry for photon and proton beams

NASA Astrophysics Data System (ADS)

Khachonkham, Suphalak; Dreindl, Ralf; Heilemann, Gerd; Lechner, Wolfgang; Fuchs, Hermann; Palmans, Hugo; Georg, Dietmar; Kuess, Peter

2018-03-01

Recently, a new type of radiochromic film, the EBT-XD film, has been introduced for high dose radiotherapy. The EBT-XD film contains the same structure as the EBT3 film but has a slightly different composition and a thinner active layer. This study benchmarks the EBT-XD against EBT3 film for 6 MV and 10 MV photon beams, as well as for 97.4 MeV and 148.2 MeV proton beams and 15-100 kV x-rays. Dosimetric and film reading characteristics, such as post irradiation darkening, film orientation effect, lateral response artifact (LRA), film sensitivity, energy and beam quality dependency were investigated. Furthermore, quenching effects in the Bragg peak were investigated for a single proton beam energy for both film types, in addition measurements were performed in a spread-out Bragg peak. EBT-XD films showed the same characteristic on film darkening as EBT3. The effects between portrait and landscape orientation were reduced by 3.1% (in pixel value) for EBT-XD compared to EBT3 at a dose of 2000 cGy. The LRA is reduced for EBT-XD films for all investigated dose ranges. The sensitivity of EBT-XD films is superior to EBT3 for doses higher than 500 cGy. In addition, EBT-XD showed a similar dosimetric response for photon and proton irradiation with low energy and beam quality dependency. A quenching effect of 10% was found for both film types. The slight decrease in the thickness of the active layer and different composition configuration of EBT-XD resulted in a reduced film orientation effect and LRA, as well as a sensitivity increase in high-dose regions for both photon and proton beams. Overall, the EBT-XD film improved regarding film reading characteristics and showed advantages in the high-dose region for photon and proton beams.

Characteristic of EBT-XD and EBT3 radiochromic film dosimetry for photon and proton beams.

PubMed

Khachonkham, Suphalak; Dreindl, Ralf; Heilemann, Gerd; Lechner, Wolfgang; Fuchs, Hermann; Palmans, Hugo; Georg, Dietmar; Kuess, Peter

2018-03-15

Recently, a new type of radiochromic film, the EBT-XD film, has been introduced for high dose radiotherapy. The EBT-XD film contains the same structure as the EBT3 film but has a slightly different composition and a thinner active layer. This study benchmarks the EBT-XD against EBT3 film for 6 MV and 10 MV photon beams, as well as for 97.4 MeV and 148.2 MeV proton beams and 15-100 kV x-rays. Dosimetric and film reading characteristics, such as post irradiation darkening, film orientation effect, lateral response artifact (LRA), film sensitivity, energy and beam quality dependency were investigated. Furthermore, quenching effects in the Bragg peak were investigated for a single proton beam energy for both film types, in addition measurements were performed in a spread-out Bragg peak. EBT-XD films showed the same characteristic on film darkening as EBT3. The effects between portrait and landscape orientation were reduced by 3.1% (in pixel value) for EBT-XD compared to EBT3 at a dose of 2000 cGy. The LRA is reduced for EBT-XD films for all investigated dose ranges. The sensitivity of EBT-XD films is superior to EBT3 for doses higher than 500 cGy. In addition, EBT-XD showed a similar dosimetric response for photon and proton irradiation with low energy and beam quality dependency. A quenching effect of 10% was found for both film types. The slight decrease in the thickness of the active layer and different composition configuration of EBT-XD resulted in a reduced film orientation effect and LRA, as well as a sensitivity increase in high-dose regions for both photon and proton beams. Overall, the EBT-XD film improved regarding film reading characteristics and showed advantages in the high-dose region for photon and proton beams.

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.

Reconstruction of Internal Doses for the Alpha-Risk Case-Control Study of Lung Cancer and Leukaemia Among European Nuclear Workers.

PubMed

Bingham, Derek; Bérard, Philippe; Birchall, Alan; Bull, Richard; Cardis, Elisabeth; Challeton-de Vathaire, Cécile; Grellier, James; Hurtgen, Christian; Puncher, Matthew; Riddell, Anthony; Thierry-Chef, Isabelle

2017-05-01

The Alpha-Risk study required the reconstruction of doses to lung and red bone marrow for lung cancer and leukaemia cases and their matched controls from cohorts of nuclear workers in the UK, France and Belgium. The dosimetrists and epidemiologists agreed requirements regarding the bioassay data, biokinetic and dosimetric models and dose assessment software to be used and doses to be reported. The best values to use for uncertainties on the monitoring data, setting of exposure regimes and characteristics of the exposure material, including lung solubility, were the responsibility of the dosimetrist responsible for each cohort. Among 1721 subjects, the median absorbed dose to the lung from alpha radiations was 2.1 mGy, with a maximum dose of 316 mGy. The lung doses calculated reflect the higher levels of exposure seen among workers in the early years of the nuclear industry compared to today. © Crown copyright 2016.

SU-E-T-120: Dosimetric Characteristics Study of NanoDotâ,,¢ for In-Vivo Dosimetry

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

Hussain, A; Wasaye, A; Gohar, R

Purpose: The purpose of the study was to analyze the dosimetric characteristics (energy dependence, reproducibility and dose linearity) of nanoDot™ optically stimulated luminescence dosimeters (OSLDs) and validate their potential use during in-vivo dosimetry, specifically TBI. The manufacturer stated accuracy is ±10% for standard nanoDot™. Methods: At AKUH, the InLight microStar OSL dosimetry system for patient in-vivo dosimetry is in use since 2012. Twenty-five standard nanoDot™ were used in the analysis. Sensitivity and reproducibility was tested in the first part with 6MV and 18 MV Varian x-ray beams. Each OSLD was irradiated to 100cGy dose at nominal SSD (100 cm). Allmore » the OSLDs were read 3 times for average reading. Dose linearity and calibration were also performed with same beams in common clinical dose range of 0 - 500 cGy. In addition, verification of TBI absolute dose at extended SSD (500cm) was also performed. Results: The reproducibility observed with the OSLD was better than the manufacturer stated limits. Measured doses vary less than ±2% in 19(76%) OSLDs, whereas less than ±3% in 6(24%) OSLDs. Their sensitivity was approximately 525 counts per cGy. Better agreement was observed between measurements, with a standard deviation of 1.8%. A linear dose response was observed with OSLDs for both 6 and 18MV beams in 0 - 500 cGy dose range. TBI measured doses at 500 cm SSD were also confirmed to be within ±0.5% and ±1.3% of the ion chamber measured doses for 6 and 18MV beams respectively. Conclusion: The dosimetric results demonstrate that nanoDot™ can be potentially used for in-vivo dosimetry verification in various clinical situations, with a high degree of accuracy and precision. In addition OSLDs exhibit better dose reproducibility with standard deviation of 1.8%. There was no significant difference in their response to 6 and 18MV beams. The dose response was also linear.« less

The evaluation of the novel pressor activity of gamma-piperidinobutyramide (WY 20051, DF480).

PubMed Central

Alps, B J; Devoy, P W; Waterfall, J F

1976-01-01

1 gamma-Piperidinobutyramide (Wy 20051, DF480) injected intravenously evoked pressor responses in the anaesthetized ganglion blocked rat preparation over the dose range 2.4 x 10(-6)-3.0 x 10(-4) mol/kg. 2 High doses (greater than 3.8 x 10(-5) mol/kg) or even repeated submaximal doses (1.9 x 10(-5) mol/kg) of Wy 20051 caused tachyphylaxis of this pressor response. 3 The noradrenaline pressor-response curve was shifted significantly to the right of the control curve following a dose of Wy 20051 (1.5 x 10(-4) mol/kg cumulative). 4 The dose-response curve for the pressor action of Wy 20051 was potentiated in reserpine-treated anaesthetized rats. In contrast, tyramine-induced pressor responses were abolished. 5 Wy 20051 contracted the guinea-pig isolated aortic spiral preparation (3.8 x 10(-5)-6.0 x 10(-4) mol) and evoked constrictor responses in the perfused mesenteric vasculature preparation of the rat (5.9 x 10(-7)-1.2 x 10(-5) mol). At higher doses the responses were reduced. 6 Wy 20051-induced constrictor responses of the perfused mesentery were unaffected by blockade of alpha-adrenoceptors or by tachyphylaxis of 5-hydroxytryptamine receptors. 7 The time for abolition of Wy 20051-induced constrictor responses of the mesentery in a calcium-free medium was not significantly different from that required for noradrenaline, but was significantly greater than that for KCl (P less than 0.001). 8 Wy 20051 and noradrenaline, but not KCl, evoked constrictor responses in the depolarized rat mesenteric vasculature. 9 The results indicate that Wy 20051 evokes pressor responses which have some of the characteristics of those of noradrenaline. However, the responses are not elicited by an alpha-adrenoceptor mechanism. PMID:3247

The response characteristics of tetrazolium violet solutions to gamma irradiation

NASA Astrophysics Data System (ADS)

Emi-Reynolds, G.; Kovács, András; Fletcher, J. J.

2007-08-01

The dosimetry characteristics of various solutions of tetrazolium violet, TV, (2,5-diphenyl-3-(1-naphthyl)-2H-tetrazolium chloride) to gamma irradiation are reported. The optical absorption spectra of these solutions show peaks between 400 and 600 nm with a shoulder at around 550 nm. The dose response of the optical absorbance values of aqueous and aqueous-alcoholic solutions containing different concentrations of TV was measured in the 250 Gy up to 75 kGy dose range. The formation of formazan product was observed due to radiolytic reduction in both solutions. Its formation was found more pronounced in N 2-saturated as well as in alkaline solutions. The results indicate that the 1 mM TV solution can be used for food irradiation and medical sterilization dosimetry at gamma irradiation facilities.

Dosimetric evaluation of lithium carbonate (Li2CO3) as a dosemeter for gamma-radiation dose measurements.

PubMed

Popoca, R; Ureña-Núñez, F

2009-06-01

This work reports the possibility of using lithium carbonate as a dosimetric material for gamma-radiation measurements. Carboxi-radical ions, CO(2)(-) and CO(3)(-), arise from the gamma irradiation of Li(2)CO(3), and these radical ions can be quantified by electron paramagnetic resonance (EPR) spectrometry. The EPR-signal response of gamma-irradiated lithium carbonate has been investigated to determine some dosimetric characteristics such as: peak-to-peak signal intensity versus gamma dose received, zero-dose response, signal fading, signal repeatability, batch homogeneity, dose rate effect and stability at different environmental conditions. Using the conventional peak-to-peak method of stable ion radicals, it is concluded that lithium carbonate could be used as a gamma dosemeter in the range of 3-100 Gy.

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

Dose-response characteristics of neonatal exposure to genistein on pituitary responsiveness to gonadotropin releasing hormone and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in postpubertal castrated female rats.

PubMed

Faber, K A; Hughes, C L

1993-01-01

Estrogen exposure during critical periods of development promotes androgenization of the brain, which is reflected in altered morphology, behavior, and cyclic hormone secretion in females. Previous work in our laboratory demonstrated that neonatal female rats injected with pharmaceutical or naturally occurring estrogens had decreased GnRH-induced LH secretion and increased volume of the SDN-POA as 42 day castrates. The current experiment defines the dose-response characteristics of neonatal exposure to the isoflavonoid phytoestrogen genistein (G) on pituitary sensitivity to GnRH and SDN-POA volume. Litters of rat pups received subcutaneous injections of either corn oil, 1, 10, 100, 200, 400, 500, or 1000 micrograms of G on days 1 to 10 of life. The litters were ovariectomized and weaned on day 21. On day 42 blood was drawn from right atrial catheters immediately prior to, 5, 10, 15, and 30 min following a single injection of 50 ng/kg of GnRH. Only the 10 micrograms dose of G was associated with increased pituitary response to GnRH, while progressive increases in exposure levels of G were associated with decreasing LH secretion. The SDN-POA volume was increased in only the 500 micrograms and 1000 micrograms exposure groups compared to controls. The results confirm that low doses of G have nonandrogenizing, pituitary-sensitizing effects, while higher doses of G mimic the more typical effects of estrogens. The use of both morphologic and physiologic end points more completely defines the reproductive consequences of environmental estrogen exposure during critical periods of CNS development.

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.

PubMed

Kiernan, Michael S; Stevens, Susanna R; Tang, W H Wilson; Butler, Javed; Anstrom, Kevin J; Birati, Edo Y; Grodin, Justin L; Gupta, Divya; Margulies, Kenneth B; LaRue, Shane; Dávila-Román, Victor G; Hernandez, Adrian F; de Las Fuentes, Lisa

2018-03-01

Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population. Copyright © 2018 Elsevier Inc. All rights reserved.

Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

PubMed Central

Hou, Jue; Wang, Fan; Kong, Peizhong; Yu, Peter K. N.; Wang, Hongzhi; Han, Wei

2015-01-01

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose. PMID:25886619

Dosimetric characteristics of fabricated silica fibre for postal radiotherapy dose audits

NASA Astrophysics Data System (ADS)

Fadzil, M. S. Ahmad; Ramli, N. N. H.; Jusoh, M. A.; Kadni, T.; Bradley, D. A.; Ung, N. M.; Suhairul, H.; Mohd Noor, N.

2014-11-01

Present investigation aims to establish the dosimetric characteristics of a novel fabricated flat fibre TLD system for postal radiotherapy dose audits. Various thermoluminescence (TL) properties have been investigated for five sizes of 6 mol% Ge-doped optical fibres. Key dosimetric characteristics including reproducibility, linearity, fading and energy dependence have been established. Irradiations were carried out using a linear accelerator (linac) and a Cobalt-60 machine. For doses from 0.5 Gy up to 10 Gy, Ge-doped flat fibres exhibit linearity between TL yield and dose, reproducible to better than 8% standard deviation (SD) following repeat measurements (n = 3). For photons generated at potentials from 1.25 MeV to 10 MV an energy-dependent response is noted, with a coefficient of variation (CV) of less than 40% over the range of energies investigated. For 6.0 mm length flat fibres 100 μm thick × 350 pm wide, the TL fading loss following 30 days of storage at room temperature was < 8%. The Ge-doped flat fibre system represents a viable basis for use in postal radiotherapy dose audits, corrections being made for the various factors influencing the TL yield.

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.

Persistence of memory B-cell and T-cell responses to the quadrivalent HPV vaccine in HIV-infected children.

PubMed

Weinberg, Adriana; Huang, Sharon; Moscicki, Anna-Barbara; Saah, Afred; Levin, Myron J

2018-04-24

To determine the magnitude and persistence of quadrivalent human papillomavirus (HPV)16 and HPV18 B-cell and T-cell memory after three or four doses of quadrivalent HPV vaccine (QHPV) in HIV-infected children. Seventy-four HIV-infected children immunized with four doses and 23 with three doses of QHPV had HPV16 and HPV18 IgG B-cell and IFNγ and IL2 T-cell ELISPOT performed at 2, 3.5 and 4-5 years after the last dose. HPV16 and HPV18 T-cell responses were similar in both treatment groups, with higher responses to HPV16 vs. HPV18. These HPV T-cell responses correlated with HIV disease characteristics at the study visits. Global T-cell function declined over time as measured by nonspecific mitogenic stimulation. B-cell memory was similar across treatment groups and HPV genotypes. There was a decline in HPV-specific B-cell memory over time that reached statistical significance for HPV16 in the four-dose group. B-cell and T-cell memory did not significantly differ after either three or four doses of QHPV in HIV-infected children. The clinical consequences of decreasing global T-cell function and HPV B-cell memory over time in HIV-infected children requires further investigation.

Functional heartburn: the stimulus, the pain, and the brain

PubMed Central

Fass, R; Tougas, G

2002-01-01

Functional heartburn is a common disorder and appears to be composed of several distinct subgroups. Identifying the different subgroups based on clinical history only is not achievable at present. The mechanisms responsible for pain, clinical characteristics, and the optimal therapeutic approach remain poorly understood. Response to potent antireflux treatment is relatively limited. Current and future treatment strategies for functional heartburn patients who have failed standard dose proton pump inhibitors (PPIs) include increased PPI dose in some, as well as addition of pain modulators in others. PMID:12427796

Parotid gland mean dose as a xerostomia predictor in low-dose domains.

PubMed

Gabryś, Hubert Szymon; Buettner, Florian; Sterzing, Florian; Hauswald, Henrik; Bangert, Mark

2017-09-01

Xerostomia is a common side effect of radiotherapy resulting from excessive irradiation of salivary glands. Typically, xerostomia is modeled by the mean dose-response characteristic of parotid glands and prevented by mean dose constraints to either contralateral or both parotid glands. The aim of this study was to investigate whether normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands are suitable for the prediction of xerostomia in a highly conformal low-dose regime of modern intensity-modulated radiotherapy (IMRT) techniques. We present a retrospective analysis of 153 head and neck cancer patients treated with radiotherapy. The Lyman Kutcher Burman (LKB) model was used to evaluate predictive power of the parotid gland mean dose with respect to xerostomia at 6 and 12 months after the treatment. The predictive performance of the model was evaluated by receiver operating characteristic (ROC) curves and precision-recall (PR) curves. Average mean doses to ipsilateral and contralateral parotid glands were 25.4 Gy and 18.7 Gy, respectively. QUANTEC constraints were met in 74% of patients. Mild to severe (G1+) xerostomia prevalence at both 6 and 12 months was 67%. Moderate to severe (G2+) xerostomia prevalence at 6 and 12 months was 20% and 15%, respectively. G1 + xerostomia was predicted reasonably well with area under the ROC curve ranging from 0.69 to 0.76. The LKB model failed to provide reliable G2 + xerostomia predictions at both time points. Reduction of the mean dose to parotid glands below QUANTEC guidelines resulted in low G2 + xerostomia rates. In this dose domain, the mean dose models predicted G1 + xerostomia fairly well, however, failed to recognize patients at risk of G2 + xerostomia. There is a need for the development of more flexible models able to capture complexity of dose response in this dose regime.

A diversity index for model space selection in the estimation of benchmark and infectious doses via model averaging.

PubMed

Kim, Steven B; Kodell, Ralph L; Moon, Hojin

2014-03-01

In chemical and microbial risk assessments, risk assessors fit dose-response models to high-dose data and extrapolate downward to risk levels in the range of 1-10%. Although multiple dose-response models may be able to fit the data adequately in the experimental range, the estimated effective dose (ED) corresponding to an extremely small risk can be substantially different from model to model. In this respect, model averaging (MA) provides more robustness than a single dose-response model in the point and interval estimation of an ED. In MA, accounting for both data uncertainty and model uncertainty is crucial, but addressing model uncertainty is not achieved simply by increasing the number of models in a model space. A plausible set of models for MA can be characterized by goodness of fit and diversity surrounding the truth. We propose a diversity index (DI) to balance between these two characteristics in model space selection. It addresses a collective property of a model space rather than individual performance of each model. Tuning parameters in the DI control the size of the model space for MA. © 2013 Society for Risk Analysis.

SPIRIT: A seamless phase I/II randomized design for immunotherapy trials.

PubMed

Guo, Beibei; Li, Daniel; Yuan, Ying

2018-06-07

Immunotherapy-treatments that enlist the immune system to battle tumors-has received widespread attention in cancer research. Due to its unique features and mechanisms for treating cancer, immunotherapy requires novel clinical trial designs. We propose a Bayesian seamless phase I/II randomized design for immunotherapy trials (SPIRIT) to find the optimal biological dose (OBD) defined in terms of the restricted mean survival time. We jointly model progression-free survival and the immune response. Progression-free survival is used as the primary endpoint to determine the OBD, and the immune response is used as an ancillary endpoint to quickly screen out futile doses. Toxicity is monitored throughout the trial. The design consists of two seamlessly connected stages. The first stage identifies a set of safe doses. The second stage adaptively randomizes patients to the safe doses identified and uses their progression-free survival and immune response to find the OBD. The simulation study shows that the SPIRIT has desirable operating characteristics and outperforms the conventional design. Copyright © 2018 John Wiley & Sons, Ltd.

Improvements in opti-chromic dosimeters for radiation processing

NASA Astrophysics Data System (ADS)

Humpherys, K. C.; Kantz, A. D.

"Opti-Chromic" dosimeters consisting of radiachromic dye in flourinated polymer tubing have been introduced as a dosimetry system in the range from 10 1 to 5 × 10 4 Gy. Batches of "Opti-Chromic" dosimeters have been produced to evaluate performance under large scale industrial conditions. A systematic study was undertaken to determine the effect of various dosimeter parameters on radiation sensitivity, shelf life, and response characteristics at the higher absorbed doses. These parameters were (A) Type of flourinated polymer tubing; (B) Organic solvent used to activate the radiachromic dye; (C) Concentration of radiachromic dye; (D) Additives to provide proper viscosity, color stability, and high-dose response. Prototype batches were produced and experimental dosimeters exposed to a range of absorbed doses and the response measured as a function of shelf life and dose. The results of the study are presented, and an improved formulation recommended for application to Food Processing. Other formulations may be of value in specific requirements of sensitivity or temperature.

Comparison of thermoluminescence response of different sized Ge-doped flat fibers as a dosimeter

NASA Astrophysics Data System (ADS)

Begum, Mahfuza; Mizanur Rahman, A. K. M.; Abdul-Rashid, H. A.; Yusoff, Z.; Mat-Sharif, K. A.; Zulkifli, M. I.; Muhamad-Yasin, S. Z.; Ung, N. M.; Kadir, A. B. A.; Amin, Y. M.; Bradley, D. A.

2015-11-01

Prime dosimetric properties, including dose-response, linearity with dose, energy response, fading and threshold doses were investigated for three different dimension Ge-doped flat fibers. The results of measurement were also compared with two of the more commonly used standard TLD media, TLD-100 (LiF:Mg,Ti-7.5%6LiF) and TLD-700 (7LiF:Mg,Ti-99.9%7LiF) chips. The flat cross-section samples (60×180) μm2, (100×350) μm2 and (200×750) μm2 were fabricated using the Modified Chemical Vapor Deposition (MCVD) process and pulled from the same "preform." In the study, all flat fiber samples provided good linear dose-response for the photon and electron beams generated using a medical linear accelerator (LINAC), for doses in the range 0.5-8 Gy. Among the samples, the smallest dimension flat fiber provided the best response, with a sensitivity of some 61% and 54%, respectively of that of the TLD-100 and TLD-700 chips. The energy responses of the samples were studied for various photon (6 MV, 10 MV) and electron (6 MeV, 9 MeV) beam energies. TL fading of around 20% was observed over a period of thirty (30) days. These favorable TL characteristics point towards promising development of Ge-doped flat fibers for use in radiotherapy dosimetry.

Dosimetry characteristics of HDPE-SWCNT nanocomposite for real time application

NASA Astrophysics Data System (ADS)

Malekie, Shahryar; Ziaie, Farhood; Feizi, Shahzad; Esmaeli, Abdolreza

2016-10-01

In this experimental work, different dosimetric characteristics of high density polyethylene-single wall carbon nanotube nanocomposite were investigated. The nanocomposite samples were prepared with different nanotube contents of 0.22, 0.25, and 0.39 weight percentages which were before, exactly in, and after percolation region of the nanocomposite, respectively. The samples were exposed to 60Co gamma radiation source over the dose rate of 65-214 mGy/min, while the applied bias was 100 V. A linear response achieved for the sample contained 0.25 nanotube wt% verified that the percolation threshold is the optimum point for dosimetric purposes. The current-voltage characteristics curve measured for 0.25 CNT wt% nanocomposite showed that the behavior of this sample was bias polarity independent. Also, the results showed that the response of this nanocomposite was energy-independent. The maximum discrepancy of photocurrent due to angular variation within 0-90° with respect to beam incidence and the reproducibility of the response were measured as 5.4% and 0.8%, respectively. The stability study showed that this material may be suitable for protection dose level control. Therefore, this kind of nanocomposite requiring calibration can be used as a real-time dosimeter.

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.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

PubMed

Chan, Noel; Sager, Philip T; Lawrence, Jack; Ortel, Thomas's; Reilly, Paul; Berkowitz, Scott; Kubitza, Dagmar; Eikelboom, John; Florian, Jeffry; Stockbridge, Norman; Rose, Martin; Temple, Robert; Seltzer, Jonathan H

2018-05-01

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. Copyright © 2017. Published by Elsevier Inc.

Polybutadiene and Styrene-Butadiene rubbers for high-dose dosimetry

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

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

2015-07-01

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

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

Dose-response relationships for environmentally mediated infectious disease transmission models

PubMed Central

Eisenberg, Joseph N. S.

2017-01-01

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

Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

NASA Astrophysics Data System (ADS)

Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

2004-01-01

Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity.

Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

NASA Technical Reports Server (NTRS)

Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

2004-01-01

Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

The QDREC web server: determining dose-response characteristics of complex macroparasites in phenotypic drug screens.

PubMed

Asarnow, Daniel; Rojo-Arreola, Liliana; Suzuki, Brian M; Caffrey, Conor R; Singh, Rahul

2015-05-01

Neglected tropical diseases (NTDs) caused by helminths constitute some of the most common infections of the world's poorest people. The etiological agents are complex and recalcitrant to standard techniques of molecular biology. Drug screening against helminths has often been phenotypic and typically involves manual description of drug effect and efficacy. A key challenge is to develop automated, quantitative approaches to drug screening against helminth diseases. The quantal dose-response calculator (QDREC) constitutes a significant step in this direction. It can be used to automatically determine quantitative dose-response characteristics and half-maximal effective concentration (EC50) values using image-based readouts from phenotypic screens, thereby allowing rigorous comparisons of the efficacies of drug compounds. QDREC has been developed and validated in the context of drug screening for schistosomiasis, one of the most important NTDs. However, it is equally applicable to general phenotypic screening involving helminths and other complex parasites. QDREC is publically available at: http://haddock4.sfsu.edu/qdrec2/. Source code and datasets are at: http://tintin.sfsu.edu/projects/phenotypicAssays.html. rahul@sfsu.edu. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

'Real-life' study of imatinib therapy in chronic phase-chronic myeloid leukemia: A novel retrospective observational longitudinal analysis.

PubMed

Merante, Serena; Ferretti, Virginia; Elena, Chiara; Calvello, Celeste; Rocca, Barbara; Zappatore, Rita; Cavigliano, Paola; Orlandi, Ester

2017-01-01

Imatinib is a cornerstone of treatment of chronic myeloid leukemia. It remains unclear whether transient treatment discontinuation or dose changes affect outcome and this approach has not yet been approved for use outside clinical trials. We conducted a retrospective single-institution observational study to evaluate factors affecting response in 'real-life' clinical practice in 138 chronic myeloid leukemia patients in chronic phase treated with imatinib. We used a novel longitudinal data analytical model, with a generalized estimating equation model, to study BCR-ABL variation according to continuous standard dose, change in dose or discontinuation; BCR-ABL transcript levels were recorded. Treatment history was subdivided into time periods for which treatment was given at constant dosage (total 483 time periods). Molecular and cytogenetic complete response was observed after 154 (32%) and 358 (74%) time periods, respectively. After adjusting for length of time period, no association between dose and cytogenetic complete response rate was observed. There was a significantly lower molecular complete response rate after time periods at a high imatinib dosage. This statistical approach can identify individual patient variation in longitudinal data collected over time and suggests that changes in dose or discontinuation of therapy could be considered in patients with appropriate biological characteristics.

Germanium-doped optical fiber for real-time radiation dosimetry

NASA Astrophysics Data System (ADS)

Mizanur Rahman, A. K. M.; Zubair, H. T.; Begum, Mahfuza; Abdul-Rashid, H. A.; Yusoff, Z.; Ung, N. M.; Mat-Sharif, K. A.; Wan Abdullah, W. S.; Amouzad Mahdiraji, Ghafour; Amin, Y. M.; Maah, M. J.; Bradley, D. A.

2015-11-01

Over the past three decades growing demand for individualized in vivo dosimetry and subsequent dose verification has led to the pursuit of newer, novel and economically feasible materials for dosimeters. These materials are to facilitate features such as real-time sensing and fast readouts. In this paper, purposely composed SiO2:Ge optical fiber is presented as a suitable candidate for dosimetry. The optical fiber is meant to take advantage of the RL/OSL technique, providing both online remote monitoring of dose rate, and fast readouts for absorbed dose. A laboratory-assembled OSL reader has been used to acquire the RL/OSL response to LINAC irradiations (6 MV photons). The notable RL characteristics observed include constant level of luminescence for the same dose rate (providing better consistency compared to TLD-500), and linearity of response in the radiotherapy range (1 Gy/min to 6 Gy/min). The OSL curve was found to conform to an exponential decay characteristic (illumination with low LED source). The Ge doping resulted in an effective atomic number, Zeff, of 13.5 (within the bone equivalent range). The SiO2:Ge optical fiber sensor, with efficient coupling, can be a viable solution for in vivo dosimetry, besides a broad range of applications.

Optically stimulated luminescence of borate glasses containing magnesia, quicklime, lithium and potassium carbonates

NASA Astrophysics Data System (ADS)

Valença, J. V. B.; Silveira, I. S.; Silva, A. C. A.; Dantas, N. O.; Antonio, P. L.; Caldas, L. V. E.; d'Errico, F.; Souza, S. O.

2017-11-01

The OSL characteristics of three different borate glass matrices containing magnesia (LMB), quicklime (LCB) or potassium carbonate (LKB) were examined. Five different formulations for each composition were produced using a melt-quenching method and analyzed in terms of both dose-response curves and OSL shape decay. The samples were irradiated using a 90Sr/90Y beta source with doses up to 30 Gy. Dose-response curves were plotted using the initial OSL intensity as the chosen parameter. The OSL analysis showed that LKB glasses are the most sensitive to beta irradiation. For the most sensitive LKB composition, the irradiation process was also done using a 60Co gamma source in a dose range from 200 to 800 Gy. In all cases, no saturation was observed. A fitting process using a three-term exponential function was performed for the most sensitive formulations of each composition, which suggested a similar behavior in the OSL decay.

Radiographic film dosimetry of proton beams for depth‐dose constancy check and beam profile measurement

PubMed Central

Teran, Anthony; Ghebremedhin, Abiel; Johnson, Matt; Patyal, Baldev

2015-01-01

Radiographic film dosimetry suffers from its energy dependence in proton dosimetry. This study sought to develop a method of measuring proton beams by the film and to evaluate film response to proton beams for the constancy check of depth dose (DD). It also evaluated the film for profile measurements. To achieve this goal, from DDs measured by film and ion chamber (IC), calibration factors (ratios of dose measured by IC to film responses) as a function of depth in a phantom were obtained. These factors imply variable slopes (with proton energy and depth) of linear characteristic curves that relate film response to dose. We derived a calibration method that enables utilization of the factors for acquisition of dose from film density measured at later dates by adapting to a potentially altered processor condition. To test this model, the characteristic curve was obtained by using EDR2 film and in‐phantom film dosimetry in parallel with a 149.65 MeV proton beam, using the method. An additional validation of the model was performed by concurrent film and IC measurement perpendicular to the beam at various depths. Beam profile measurements by the film were also evaluated at the center of beam modulation. In order to interpret and ascertain the film dosimetry, Monte Carlos simulation of the beam was performed, calculating the proton fluence spectrum along depths and off‐axis distances. By multiplying respective stopping powers to the spectrum, doses to film and water were calculated. The ratio of film dose to water dose was evaluated. Results are as follows. The characteristic curve proved the assumed linearity. The measured DD approached that of IC, but near the end of the spread‐out Bragg peak (SOBP), a spurious peak was observed due to the mismatch of distal edge between the calibration and measurement films. The width of SOBP and the proximal edge were both reproducible within a maximum of 5 mm; the distal edge was reproducible within 1 mm. At 5 cm depth, the dose was reproducible within 10%. These large discrepancies were identified to have been contributed by film processor uncertainty across a layer of film and the misalignment of film edge to the frontal phantom surface. The deviations could drop from 5 to 2 mm in SOBP and from 10% to 4.5% at 5 cm depth in a well‐controlled processor condition (i.e., warm up). In addition to the validation of the calibration method done by the DD measurements, the concurrent film and IC measurement independently validated the model by showing the constancy of depth‐dependent calibration factors. For profile measurement, the film showed good agreement with ion chamber measurement. In agreement with the experimental findings, computationally obtained ratio of film dose to water dose assisted understanding of the trend of the film response by revealing relatively large and small variances of the response for DD and beam profile measurements, respectively. Conclusions are as follows. For proton beams, radiographic film proved to offer accurate beam profile measurements. The adaptive calibration method proposed in this study was validated. Using the method, film dosimetry could offer reasonably accurate DD constancy checks, when provided with a well‐controlled processor condition. Although the processor warming up can promote a uniform processing across a single layer of the film, the processing remains as a challenge. PACS number: 87 PMID:26103499

Investigation of EBT2 and EBT3 films for proton dosimetry in the 4-20 MeV energy range.

PubMed

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

2015-03-01

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

A Path Model for Evaluating Dosing Parameters for Children With Cerebral Palsy

PubMed Central

Christy, Jennifer B.; Heathcock, Jill C.; Kolobe, Thubi H.A.

2014-01-01

Dosing of pediatric rehabilitation services for children with cerebral palsy (CP) has been identified as a national priority. Establishing dosing parameters for pediatric physical therapy interventions is critical for informing clinical decision making, health policy, and guidelines for reimbursement. The purpose of this perspective article is to describe a path model for evaluating dosing parameters of interventions for children with CP. The model is intended for dose-related and effectiveness studies of pediatric physical therapy interventions. The premise of the model is: Intervention type (focus on body structures, activity, or the environment) acts on a child first through the family, then through the dose (frequency, intensity, time), to yield structural and behavioral changes. As a result, these changes are linked to improvements in functional independence. Community factors affect dose as well as functional independence (performance and capacity), influencing the relationships between type of intervention and intervention responses. The constructs of family characteristics; child characteristics (eg, age, level of severity, comorbidities, readiness to change, preferences); plastic changes in bone, muscle, and brain; motor skill acquisition; and community access warrant consideration from researchers who are designing intervention studies. Multiple knowledge gaps are identified, and a framework is provided for conceptualizing dosing parameters for children with CP. PMID:24231231

Mechanisms responsible for the chromosome and gene mutations driving carcinogenesis: Implications for dose-response characteristics of mutagenic carcinogens

EPA Science Inventory

Through the use of high throughput DNA sequencing techniques, it has been possible to characterize a number of tumor types at the molcular level. This has led to the concept that there are "driver" mutations and "passenger" mutations, with an estimate of the number of the driver...

EPR/alanine dosimetry for two therapeutic proton beams

NASA Astrophysics Data System (ADS)

Marrale, Maurizio; Carlino, Antonio; Gallo, Salvatore; Longo, Anna; Panzeca, Salvatore; Bolsi, Alessandra; Hrbacek, Jan; Lomax, Tony

2016-02-01

In this work the analysis of the electron paramagnetic resonance (EPR) response of alanine pellets exposed to two different clinical proton beams employed for radiotherapy is performed. One beam is characterized by a passive delivery technique and is dedicated to the eyes treatment (OPTIS2 beam line). Alanine pellets were irradiated with a 70 MeV proton beam corresponding to 35 mm range in eye tissue. We investigated how collimators with different sizes and shape used to conform the dose to the planned target volume influence the delivered dose. For this purpose we performed measurements with varying the collimator size (Output Factor) and the results were compared with those obtained with other dosimetric techniques (such as Markus chamber and diode detector). This analysis showed that the dosimeter response is independent of collimator diameter if this is larger than or equal to 10 mm. The other beam is characterized by an active spot-scanning technique, the Gantry1 beam line (maximum energy 230 MeV), and is used to treat deep-seated tumors. The dose linearity of alanine response in the clinical dose range was tested and the alanine dose response at selected locations in depth was measured and compared with the TPS planned dose in a quasi-clinical scenario. The alanine response was found to be linear in the dose in the clinical explored range (from 10 to 70 Gy). Furthermore, a depth dose profile in a quasi-clinical scenario was measured and compared to the dose computed by the Treatment Planning System PSIPLAN. The comparison of calibrated proton alanine measurements and TPS dose shows a difference under 1% in the SOBP and a "quenching" effect up to 4% in the distal part of SOBP. The positive dosimetric characteristics of the alanine pellets confirm the feasibility to use these detectors for "in vivo" dosimetry in clinical proton beams.

The Thermoluminescence Response of Ge-Doped Flat Fibers to Gamma Radiation

PubMed Central

Mat Nawi, Siti Nurasiah Binti; Wahib, Nor Fadira Binti; Zulkepely, Nurul Najua Binti; Amin, Yusoff Bin Mohd; Min, Ung Ngie; Bradley, David Andrew; Md Nor, Roslan Bin; Maah, Mohd Jamil

2015-01-01

Study has been undertaken of the thermoluminescence (TL) yield of various tailor-made flat cross-section 6 mol% Ge-doped silica fibers, differing only in respect of external dimensions. Key TL dosimetric characteristics have been investigated, including glow curves, dose response, sensitivity, fading and reproducibility. Using a 60Co source, the samples were irradiated to doses within the range 1 to 10 Gy. Prior to irradiation, the flat fibers were sectioned into 6 mm lengths, weighed, and annealed at 400 °C for 1 h. TL readout was by means of a Harshaw Model 3500 TLD reader, with TLD-100 chips (LiF:Mg, Ti) used as a reference dosimeter to allow the relative response of the fibers to be evaluated. The fibers have been found to provide highly linear dose response and excellent reproducibility over the range of doses investigated, demonstrating high potential as TL-mode detectors in radiation medicine applications. Mass for mass, the results show the greatest TL yield to be provided by fibers of the smallest cross-section, analysis indicating this to be due to minimal light loss in transport of the TL through the bulk of the silica medium. PMID:26307987

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

Dosimetric evaluation of the OneDoseTM MOSFET for measuring kilovoltage imaging dose from image-guided radiotherapy procedures.

PubMed

Ding, George X; Coffey, Charles W

2010-09-01

The purpose of this study is to investigate the feasibility of using a single-use dosimeter, OneDose MOSFET designed for in vivo patient dosimetry, for measuring the radiation dose from kilovoltage (kV) x rays resulting from image-guided procedures. The OneDose MOSFET dosimeters were precalibrated by the manufacturer using Co-60 beams. Their energy response and characteristics for kV x rays were investigated by using an ionization chamber, in which the air-kerma calibration factors were obtained from an Accredited Dosimetry Calibration Laboratory (ADCL). The dosimetric properties have been tested for typical kV beams used in image-guided radiation therapy (IGRT). The direct dose reading from the OneDose system needs to be multiplied by a correction factor ranging from 0.30 to 0.35 for kilovoltage x rays ranging from 50 to 125 kVp, respectively. In addition to energy response, the OneDose dosimeter has up to a 20% reduced sensitivity for beams (70-125 kVp) incident from the back of the OneDose detector. The uncertainty in measuring dose resulting from a kilovoltage beam used in IGRT is approximately 20%; this uncertainty is mainly due to the sensitivity dependence of the incident beam direction relative to the OneDose detector. The ease of use may allow the dosimeter to be suitable for estimating the dose resulting from image-guided procedures.

Comparison of Kodak EDR2 and Gafchromic EBT film for intensity-modulated radiation therapy dose distribution verification.

PubMed

Sankar, A; Ayyangar, Komanduri M; Nehru, R Mothilal; Kurup, P G Gopalakrishna; Murali, V; Enke, Charles A; Velmurugan, J

2006-01-01

The quantitative dose validation of intensity-modulated radiation therapy (IMRT) plans require 2-dimensional (2D) high-resolution dosimetry systems with uniform response over its sensitive region. The present work deals with clinical use of commercially available self-developing Radio Chromic Film, Gafchromic EBT film, for IMRT dose verification. Dose response curves were generated for the films using a VXR-16 film scanner. The results obtained with EBT films were compared with the results of Kodak extended dose range 2 (EDR2) films. The EBT film had a linear response between the dose range of 0 to 600 cGy. The dose-related characteristics of the EBT film, such as post irradiation color growth with time, film uniformity, and effect of scanning orientation, were studied. There was up to 8.6% increase in the color density between 2 to 40 hours after irradiation. There was a considerable variation, up to 8.5%, in the film uniformity over its sensitive region. The quantitative differences between calculated and measured dose distributions were analyzed using DTA and Gamma index with the tolerance of 3% dose difference and 3-mm distance agreement. The EDR2 films showed consistent results with the calculated dose distributions, whereas the results obtained using EBT were inconsistent. The variation in the film uniformity limits the use of EBT film for conventional large-field IMRT verification. For IMRT of smaller field sizes (4.5 x 4.5 cm), the results obtained with EBT were comparable with results of EDR2 films.

Study of thermoluminescence response of purple to violet amethyst quartz from Balikesir, Turkey

NASA Astrophysics Data System (ADS)

Nur, N.; Yeğingil, Z.; Topaksu, M.; Kurt, K.; Doğan, T.; Sarıgül, N.; Yüksel, M.; Altunal, V.; Özdemir, A.; Güçkan, V.; Günay, I.

2015-09-01

In thermoluminescence (TL) dosimetry, the phosphor amethyst quartz as a thermoluminescent, appears to be one of the materials arousing the highest interest. In this study the dosimetric characteristics of natural amethyst quartz crystals collected from Balikesir-Dursunbey (Turkey) were investigated for the purpose of determination of the general properties that phosphors should have in order to be useful for thermoluminescence dosimetry. The natural thermoluminescence was drained by annealing the powder samples at 450 °C for 1.5 h. The effects of high temperature annealing, dose response curves, glow curves after a postirradiation annealing, reusability of the samples and storage of trapped electrons in dark at room temperature were clarified through irradiating the samples with the desired exposures by 90Sr/90Y beta particles. Isothermal annealing before and after irradiation was found to have a definite effect upon the TL glow curve of amethyst crystal powder. The same sample varied in sensitivity depending upon its previous thermal and radiation history. The peak heights of the glow peaks were examined with respect to dose response at dose levels between 1 Gy and 5 kGy. The intermediate temperature (IT) and high temperature (HT) peaks of 230 °C and 300 °C, respectively, exhibit dose-response curves as superlinear when dose is on the logarithmic scale except the dose response of 300 °C peak for the dose values of 1 < D < 20 Gy in which linear dose response was acquired. At the end of the storage time between exposure and readout which was about one month at room temperature, the emitted light reduction was 14% comparing to the initial state. Repeating the measurements of the same sample, exposed with 0.1, 0.5, 0.8 and 1 kGy beta exposures, resulted in between 4% and 11% increase in the TL sensitivity of the material.

Real-time dosimetry in radiotherapy using tailored optical fibers

NASA Astrophysics Data System (ADS)

Rahman, A. K. M. Mizanur; Zubair, H. T.; Begum, Mahfuza; Abdul-Rashid, H. A.; Yusoff, Z.; Omar, Nasr Y. M.; Ung, N. M.; Mat-Sharif, K. A.; Bradley, D. A.

2016-05-01

Real-time dosimetry plays an important role for accurate patient-dose measurement during radiotherapy. A tiny piece of laboratory fabricated Ge-doped optical fiber has been investigated as a radioluminescence (RL) sensor for real-time dosimetry over the dose range from 1 Gy to 8 Gy under 6 MV photon beam by LINAC. Fiber-coupled software-based RL prototype system was used to assess essential dosimetric characteristics including dose response linearity, dose rate dependency, sensitivity, repeatability and output dependence on field sizes. The consistency level of RL photon counts versus dose rate was also compared with that of standard Al2O3:C chips. Sensitivity of Ge-doped fiber were found to be sufficiently sensitive for practical use and also provided linear dose responses for various dose rates from 100 cGy/min to 600 cGy/min using both 6 MV photon and 6 MeV electron beams. SEM-EDX analysis was performed to identify Ge-dopant concentration level within the optical fiber RL material. Accumulated doses were also estimated using simple integral technique and the error was found to be around less than 1% under dissimilar dose rates or repeat measurements. The evaluation of the Ge-doped optical fiber based RL dosimeter system indicates its potential in medical dosimetry.

Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy.

PubMed

Herzog, Roland W; Fields, Paul A; Arruda, Valder R; Brubaker, Jeff O; Armstrong, Elina; McClintock, Darryl; Bellinger, Dwight A; Couto, Linda B; Nichols, Timothy C; High, Katherine A

2002-07-20

Intramuscular injection of an adeno-associated virus (AAV) vector has resulted in vector dose-dependent, stable expression of canine factor IX (cF.IX) in hemophilia B dogs with an F.IX missense mutation (Herzog et al., Nat. Med. 1999;5:56-63). The use of a species-specific transgene allowed us to study risks and characteristics of antibody formation against the therapeutic transgene product. We analyzed seven dogs that had been injected at a single time point at multiple intramuscular sites with varying vector doses (dose per kilogram, dose per animal, dose per site). Comparison of individual animals suggests an increased likelihood of inhibitory anti-cF.IX (inhibitor) development with increased vector doses, with dose per site showing the strongest correlation with the risk of inhibitor formation. In six of seven animals, such immune responses were either absent or transient, and therefore did not prevent sustained systemic expression of cF.IX. Transient inhibitory/neutralizing anti-cF.IX responses occurred at vector doses of 2 x 10(12)/site, whereas a 6-fold higher dose resulted in a longer lasting, higher titer inhibitor. Anti-cF.IX was efficiently blocked in an eighth animal that was injected with a high vector dose per site, but in addition received transient immune suppression. Inhibitor formation was characterized by synthesis of two IgG subclasses and in vitro proliferation of lymphocytes to cF.IX antigen, indicating a helper T cell-dependent mechanism. Anti-cF.IX formation is likely influenced by the extent of local antigen presentation and may be avoided by limited vector doses or by transient immune modulation.

Hepatitis C treatment among racial and ethnic groups in the IDEAL trial.

PubMed

Muir, A J; Hu, K-Q; Gordon, S C; Koury, K; Boparai, N; Noviello, S; Albrecht, J K; Sulkowski, M S; McCone, J

2011-04-01

Previous studies of chronic hepatitis C virus (HCV) treatment have demonstrated variations in response among racial and ethnic groups including poorer efficacy rates among African American and Hispanic patients. The individualized dosing efficacy vs flat dosing to assess optimaL pegylated interferon therapy (IDEAL) trial enrolled 3070 patients from 118 United States centres to compare treatment with peginterferon (PEG-IFN) alfa-2a and ribavirin (RBV) and two doses of PEG-IFN alfa-2b and RBV. This analysis examines treatment response among the major racial and ethnic groups in the trial. Overall, sustained virologic response (SVR) rates were 44% for white, 22% for African American, 38% for Hispanic and 59% for Asian American patients. For patients with undetectable HCV RNA at treatment week 4, the positive predictive value of SVR was 86% for white, 92% for African American, 83% for Hispanic and 89% for Asian American patients. The positive predictive values of SVR in those with undetectable HCV RNA at treatment week 12 ranged from 72% to 81%. Multivariate regression analysis using baseline characteristics demonstrated that treatment regimen was not a predictor of SVR. Despite wide-ranging SVR rates among the different racial and ethnic groups, white and Hispanic patients had similar SVR rates. In all groups, treatment response was largely determined by antiviral activity in the first 12 weeks of treatment. Therefore, decisions regarding HCV treatment should consider the predictive value of the early on-treatment response, not just baseline characteristics, such as race and ethnicity. © 2010 Blackwell Publishing Ltd.

Dose and dose rate effects of whole-body proton-irradiation on lymphocyte blastogenesis and hematological variables: part II

NASA Technical Reports Server (NTRS)

Pecaut, Michael J.; Gridley, Daila S.; Smith, Anna L.; Nelson, Gregory A.

2002-01-01

The goal of part II of this study was to evaluate functional characteristics of leukocytes and circulating blood cell parameters after whole-body proton irradiation at varying doses and at low- and high-dose-rates (LDR and HDR, respectively). C57BL/6 mice (n=51) were irradiated and euthanized at 4 days post-exposure for assay. Significant radiation dose- (but not dose-rate-) dependent decreases were observed in splenocyte responses to T and B cell mitogens when compared to sham-irradiated controls (P<0.001). Spontaneous blastogenesis, also significantly dose-dependent, was increased in both blood and spleen (P<0.001). Red blood cell counts, hemoglobin concentration, and hematocrit were decreased in a dose-dependent manner (P<0.05), whereas thrombocyte numbers were only slightly affected. Comparison of proton- and gamma-irradiated groups (both receiving 3 Gy at HDR) showed a higher level of spontaneous blastogenesis in blood leukocytes and a lower splenocyte response to concanavalin A following proton irradiation (P<0.05). There were no dose rate effects. Collectively, the data demonstrate that the measurements in blood and spleen were largely dependent upon the total dose of proton radiation and that an 80-fold difference in the dose rate was not a significant factor. A difference, however, was found between protons and gamma-rays in the degree of change induced in some of the measurements.

Dose response models and a quantitative microbial risk assessment framework for the Mycobacterium avium complex that account for recent developments in molecular biology, taxonomy, and epidemiology.

PubMed

Hamilton, Kerry A; Weir, Mark H; Haas, Charles N

2017-02-01

Mycobacterium avium complex (MAC) is a group of environmentally-transmitted pathogens of great public health importance. This group is known to be harbored, amplified, and selected for more human-virulent characteristics by amoeba species in aquatic biofilms. However, a quantitative microbial risk assessment (QMRA) has not been performed due to the lack of dose response models resulting from significant heterogeneity within even a single species or subspecies of MAC, as well as the range of human susceptibilities to mycobacterial disease. The primary human-relevant species and subspecies responsible for the majority of the human disease burden and present in drinking water, biofilms, and soil are M. avium subsp. hominissuis, M. intracellulare, and M. chimaera. A critical review of the published literature identified important health endpoints, exposure routes, and susceptible populations for MAC risk assessment. In addition, data sets for quantitative dose-response functions were extracted from published in vivo animal dosing experiments. As a result, seven new exponential dose response models for human-relevant species of MAC with endpoints of lung lesions, death, disseminated infection, liver infection, and lymph node lesions are proposed. Although current physical and biochemical tests used in clinical settings do not differentiate between M. avium and M. intracellulare, differentiating between environmental species and subspecies of the MAC can aid in the assessment of health risks and control of MAC sources. A framework is proposed for incorporating the proposed dose response models into susceptible population- and exposure route-specific QMRA models. Copyright © 2016 Elsevier Ltd. All rights reserved.

Introduction of a deformable x-ray CT polymer gel dosimetry system

NASA Astrophysics Data System (ADS)

Maynard, E.; Heath, E.; Hilts, M.; Jirasek, A.

2018-04-01

This study introduces the first 3D deformable dosimetry system based on x-ray computed tomography (CT) polymer gel dosimetry and establishes the setup reproducibility, deformation characteristics and dose response of the system. A N-isopropylacrylamide (NIPAM)-based gel formulation optimized for x-ray CT gel dosimetry was used, with a latex balloon serving as the deformable container and low-density polyethylene and polyvinyl alcohol providing additional oxygen barrier. Deformable gels were irradiated with a 6 MV calibration pattern to determine dosimetric response and a dosimetrically uniform plan to determine the spatial uniformity of the response. Wax beads were added to each gel as fiducial markers to track the deformation and setup of the gel dosimeters. From positions of the beads on CT images the setup reproducibility and the limits and reproducibility of gel deformation were determined. Comparison of gel measurements with Monte Carlo dose calculations found excellent dosimetric accuracy, comparable to that of an established non-deformable dosimetry system, with a mean dose discrepancy of 1.5% in the low-dose gradient region and a gamma pass rate of 97.9% using a 3%/3 mm criterion. The deformable dosimeter also showed good overall spatial dose uniformity throughout the dosimeter with some discrepancies within 20 mm of the edge of the container. Tracking of the beads within the dosimeter found that sub-millimetre setup accuracy is achievable with this system. The dosimeter was able to deform and relax when externally compressed by up to 30 mm without sustaining any permanent damage. Internal deformations in 3D produced average marker movements of up to 12 mm along the direction of compression. These deformations were also shown to be reproducible over 100 consecutive deformations. This work has established several important characteristics of a new deformable dosimetry system which shows promise for future clinical applications, including the validation of deformable dose accumulation algorithms.

Evaluation of the uncertainty in an EBT3 film dosimetry system utilizing net optical density.

PubMed

Marroquin, Elsa Y León; Herrera González, José A; Camacho López, Miguel A; Barajas, José E Villarreal; García-Garduño, Olivia A

2016-09-08

Radiochromic film has become an important tool to verify dose distributions for intensity-modulated radiotherapy (IMRT) and quality assurance (QA) procedures. A new radiochromic film model, EBT3, has recently become available, whose composition and thickness of the sensitive layer are the same as those of previous EBT2 films. However, a matte polyester layer was added to EBT3 to prevent the formation of Newton's rings. Furthermore, the symmetrical design of EBT3 allows the user to eliminate side-orientation dependence. This film and the flatbed scanner, Epson Perfection V750, form a dosimetry system whose intrinsic characteristics were studied in this work. In addition, uncertainties associated with these intrinsic characteristics and the total uncertainty of the dosimetry system were determined. The analysis of the response of the radiochromic film (net optical density) and the fitting of the experimental data to a potential function yielded an uncertainty of 2.6%, 4.3%, and 4.1% for the red, green, and blue channels, respectively. In this work, the dosimetry system presents an uncertainty in resolving the dose of 1.8% for doses greater than 0.8 Gy and less than 6 Gy for red channel. The films irradiated between 0 and 120 Gy show differences in the response when scanned in portrait or landscape mode; less uncertainty was found when using the portrait mode. The response of the film depended on the position on the bed of the scanner, contributing an uncertainty of 2% for the red, 3% for the green, and 4.5% for the blue when placing the film around the center of the bed of scanner. Furthermore, the uniformity and reproducibility radiochromic film and reproducibility of the response of the scanner contribute less than 1% to the overall uncertainty in dose. Finally, the total dose uncertainty was 3.2%, 4.9%, and 5.2% for red, green, and blue channels, respectively. The above uncertainty values were obtained by mini-mizing the contribution to the total dose uncertainty of the film orientation and film homogeneity. © 2016 The Authors.

Evaluation of the uncertainty in an EBT3 film dosimetry system utilizing net optical density

PubMed Central

Marroquin, Elsa Y. León; Herrera González, José A.; Camacho López, Miguel A.; Barajas, José E. Villarreal

2016-01-01

Radiochromic film has become an important tool to verify dose distributions for intensity‐modulated radiotherapy (IMRT) and quality assurance (QA) procedures. A new radiochromic film model, EBT3, has recently become available, whose composition and thickness of the sensitive layer are the same as those of previous EBT2 films. However, a matte polyester layer was added to EBT3 to prevent the formation of Newton's rings. Furthermore, the symmetrical design of EBT3 allows the user to eliminate side‐orientation dependence. This film and the flatbed scanner, Epson Perfection V750, form a dosimetry system whose intrinsic characteristics were studied in this work. In addition, uncertainties associated with these intrinsic characteristics and the total uncertainty of the dosimetry system were determined. The analysis of the response of the radiochromic film (net optical density) and the fitting of the experimental data to a potential function yielded an uncertainty of 2.6%, 4.3%, and 4.1% for the red, green, and blue channels, respectively. In this work, the dosimetry system presents an uncertainty in resolving the dose of 1.8% for doses greater than 0.8 Gy and less than 6 Gy for red channel. The films irradiated between 0 and 120 Gy show differences in the response when scanned in portrait or landscape mode; less uncertainty was found when using the portrait mode. The response of the film depended on the position on the bed of the scanner, contributing an uncertainty of 2% for the red, 3% for the green, and 4.5% for the blue when placing the film around the center of the bed of scanner. Furthermore, the uniformity and reproducibility radiochromic film and reproducibility of the response of the scanner contribute less than 1% to the overall uncertainty in dose. Finally, the total dose uncertainty was 3.2%, 4.9%, and 5.2% for red, green, and blue channels, respectively. The above uncertainty values were obtained by minimizing the contribution to the total dose uncertainty of the film orientation and film homogeneity. PACS number(s): 87.53.Bn PMID:27685125

Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats.

PubMed

Yang, Pamela B; Swann, Alan C; Dafny, Nachum

2006-01-17

Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas. These results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.

Random Forest Segregation of Drug Responses May Define Regions of Biological Significance.

PubMed

Bukhari, Qasim; Borsook, David; Rudin, Markus; Becerra, Lino

2016-01-01

The ability to assess brain responses in unsupervised manner based on fMRI measure has remained a challenge. Here we have applied the Random Forest (RF) method to detect differences in the pharmacological MRI (phMRI) response in rats to treatment with an analgesic drug (buprenorphine) as compared to control (saline). Three groups of animals were studied: two groups treated with different doses of the opioid buprenorphine, low (LD), and high dose (HD), and one receiving saline. PhMRI responses were evaluated in 45 brain regions and RF analysis was applied to allocate rats to the individual treatment groups. RF analysis was able to identify drug effects based on differential phMRI responses in the hippocampus, amygdala, nucleus accumbens, superior colliculus, and the lateral and posterior thalamus for drug vs. saline. These structures have high levels of mu opioid receptors. In addition these regions are involved in aversive signaling, which is inhibited by mu opioids. The results demonstrate that buprenorphine mediated phMRI responses comprise characteristic features that allow a supervised differentiation from placebo treated rats as well as the proper allocation to the respective drug dose group using the RF method, a method that has been successfully applied in clinical studies.

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

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

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

1990-05-01

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

Heavy particle irradiation, neurochemistry and behavior: thresholds, dose- response curves and recovery of function

NASA Astrophysics Data System (ADS)

Rabin, B.; Joseph, J.; Shukitt-Hale, B.

Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation- induced disruption of dopaminergic function disrupts a variety of behaviors that are dependent upon the integrity of the dopaminergic system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, spatial learning and memory (Morris water maze), and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current presentation will review the data relevant to the degree to which these characteristics are in fact common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity. Supported by N.A.S.A. Grant NAG9-1190.

Characterization of a gated fiber-optic-coupled detector for application in clinical electron beam dosimetry

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

Tanyi, James A.; Nitzling, Kevin D.; Lodwick, Camille J.

2011-02-15

Purpose: Assessment of the fundamental dosimetric characteristics of a novel gated fiber-optic-coupled dosimetry system for clinical electron beam irradiation. Methods: The response of fiber-optic-coupled dosimetry system to clinical electron beam, with nominal energy range of 6-20 MeV, was evaluated for reproducibility, linearity, and output dependence on dose rate, dose per pulse, energy, and field size. The validity of the detector system's response was assessed in correspondence with a reference ionization chamber. Results: The fiber-optic-coupled dosimetry system showed little dependence to dose rate variations (coefficient of variation {+-}0.37%) and dose per pulse changes (with 0.54% of reference chamber measurements). The reproducibilitymore » of the system was {+-}0.55% for dose fractions of {approx}100 cGy. Energy dependence was within {+-}1.67% relative to the reference ionization chamber for the 6-20 MeV nominal electron beam energy range. The system exhibited excellent linear response (R{sup 2}=1.000) compared to reference ionization chamber in the dose range of 1-1000 cGy. The output factors were within {+-}0.54% of the corresponding reference ionization chamber measurements. Conclusions: The dosimetric properties of the gated fiber-optic-coupled dosimetry system compare favorably to the corresponding reference ionization chamber measurements and show considerable potential for applications in clinical electron beam radiotherapy.« less

Dosimetric characteristics of PASSAG as a new polymer gel dosimeter with negligible toxicity

NASA Astrophysics Data System (ADS)

Farhood, Bagher; Abtahi, Seyed Mohammad Mahdi; Geraily, Ghazale; Ghorbani, Mehdi; Mahdavi, Seied Rabi; Zahmatkesh, Mohammad Hasan

2018-06-01

Despite many advantages of polymer gel dosimeters, their clinical use is only not realized now. Toxicity of polymer gel dosimeters can be considered as one of their main limitations for use in routine clinical applications. In the current study, a new polymer gel dosimeter is introduced with negligible toxicity. For this purpose, 2-Acrylamido-2-Methy-1-PropaneSulfonic acid (AMPS) sodium salt monomer was replaced instead of acrylamide monomer used in PAGAT gel dosimeter by using %6 T and %50 C to the gel formula and the new formulation is called PASSAG (Poly AMPS Sodium Salt and Gelatin) polymer gel dosimeter. The irradiation of gel dosimeters was carried out using a Co-60 therapy machine. MRI technique was used to quantify the dose responses of the PASSAG gel dosimeter. Then, the MRI responses (R2) of the gel dosimeter was analyzed at different dose values, post-irradiation times, and scanning temperatures. The results showed that the new gel formulation has a negligible toxicity and it is also eco-friendly. In addition, carcinogenicity and genetic toxicity tests are negative for the monomer used in PASSAG. The radiological properties of PASSAG gel dosimeter showed that this substance can be considered as a soft tissue/water equivalent material. Furthermore, dosimetric evaluation of the new polymer gel dosimeter revealed an excellent linear R2-dose response in the evaluated dose range (0-15 Gy). The R2-dose sensitivity and dose resolution of PASSAG gel dosimeter were 0.081 s-1Gy-1 (in 0-15 Gy dose range) and 1 Gy (in 0-10 Gy dose range), respectively. Moreover, it was shown that the R2-dose sensitivity and dose resolution of the new gel dosimeter improves over time after irradiation. It was also found that the R2 response of the PASSAG gel dosimeter has less dependency to the 18, 20, and 24 °C scanning temperature in comparison to that of room temperature (22 °C).

Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study.

PubMed

Papaleo, Enrico; Zaffagnini, Stefano; Munaretto, Maria; Vanni, Valeria Stella; Rebonato, Giorgia; Grisendi, Valentina; Di Paola, Rossana; La Marca, Antonio

2016-12-01

To externally validate a nomogram based on ovarian reserve markers as a tool to optimize the FSH starting dose in IVF/ICSI cycles. A two-centres retrospective study including 398 infertile women undergoing their first IVF/ICSI cycle (June 2013-June 2014). IVF data were retrieved from two independent IVF centres in Italy (San Raffaele Hospital, Centre 1; Verona Hospital, Centre 2). A central lab for the routine measurement of AMH and FSH was used for both centres. All women were treated based on physical and hormonal characteristics according to locally adopted protocols. The nomogram was then retrospectively applied to the patients comparing the calculated starting dose to the one actually given. In Centre 1, 64/131 women (48.8%) had an ovarian response below the target. While 45 of these patients were treated with a maximal FSH starting dose (≥225 IU), n=19/131 (14.5%) were treated with a submaximal dose. The vast majority of them (n=17/19) would have received a higher FSH starting dose by using the nomogram. Seventeen patients (n=17/131) had hyper response and about half of them would have been treated with a reduced FSH starting dose according to the nomogram. In Centre 2, 142/267 patients (53.2%) had an ovarian response below the target. While 136 of these were treated with a maximal FSH starting dose (≥225 IU), n=6/267 were treated with a submaximal dose. The majority of them (n=5/6) would have received a higher FSH starting dose. Thirty-two (n=32/267) patients had hyper response and more than half of them would have been treated with a reduced FSH dose. In both Centres, applying the nomogram would have resulted in more appropriate FSH starting doses compared to the the ones actually given based on clinicians choices. The use of an objective algorithm based on patient's age, serum FSH and AMH levels may thus be an effective advice on the selection of the tailored FSH starting dose. Hence, the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Characterization of a prototype MR-compatible Delta4 QA system in a 1.5 tesla MR-linac

NASA Astrophysics Data System (ADS)

de Vries, J. H. W.; Seravalli, E.; Houweling, A. C.; Woodings, S. J.; van Rooij, R.; Wolthaus, J. W. H.; Lagendijk, J. J. W.; Raaymakers, B. W.

2018-01-01

To perform patient plan quality assurance (QA) on a newly installed MR-linac (MRL) it is necessary to have an MR-compatible QA device. An MR compatible device (MR-Delta4) has been developed together with Scandidos AB (Uppsala, Sweden). The basic characteristics of the detector response, such as short-term reproducibility, dose linearity, field size dependency, dose rate dependency, dose-per-pulse dependency and angular dependency, were investigated for the clinical Delta4-PT as well as for the MR compatible version. All tests were performed with both devices on a conventional linac and the MR compatible device was tested on the MRL as well. No statistically significant differences were found in the short-term reproducibility (<0.1%), dose linearity (⩽0.5%), field size dependency (<2.0% for field sizes larger than 5  ×  5 cm2), dose rate dependency (<1.0%) or angular dependency for any phantom/linac combination. The dose-per-pulse dependency (<0.8%) was found to be significantly different between the two devices. This difference can be explained by the fact that the diodes in the clinical Delta4-PT were irradiated with a much larger dose than the MR-Delta4-PT ones. The absolute difference between the devices (<0.5%) was found to be small, so no clinical impact is expected. For both devices, the results were consistent with the characteristics of the Delta4-PT device reported in the literature (Bedford et al 2009 Phys. Med. Biol. 54 N167-76 Sadagopan et al 2009 J. Appl. Clin. Med. Phys. 10 2928). We found that the characteristics of the MR compatible Delta4 phantom were found to be comparable to the clinically used one. Also, the found characteristics do not differ from the previously reported characteristics of the commercially available non-MR compatible Delta4-PT phantom. Therefore, the MR compatible Delta4 prototype was found to be safe and effective for use in the 1.5 tesla magnetic field of the Elekta MR-linac

Effect of thermal annealing on the thermoluminescent properties of nano-calcium fluoride and its dose-response characteristics.

PubMed

Mundupuzhakal, J K; Biswas, R H; Chauhan, S; Varma, V; Acharya, Y B; Chakrabarty, B S

2015-12-01

Nano-CaF2, prepared by the co-precipitation method, was annealed under different annealing conditions to improve its thermoluminescence (TL) characteristics. Different annealing parameters, such as temperature (400-700°C), duration (1-4 h) and environment (vacuum and air), were explored. The effect on TL sensitivity, peak position (Tm) and full-width at half-maximum (FWHM) with respect to the different annealing conditions are discussed as they are the measure of crystallinity of the material. Annealing temperature of 500°C with annealing duration of two and a half hours in vacuum provided the highest luminescence response (i.e. maximum sensitivity, minimum peak temperature and FWHM). Wide detectable dose range (5 mGy to 2 kGy), absence of thermal quenching and sufficient activation energy (1.04 eV) of this phosphor make it suitable for dosimetric applications. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Preliminary study of the dosimetric characteristics of 3D-printed materials with megavoltage photons

NASA Astrophysics Data System (ADS)

Jeong, Seonghoon; Yoon, Myonggeun; Chung, Weon Kuu; Kim, Dong Wook

2015-07-01

These days, 3D-printers are on the rise in various fields including radiation therapy. This preliminary study aimed to estimate the dose characteristics of 3D-printer materials that could be used as compensators or immobilizers in radiation treatment. The cubes with length of 5 cm and different densities of 50%, 75% and 100% were printed by using a 3D-printer. Planning CT scans of the cubes were performed by using a CT simulator (Brilliance CT, Philips Medical System, Netherlands). Dose distributions behind the cube were calculated after a 6 MV photon beam had passed through the cube. The dose responses for the 3D-printed cube, air and water were measured by using EBT3 film and a 2D array detector. When the results of air case were normalized to 100, the dose calculated by the TPS and the measured doses to 50% and 75% cube were of the 96 ~ 99. The measured and the calculated doses to water and to 100% of the cube were 82 ~ 84. The HU values for the 50%, 75% and 100% density cases were -910, -860 and -10, respectively. The dose characteristics of the 50% and the 75% products were similar to that of air while the 100% product seemed to be similar to that of water. This information will provide guidelines for making an immobilization tool that can play the role of a compensator and for making a real human phantom that can exactly describe the inside of the human body. This study was necessary for Poly Lactic Acid (PLA) based 3D-printer users who are planning to make something related to radiation therapy.

Characterization of a novel two dimensional diode array the "magic plate" as a radiation detector for radiation therapy treatment.

PubMed

Wong, J H D; Fuduli, I; Carolan, M; Petasecca, M; Lerch, M L F; Perevertaylo, V L; Metcalfe, P; Rosenfeld, A B

2012-05-01

Intensity modulated radiation therapy (IMRT) utilizes the technology of multileaf collimators to deliver highly modulated and complex radiation treatment. Dosimetric verification of the IMRT treatment requires the verification of the delivered dose distribution. Two dimensional ion chamber or diode arrays are gaining popularity as a dosimeter of choice due to their real time feedback compared to film dosimetry. This paper describes the characterization of a novel 2D diode array, which has been named the "magic plate" (MP). It was designed to function as a 2D transmission detector as well as a planar detector for dose distribution measurements in a solid water phantom for the dosimetric verification of IMRT treatment delivery. The prototype MP is an 11 × 11 detector array based on thin (50 μm) epitaxial diode technology mounted on a 0.6 mm thick Kapton substrate using a proprietary "drop-in" technology developed by the Centre for Medical Radiation Physics, University of Wollongong. A full characterization of the detector was performed, including radiation damage study, dose per pulse effect, percent depth dose comparison with CC13 ion chamber and build up characteristics with a parallel plane ion chamber measurements, dose linearity, energy response and angular response. Postirradiated magic plate diodes showed a reproducibility of 2.1%. The MP dose per pulse response decreased at higher dose rates while at lower dose rates the MP appears to be dose rate independent. The depth dose measurement of the MP agrees with ion chamber depth dose measurements to within 0.7% while dose linearity was excellent. MP showed angular response dependency due to the anisotropy of the silicon diode with the maximum variation in angular response of 10.8% at gantry angle 180°. Angular dependence was within 3.5% for the gantry angles ± 75°. The field size dependence of the MP at isocenter agrees with ion chamber measurement to within 1.1%. In the beam perturbation study, the surface dose increased by 12.1% for a 30 × 30 cm(2) field size at the source to detector distance (SDD) of 80 cm whilst the transmission for the MP was 99%. The radiation response of the magic plate was successfully characterized. The array of epitaxial silicon based detectors with "drop-in" packaging showed properties suitable to be used as a simplified multipurpose and nonperturbing 2D radiation detector for radiation therapy dosimetric verification.

Thermoluminescence of nanocrystalline CaSO{sub 4}: Dy for gamma dosimetry and calculation of trapping parameters using deconvolution method

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

Mandlik, Nandkumar, E-mail: ntmandlik@gmail.com; Patil, B. J.; Bhoraskar, V. N.

2014-04-24

Nanorods of CaSO{sub 4}: Dy having diameter 20 nm and length 200 nm have been synthesized by the chemical coprecipitation method. These samples were irradiated with gamma radiation for the dose varying from 0.1 Gy to 50 kGy and their TL characteristics have been studied. TL dose response shows a linear behavior up to 5 kGy and further saturates with increase in the dose. A Computerized Glow Curve Deconvolution (CGCD) program was used for the analysis of TL glow curves. Trapping parameters for various peaks have been calculated by using CGCD program.

Thermoluminescence of nanocrystalline CaSO4: Dy for gamma dosimetry and calculation of trapping parameters using deconvolution method

NASA Astrophysics Data System (ADS)

Mandlik, Nandkumar; Patil, B. J.; Bhoraskar, V. N.; Sahare, P. D.; Dhole, S. D.

2014-04-01

Nanorods of CaSO4: Dy having diameter 20 nm and length 200 nm have been synthesized by the chemical coprecipitation method. These samples were irradiated with gamma radiation for the dose varying from 0.1 Gy to 50 kGy and their TL characteristics have been studied. TL dose response shows a linear behavior up to 5 kGy and further saturates with increase in the dose. A Computerized Glow Curve Deconvolution (CGCD) program was used for the analysis of TL glow curves. Trapping parameters for various peaks have been calculated by using CGCD program.

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

PubMed

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

2017-01-01

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

Random Forest Segregation of Drug Responses May Define Regions of Biological Significance

PubMed Central

Bukhari, Qasim; Borsook, David; Rudin, Markus; Becerra, Lino

2016-01-01

The ability to assess brain responses in unsupervised manner based on fMRI measure has remained a challenge. Here we have applied the Random Forest (RF) method to detect differences in the pharmacological MRI (phMRI) response in rats to treatment with an analgesic drug (buprenorphine) as compared to control (saline). Three groups of animals were studied: two groups treated with different doses of the opioid buprenorphine, low (LD), and high dose (HD), and one receiving saline. PhMRI responses were evaluated in 45 brain regions and RF analysis was applied to allocate rats to the individual treatment groups. RF analysis was able to identify drug effects based on differential phMRI responses in the hippocampus, amygdala, nucleus accumbens, superior colliculus, and the lateral and posterior thalamus for drug vs. saline. These structures have high levels of mu opioid receptors. In addition these regions are involved in aversive signaling, which is inhibited by mu opioids. The results demonstrate that buprenorphine mediated phMRI responses comprise characteristic features that allow a supervised differentiation from placebo treated rats as well as the proper allocation to the respective drug dose group using the RF method, a method that has been successfully applied in clinical studies. PMID:27014046

Comparison of febrile responsiveness of rats and rabbits to endogenous pyrogen.

PubMed

Stitt, J T; Shimada, S G; Bernheim, H A

1985-12-01

The fever responses of rats and rabbits were compared in detail using a single common source of semipurified endogenous pyrogen prepared from human monocytes. The characteristics and dynamics of the fever-response curves for each species were examined and their dose-response curves were determined and compared. The fevers displayed by rats were qualitatively similar to those of rabbits, but, typically, they developed and terminated more rapidly than those of rabbits. Rabbits were much more sensitive to the endogenous pyrogen than rats. The threshold dose of pyrogen required to elicit a fever was 5 times lower in the rabbit, and the slope of the rabbit's dose-response curve was 1.5 times steeper than that of the rat. The maximum fevers attainable in rabbits were approximately twice those attainable in rats. It was also shown that the more rapid febrile responses of the rat were not due to the 10-fold smaller mass of the rat; instead, we proposed that this difference was more likely due to a closer diffusional proximity of the pyrogen receptor sites to the circulation in rats. The lower sensitivity of the rat to endogenous pyrogen was attributed to a relative insensitivity of the pyrogen receptor sites in rats in the translation of the endogenous pyrogen stimulus into fever.

Chlorine truck attack consequences and mitigation.

PubMed

Barrett, Anthony Michael; Adams, Peter J

2011-08-01

We develop and apply an integrated modeling system to estimate fatalities from intentional release of 17 tons of chlorine from a tank truck in a generic urban area. A public response model specifies locations and actions of the populace. A chemical source term model predicts initial characteristics of the chlorine vapor and aerosol cloud. An atmospheric dispersion model predicts cloud spreading and movement. A building air exchange model simulates movement of chlorine from outdoors into buildings at each location. A dose-response model translates chlorine exposures into predicted fatalities. Important parameters outside defender control include wind speed, atmospheric stability class, amount of chlorine released, and dose-response model parameters. Without fast and effective defense response, with 2.5 m/sec wind and stability class F, we estimate approximately 4,000 (half within ∼10 minutes) to 30,000 fatalities (half within ∼20 minutes), depending on dose-response model. Although we assume 7% of the population was outdoors, they represent 60-90% of fatalities. Changing weather conditions result in approximately 50-90% lower total fatalities. Measures such as sheltering in place, evacuation, and use of security barriers and cryogenic storage can reduce fatalities, sometimes by 50% or more, depending on response speed and other factors. © 2011 Society for Risk Analysis.

Optically stimulated luminescence (OSL) of carbon-doped aluminum oxide (Al{sub 2}O{sub 3}:C) for film dosimetry in radiotherapy

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

Schembri, V.; Heijmen, B. J. M.

2007-06-15

Introduction and Purpose: Conventional x-ray films and radiochromic films have inherent challenges for high precision radiotherapy dosimetry. Here we have investigated basic characteristics of optically stimulated luminescence (OSL) of irradiated films containing carbon-doped aluminum oxide (Al{sub 2}O{sub 3}:C) for dosimetry in therapeutic photon and electron beams. Materials and Methods: The OSL films consist of a polystyrene sheet, with a top layer of a mixture of single crystals of Al{sub 2}O{sub 3}:C, ground into a powder, and a polyester base. The total thickness of the films is 0.3 mm. Measurements have been performed in a water equivalent phantom, using 4, 6,more » 10, and 18 MV photon beams, and 6-22 MeV electron beams. The studies include assessment of the film response (acquired OSL signal/delivered dose) on delivered dose (linearity), dose rate (1-6 Gy/min), beam quality, field size and depth (6 MV, ranges 4x4-30x30 cm{sup 2}, d{sub max}-35 cm). Doses have been derived from ionization chamber measurements. OSL films have also been compared with conventional x-ray and GafChromic films for dosimetry outside the high dose area, with a high proportion of low dose scattered photons. In total, 787 OSL films have been irradiated. Results: Overall, the OSL response for electron beams was 3.6% lower than for photon beams. Differences between the various electron beam energies were not significant. The 6 and 18 MV photon beams differed in response by 4%. No response dependencies on dose rate were observed. For the 6 MV beam, the field size and depth dependencies of the OSL response were within {+-}2.5%. The observed inter-film response variation for films irradiated with the same dose varied from 1% to 3.2% (1 SD), depending on the measurement day. At a depth of 20 cm, 5 cm outside the 20x20 cm{sup 2} 6 and 18 MV beams, an over response of 17% was observed. In contrast to GafChromic and conventional x-ray films, the response of the Al{sub 2}O{sub 3}:C films is linear in the clinically relevant dose range 0-200 cGy. Conclusions: Measurement of the OSL signal of irradiated films containing Al{sub 2}O{sub 3}:C is a promising technique for film dosimetry in radiotherapy with no or small response variations with dose rate, beam quality, field size and depth, and a linear response from 0 to 200 cGy.« less

Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon

PubMed Central

Verhoef, Talitha I; Redekop, William K; Daly, Ann K; van Schie, Rianne M F; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse

2014-01-01

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose–response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials. PMID:23919835

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

PubMed

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

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

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

Tissue responses to low protracted doses of high let radiations or photons: Early and late damage relevant to radio-protective countermeasures

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

Ainsworth, E.J.; Afzal, S.M.J.; Crouse, D.A.

1988-01-01

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for ..gamma..-radiation. When total doses of 96 or 247 cGy of neutrons or ..gamma.. rays were givenmore » as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and ..gamma..-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. 63 refs., 6 figs., 7 tabs.« less

Characterization of a new transmission detector for patient individualized online plan verification and its influence on 6MV X-ray beam characteristics.

PubMed

Thoelking, Johannes; Sekar, Yuvaraj; Fleckenstein, Jens; Lohr, Frank; Wenz, Frederik; Wertz, Hansjoerg

2016-09-01

Online verification and 3D dose reconstruction on daily patient anatomy have the potential to improve treatment delivery, accuracy and safety. One possible implementation is to recalculate dose based on online fluence measurements with a transmission detector (TD) attached to the linac. This study provides a detailed analysis of the influence of a new TD on treatment beam characteristics. The influence of the new TD on surface dose was evaluated by measurements with an Advanced Markus Chamber (Adv-MC) in the build-up region. Based on Monte Carlo simulations, correction factors were determined to scale down the over-response of the Adv-MC close to the surface. To analyze the effects beyond dmax percentage depth dose (PDD), lateral profiles and transmission measurements were performed. All measurements were carried out for various field sizes and different SSDs. Additionally, 5 IMRT-plans (head & neck, prostate, thorax) and 2 manually created test cases (3×3cm(2) fields with different dose levels, sweeping gap) were measured to investigate the influence of the TD on clinical treatment plans. To investigate the performance of the TD, dose linearity as well as dose rate dependency measurements were performed. With the TD inside the beam an increase in surface dose was observed depending on SSD and field size (maximum of +11%, SSD = 80cm, field size = 30×30cm(2)). Beyond dmax the influence of the TD on PDDs was below 1%. The measurements showed that the transmission factor depends slightly on the field size (0.893-0.921 for 5×5cm(2) to 30×30cm(2)). However, the evaluation of clinical IMRT-plans measured with and without the TD showed good agreement after using a single transmission factor (γ(2%/2mm) > 97%, δ±3% >95%). Furthermore, the response of TD was found to be linear and dose rate independent (maximum difference <0.5% compared to reference measurements). When placed in the path of the beam, the TD introduced a slight, clinically acceptable increase of the skin dose even for larger field sizes and smaller SSDs and the influence of the detector on the dose beyond dmax as well as on clinical IMRT-plans was negligible. Since there was no dose rate dependency and the response was linear, the device is therefore suitable for clinical use. Only its absorption has to be compensated during treatment planning, either by the use of a single transmission factor or by including the TD in the incident beam model. Copyright © 2015. Published by Elsevier GmbH.

Feasibility study of a lead(II) iodide-based dosimeter for quality assurance in therapeutic radiology

NASA Astrophysics Data System (ADS)

Heo, Y. J.; Kim, K. T.; Oh, K. M.; Lee, Y. K.; Ahn, K. J.; Cho, H. L.; Kim, J. Y.; Min, B. I.; Mun, C. W.; Park, S. K.

2017-09-01

The most widely used form of radiotherapy to treat tumors uses a linear accelerator, and the apparatus requires regular quality assurance (QA). QA for a linear accelerator demands accuracy throughout, from mock treatment and treatment planning, up to treatment itself. Therefore, verifying a radiation dose is essential to ensure that the radiation is being applied as planned. In current clinical practice, ionization chambers and diodes are used for QA. However, using conventional gaseous ionization chambers presents drawbacks such as complex analytical procedures, difficult measurement procedures, and slow response time. In this study, we discuss the potential of a lead(II) iodide (PbI2)-based radiation dosimeter for radiotherapy QA. PbI2 is a semiconductor material suited to measurements of X-rays and gamma rays, because of its excellent response properties to radiation signals. Our results show that the PbI2-based dosimeter offers outstanding linearity and reproducibility, as well as dose-independent characteristics. In addition, percentage depth dose (PDD) measurements indicate that the error at a fixed reference depth Dmax was 0.3%, very similar to the measurement results obtained using ionization chambers. Based on these results, we confirm that the PbI2-based dosimeter has all the properties required for radiotherapy: stable dose detection, dose linearity, and rapid response time. Based on the evidence of this experimental verification, we believe that the PbI2-based dosimeter could be used commercially in various fields for precise measurements of radiation doses in the human body and for measuring the dose required for stereotactic radiosurgery or localized radiosurgery.

Dietary protein intake, energy deficit, and nitrogen balance in normal-weight adults: a randomized controlled

USDA-ARS?s Scientific Manuscript database

Consuming protein at levels higher than the recommended dietary allowance (RDA) may be metabolically advantageous for overweight and obese individuals attempting weight loss. However, the dose-response characteristics that define the optimal level of dietary protein necessary to sustain measures of...

Development of a stable and sensitive semiconductor detector by using a mixture of lead(II) iodide and lead monoxide for NDT radiation dose detection

NASA Astrophysics Data System (ADS)

Heo, Y. J.; Kim, K. T.; Han, M. J.; Moon, C. W.; Kim, J. E.; Park, J. K.; Park, S. K.

2018-03-01

Recently, high-energy radiation has been widely used in various industrial fields, including the medical industry, and increasing research efforts have been devoted to the development of radiation detectors to be used with high-energy radiation. In particular, nondestructive industrial applications use high-energy radiation for ships and multilayered objects for accurate inspection. Therefore, it is crucial to verify the accuracy of radiation dose measurements and evaluate the precision and reproducibility of the radiation output dose. Representative detectors currently used for detecting the dose in high-energy regions include Si diodes, diamond diodes, and ionization chambers. However, the process of preparing these detectors is complex in addition to the processes of conducting dosimetric measurements, analysis, and evaluation. Furthermore, the minimum size that can be prepared for a detector is limited. In the present study, the disadvantages of original detectors are compensated by the development of a detector made of a mixture of polycrystalline PbI2 and PbO powder, which are both excellent semiconducting materials suitable for detecting high-energy gamma rays and X-rays. The proposed detector shows characteristics of excellent reproducibility and stable signal detection in response to the changes in energy, and was analyzed for its applicability. Moreover, the detector was prepared through a simple process of particle-in-binder to gain control over the thickness and meet the specific value designated by the user. A mixture mass ratio with the highest reproducibility was determined through reproducibility testing with respect to changes in the photon energy. The proposed detector was evaluated for its detection response characteristics with respect to high-energy photon beam, in terms of dose-rate dependence, sensitivity, and linearity evaluation. In the reproducibility assessment, the detector made with 15 wt% PbO powder showed the best characteristics of 0.59% and 0.25% at 6 and 15 MV, respectively. Based on its selection in the reproducibility assessment, the 15 wt% PbO detector showed no dependence on the dose-rate changes, with R-SD < 1%. Finally, a coefficient of determination of 1 in the linearity assessment demonstrated very good linearity with regards to changes in dose. These results demonstrate the applicability and usefulness of the proposed detector made from a mixture of PbI2 and PbO semiconductors.

Defect sink characteristics of specific grain boundary types in 304 stainless steels under high dose neutron environments

DOE PAGES

Field, Kevin G.; Yang, Ying; Busby, Jeremy T.; ...

2015-03-09

Radiation induced segregation (RIS) is a well-studied phenomena which occurs in many structurally relevant nuclear materials including austenitic stainless steels. RIS occurs due to solute atoms preferentially coupling to mobile point defect fluxes that migrate and interact with defect sinks. Here, a 304 stainless steel was neutron irradiated up to 47.1 dpa at 320 °C. Investigations into the RIS response at specific grain boundary types were utilized to determine the sink characteristics of different boundary types as a function of irradiation dose. A rate theory model built on the foundation of the modified inverse Kirkendall (MIK) model is proposed andmore » benchmarked to the experimental results. This model, termed the GiMIK model, includes alterations in the boundary conditions based on grain boundary structure and includes expressions for interstitial binding. This investigation, through experiment and modeling, found specific grain boundary structures exhibit unique defect sink characteristics depending on their local structure. Furthermore, such interactions were found to be consistent across all doses investigated and had larger global implications including precipitation of Ni-Si clusters near different grain boundary types.« less

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

Optically Stimulated Luminescent Dosimetry for High Dose Rate Brachytherapy

PubMed Central

Tien, Christopher Jason; Ebeling, Robert; Hiatt, Jessica R.; Curran, Bruce; Sternick, Edward

2012-01-01

Purpose: The objective was to determine whether optically stimulated luminescent dosimeters (OSLDs) were appropriate for in vivo measurements in high dose rate brachytherapy. In order to make this distinction, three dosimetric characteristics were tested: dose linearity, dose rate dependence, and angular dependence. The Landauer nanoDot™ OSLDs were chosen due to their popularity and their availability commercially. Methods: To test the dose linearity, each OSLD was placed at a constant location and the dwell time was varied. Next, in order to test the dose rate dependence, each OSLD was placed at different OLSD-to-source distances and the dwell time was held constant. A curved geometry was created using a circular Accuboost® applicator in order to test angular dependence. Results: The OSLD response remained linear for high doses and was independent of dose rate. For doses up to 600 cGy, the linear coefficient of determination was 0.9988 with a response of 725 counts per cGy. The angular dependence was significant only in “edge-on” scenarios. Conclusion: OSLDs are conveniently read out using commercially available readers. OSLDs can be re-read and serve as a permanent record for clinical records or be annealed using conventional fluorescent light. Lastly, OSLDs are produced commercially for $5 each. Due to these convenient features, in conjunction with the dosimetric performance, OSLDs should be considered a clinically feasible and attractive tool for in vivo HDR brachytherapy measurements. PMID:22888476

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

PubMed

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

2018-03-28

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

Radiation-induced genomic instability: radiation quality and dose response

NASA Technical Reports Server (NTRS)

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

2003-01-01

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

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.

The response of Kodak EDR2 film in high-energy electron beams.

PubMed

Gerbi, Bruce J; Dimitroyannis, Dimitri A

2003-10-01

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

The Effect of Evaporated Salt Solutions on the Optical Dating Properties of JSC Mars-1: "Seasoning" for a Mars Soil Simulant

NASA Astrophysics Data System (ADS)

Lepper, Kenneth

2009-08-01

Optically stimulated luminescence dating, or optical dating, is an established terrestrial geochronometric technique that is being adapted to date sedimentary deposits and landforms on the surface of Mars. Recent discoveries have highlighted the astrobiological significance and occurrence of halite on the surface of Mars. The objective of the experiments in this study was to create a simplistic analogue of the sedimentary material that would result from evaporation of ion-containing pore water out of martian regolith and evaluate the influence the evaporated salts would have on in situ optical dating of silicate sediments. The radiation dose response, as measured by infrared stimulated luminescence (IRSL), from evaporated mixtures of JSC Mars-1 and solutions of sodium chloride and calcium sulfate was documented. The results suggest that the presence of CaSO4 and NaCl within the aggregated particles does not have adverse effects on IRSL dose response and that aggregates of this type exhibit dose response characteristics that are appropriate for optical dating.

Characteristics and Predictors of Early and Delayed Responders to Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration: A Retrospective Analysis from the ANCHOR, MARINA, HARBOR, and CATT Trials.

PubMed

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

2016-01-01

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

Characteristics, management and response to alteplase in China versus non-China participants of the ENCHANTED trial.

PubMed

Song, Lily; Wang, Xia; Robinson, Thompson; Lindley, Richard I; Arima, Hisatomi; Lavados, Pablo M; Chen, Xiaoying; Chalmers, John; Anderson, Craig S

2017-06-01

The characteristics of patients with acute ischaemic stroke (AIS) and their management vary across regions, which may influence outcomes. We examined for differential patterns of outcome between China and non-China participants of the ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED), which tested different alteplase doses in AIS. ENCHANTED was an international, multicentre, open, blinded-endpoint trial of the effects of low-dose (0.6 mg/kg) versus standard-dose (0.9 mg/kg) intravenous alteplase on 90-day disability outcomes and symptomatic intracerebral haemorrhage (sICH) in 3310 patients with AIS. Participants (n=1419, 48%) in China were younger, and more often male, hypertensive and with prior stroke and coronary artery disease, but less likely to have atrial fibrillation and use antihypertensive, antithrombotic and lipid-lowering agents, compared with non-China patients with AIS. Although China participants had more AIS due to large artery occlusion, were treated later and had differing ancillary management, there was no significant difference in 90-day modified Rankin scale scores 2-6 (55.6% vs 47.8%; OR, adjusted for baseline and management factors 0.87 (95% CI 0.71 to 1.07; p=0.20)) and risk of sICH (Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria: 1.4% vs 1.8%; p=0.12) compared with non-China participants. There was no heterogeneity in the treatment effects of low-dose versus standard-dose alteplase between China and non-China participants. Patients with AIS recruited to the ENCHANTED trial in China had similar outcomes in response to thrombolysis treatment despite significantly differing demographic, clinical and management factors to patients with AIS in other regions.

Dose responses in a normoxic polymethacrylic acid gel dosimeter using optimal CT scanning parameters

NASA Astrophysics Data System (ADS)

Cho, K. H.; Cho, S. J.; Lee, S.; Lee, S. H.; Min, C. K.; Kim, Y. H.; Moon, S. K.; Kim, E. S.; Chang, A. R.; Kwon, S. I.

2012-05-01

The dosimetric characteristics of normoxic polymethacrylic acid gels are investigated using optimal CT scanning parameters and the possibility of their clinical application is also considered. The effects of CT scanning parameters (tube voltage, tube current, scan time, slick thickness, field of view, and reconstruction algorithm) are experimentally investigated to determine the optimal parameters for minimizing the amount of noise in images obtained using normoxic polymethacrylic acid gel. In addition, the dose sensitivity, dose response, accuracy, and reproducibility of the normoxic polymethacrylic acid gel are evaluated. CT images are obtained using a head phantom that is fabricated for clinical applications. In addition, IMRT treatment planning is performed using a Tomotherapy radiation treatment planning system. A program for analyzing the results is produced using Visual C. A comparison between the treatment planning and the CT images of irradiated gels is performed. The dose sensitivity is found to be 2.41±0.04 HGy-1. The accuracies of dose evaluation at doses of 2 Gy and 4 Gy are 3.0% and 2.6%, respectively, and their reproducibilities are 2.0% and 2.1%, respectively. In the comparison of gel and Tomotherpay planning, the pass rate of the γ-index, based on the reference values of a dose error of 3% and a DTA of 3 mm, is 93.7%.

Estimation of thyroid radiation doses for the hanford thyroid disease study: results and implications for statistical power of the epidemiological analyses.

PubMed

Kopecky, Kenneth J; Davis, Scott; Hamilton, Thomas E; Saporito, Mark S; Onstad, Lynn E

2004-07-01

Residents of eastern Washington, northeastern Oregon, and western Idaho were exposed to I released into the atmosphere from operations at the Hanford Nuclear Site from 1944 through 1972, especially in the late 1940's and early 1950's. This paper describes the estimated doses to the thyroid glands of the 3,440 evaluable participants in the Hanford Thyroid Disease Study, which investigated whether thyroid morbidity was increased in people exposed to radioactive iodine from Hanford during 1944-1957. The participants were born during 1940-1946 to mothers living in Benton, Franklin, Walla Walla, Adams, Okanogan, Ferry, or Stevens Counties in Washington State. Whenever possible someone with direct knowledge of the participant's early life (preferably the participant's mother) was interviewed about the participant's individual dose-determining characteristics (residence history, sources and quantities of food, milk, and milk products consumed, production and processing techniques for home-grown food and milk products). Default information was used if no interview respondent was available. Thyroid doses were estimated using the computer program Calculation of Individual Doses from Environmental Radionuclides (CIDER) developed by the Hanford Environmental Dose Reconstruction Project. CIDER provided 100 sets of doses to represent uncertainty of the estimates. These sets were not generated independently for each participant, but reflected the effects of uncertainties in characteristics shared by participants. Estimated doses (medians of each participant's 100 realizations) ranged from 0.0029 mGy to 2823 mGy, with mean and median of 174 and 97 mGy, respectively. The distribution of estimated doses provided the Hanford Thyroid Disease Study with sufficient statistical power to test for dose-response relationships between thyroid outcomes and exposure to Hanford's I.

Dosimetric characterization and use of GAFCHROMIC EBT3 film for IMRT dose verification

PubMed Central

Borca, Valeria Casanova; Russo, Giuliana; Grosso, Pierangelo; Cante, Domenico; Sciacero, Piera; Girelli, Giuseppe; Porta, Maria Rosa La; Tofani, Santi

2013-01-01

Radiochromic film has become an important tool to verify dose distributions in highly conformal radiation therapy such as IMRT. Recently, a new generation of these films, EBT3, has become available. EBT3 has the same composition and thickness of the sensitive layer of the previous EBT2 films, but its symmetric layer configuration allows the user to eliminate side orientation dependence, which is reported for EBT2 films. The most important EBT3 characteristics have been investigated, such as response at high‐dose levels, sensitivity to scanner orientation and postirradiation coloration, energy and dose rate dependence, and orientation dependence with respect to film side. Additionally, different IMRT fields were measured with both EBT3 and EBT2 films and evaluated using gamma index analysis. The results obtained show that most of the characteristics of EBT3 film are similar to the EBT2 film, but the orientation dependence with respect to film side is completely eliminated in EBT3 films. The study confirms that EBT3 film can be used for clinical practice in the same way as the previous EBT2 film. PACS number: 87.56.Fc PMID:23470940

Performance of finishing beef steers in response to anabolic implant and zilpaterol hydrochloride supplementation

USDA-ARS?s Scientific Manuscript database

Our objectives were to evaluate the dose/payout pattern of trenbolone acetate (TBA) and estradiol-17b (E2) implants and feeding of zilpaterol hydrochloride (ZH) on performance and carcass characteristics of finishing beef steers. A randomized complete block design was used with a 3 × 2 factorial arr...

Sex differences in the response of children with ADHD to once-daily formulations of methylphenidate.

PubMed

Sonuga-Barke, Edmund J S; Coghill, David; Markowitz, John S; Swanson, James M; Vandenberghe, Mieke; Hatch, Simon J

2007-06-01

Studies of sex differences in methylphenidate response by children with attention-deficit/hyperactivity disorder have lacked methodological rigor and statistical power. This paper reports an examination of sex differences based on further analysis of data from a comparison of two once-daily methylphenidate formulations (the COMACS study), which addresses these shortcomings. Children (184: 48 females; mean [SD] age, 9.58 [1.83] years) entered a double-blind, crossover trial of Concerta, MetadateCD/Equasym XL, or placebo. Attention-deficit/hyperactivity disorder symptoms were recorded at seven time points across the school day on the seventh day of treatment, using a laboratory classroom setting. More females had comorbid anxiety disorder. Males and females did not differ with regard to other characteristics. Observed sex differences in pharmacodynamic symptom profiles persisted after controlling for placebo and time 0 hours attention-deficit/hyperactivity disorder scores and the presence of an anxiety disorder. Females had a statistically superior response at 1.5 hours post-dosing and an inferior response at the 12-hour time point relative to their male counterparts, no matter which methylphenidate formulation was being assessed. Dose titration of once-daily formulations of methylphenidate should ideally be based on systematic evidence of response at different periods across the day. The responses of female patients may require additional assessments later in the day to determine the optimal dose.

Tissue responses to low protracted doses of high LET radiations or photons: Early and late damage relevant to radio-protective countermeasures

NASA Astrophysics Data System (ADS)

Ainsworth, E. J.; Afzal, S. M. J.; Crouse, D. A.; Hanson, W. R.; Fry, R. J. M.

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for γ-radiation. When total doses of 96 or 247 cGy of neutrons or γ rays were given as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and γ-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. After high single doses of neutrons or γ rays, a significant age- and radiation-related deficiency in host defense mechanisms was detected by a shorter mean survival time following challenge with transplantable leukemia cells. Comparison of dose-response curves for life shortening after irradiation with fission-spectrum neutrons or high energy silicon particles indicated high initial slopes for both radiation qualities at low doses, but for higher doses of silicon, the effect per Gy decreased to a value similar to that for γ rays. The two component life-shortening curve for silicon particles has implications for the potential efficacy of radioprotectants. Recent studies on protection against early and late effects by aminothiols, prostaglandins, and other compounds are discussed.

Bolus dose response characteristics of single chain urokinase plasminogen activator and tissue plasminogen activator in a dog model of arterial thrombosis.

PubMed

Badylak, S F; Voytik, S; Klabunde, R E; Henkin, J; Leski, M

1988-11-15

Tissue plasminogen activator (t-PA) and single chain urokinase-plasminogen activator (scu-PA) are relatively "fibrin-specific" thrombolytic drugs with short plasma half lives of 6-8 minutes. Most treatment regimens with these agents utilize a bolus injection followed by continuous drug infusion, usually combined with anticoagulant therapy. The purpose of this study was to establish the dose-response characteristics for scu-PA and t-PA, when given as a single intravenous bolus injection, in a dog model of arterial thrombosis. Eight groups of 6 dogs each were given one of the following doses of scu-PA (mg/kg): 0.20, 0.50, 1.00, 2.00; or t-PA: 0.05, 0.10, 0.20; or an equivalent amount of saline (control group). All doses were given as a single bolus injection 60 minutes after formation of a totally occlusive femoral artery thrombus. Thrombolysis was measured by monitoring the continuous decrement of 125I activity from a radiolabelled thrombus. Ninety minutes after drug injection, all scu-PA treated dogs showed greater thrombolysis (30%, 45%, 56%, and 67%, respectively) than the control group (15%, p less than 0.01). The 0.10 and 0.20 mg/kg t-PA treated dogs showed greater thrombolysis (35% and 49%, respectively) than the control group (15%, p less than 0.01). Both scu-PA and t-PA caused a partial and dose-dependent decrease in alpha 2-antiplasmin activity but scu-PA caused a greater depletion (72% vs. 18%, respectively, p less than 0.05) at 60 minutes after the highest dose of drug administration. Both drugs showed a longer than expected thrombolytic effect based upon the known half lives. Neither drug caused significant changes in the prothrombin time, activated partial thromboplastin time, thrombin time, hematocrit, platelet count, or fibrin degradation product concentration. Single bolus injections of scu-PA and t-PA produce safe and effective thrombolysis in this dog model of arterial thrombosis.

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

PubMed Central

Wang, Yichuan; Solaymani-Mohammadi, Shahram; Frey, Blake; Kulkarni, Shweta; Andersen, Peter; Agger, Else Marie; Sui, Yongjun

2017-01-01

T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination. PMID:28348274

Infectivity and pathogenicity of the oomycete Aphanomyces invadans in Atlantic menhaden Brevoortia tyrannus

USGS Publications Warehouse

Kiryu, Y.; Shields, J.D.; Vogelbein, W.K.; Kator, H.; Blazer, V.S.

2003-01-01

Atlantic menhaden Brevoortia tyrannus develop characteristic skin ulcers in response to infection by the oomycete Aphanomyces invadans. To investigate pathogenicity, we conducted a dose response study. Juvenile menhaden were inoculated subcutaneously with 0, 1, 5, 10, 100, and 500 secondary zoospores per fish and monitored for 37 d post-injection (p.i.). Survival rates declined with increasing zoospore dose, with significantly different survivorship curves for the different doses. Moribund and dead fish exhibited characteristic ulcerous lesions at the injection site starting at 13 d p.i. None of the sham-injected control fish (0 zoospore treatment) died. The LD50 (lethal dose killing 50% of exposed menhaden) for inoculated fish was estimated at 9.7 zoospores; however, some fish receiving an estimated single zoospore developed infections that resulted in death. Menhaden were also challenged by aqueous exposure and confirmed that A. invadans was highly pathogenic by this more environmentally realistic route. Fish that were acclimated to culture conditions for 30 d, and presumably free of skin damage, then aqueously exposed to 100 zoospores ml-1, exhibited 14% lesion prevalence with 11% mortality. Net-handled fish that were similarly infected had a significantly higher lesion prevalence (64%) and mortality (64%). Control fish developed no lesions and did not die. Scanning electron microscopy of fish skin indicated that zoospores adhered to intact epidermis, germinated and penetrated the epithelium with a germ tube. Our results indicate that A. invadans is a primary pathogen of menhaden and is able to cause disease at very low zoospore concentrations.

Response of pMOS dosemeters on gamma-ray irradiation during its re-use.

PubMed

Pejovic, Milic M; Pejovic, Momcilo M; Jaksic, Aleksandar B

2013-08-01

Response of pMOS dosemeters during two successive irradiations with gamma-ray irradiation to a dose of 35 Gy and annealing at room and elevated temperature has been studied. The response was followed on the basis of threshold voltage shift, determined from transfer characteristics, as a function of absorbed dose or annealing time. It was shown that the threshold voltage shifts during first and second irradiation for the gate bias during irradiation of 5 and 2.5 V insignificantly differ although complete fading was not achieved after the first cycle of annealing. In order to analyse the defects formed in oxide and at the interface during irradiation and annealing, which are responsible for threshold voltage shift, midgap and charge-pumping techniques were used. It was shown that during first irradiation and annealing a dominant influence to threshold voltage shift is made by fixed oxide traps, while at the beginning of the second annealing cycle, threshold voltage shift is a consequence of both fixed oxide traps and slow switching traps.

Behavioral Alterations in Response to Fear-Provoking Stimuli and Tranylcypromine Induced by Perinatal Exposure to Bisphenol A and Nonylphenol in Male Rats

PubMed Central

Negishi, Takayuki; Kawasaki, Katsuyoshi; Suzaki, Shingo; Maeda, Haruna; Ishii, Yoshiyuki; Kyuwa, Shigeru; Kuroda, Yoichiro; Yoshikawa, Yasuhiro

2004-01-01

The purpose of this study was to examine whether perinatal exposure to two major environmental endocrine-disrupting chemicals, bisphenol A (BPA; 0.1 mg/kg/day orally) and nonylphenol [NP; 0.1 mg/kg/day (low dose) and 10 mg/kg/day (high dose) orally] daily from gestational day 3 to postnatal day 20 (transplacental and lactational exposures) would lead to behavioral alterations in the male offspring of F344 rats. Neither BPA nor NP exposure affected behavioral characteristics in an open-field test (8 weeks of age), in a measurement of spontaneous motor activity (12 weeks of age), or in an elevated plus-maze test (14 weeks of age). A passive avoidance test (13 weeks of age) showed that both BPA- and NP-treated offspring tended to delay entry into a dark compartment. An active avoidance test at 15 weeks of age revealed that BPA-treated offspring showed significantly fewer avoidance responses and low-dose NP-treated offspring exhibited slightly fewer avoidance responses. Furthermore, BPA-treated offspring significantly increased the number of failures to avoid electrical unconditioned stimuli within 5-sec electrical shock presentation compared with the control offspring. In a monoamine-disruption test using 5 mg/kg (intraperitoneal) tranylcypromine (Tcy), a monoamine oxidase inhibitor, both BPA-treated and low-dose NP-treated offspring at 22–24 weeks of age failed to show a significant increment in locomotion in response to Tcy, whereas control and high-dose NP-treated offspring significantly increased locomotion behavior after Tcy injection. In addition, when only saline was injected during a monoamine-disruption test, low-dose NP-treated offspring showed frequent rearing compared with the control offspring. The present results indicate that perinatal low-dose BPA or NP exposure irreversibly influenced the reception of fear-provoking stimuli (e.g., electrical shock), as well as monoaminergic neural pathways. PMID:15289160

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent.

PubMed

Allen, Joshua E; Crowder, Roslyn N; Crowder, Roslyn; El-Deiry, Wafik S

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer.

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent

PubMed Central

Allen, Joshua E.; Crowder, Roslyn; El-Deiry, Wafik S.

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer. PMID:26580220

A study of the variability in the febrile responses of rabbits to endogenous pyrogen.

PubMed

Stitt, J T

1985-10-01

The range of body temperature increases elicited by a standard dose of endogenous pyrogen (0.5 ml/kg iv) was examined in a population of 26 male New Zealand White rabbits. Although the mean maximum increase in rectal temperature was 0.88 +/- 0.06 degree C (SE), individual responses varied from 0.4 degree to 1.5 degree C. Three representative animals that responded to the standard dose of pyrogen with small, intermediate, and large febrile responses were selected and challenged with the same dose of pyrogen on eight separate occasions, and the variability of these responses was examined. There was little variability within the characteristic responses of any particular animal to the repeated challenges. The variability of the febrile responses elicited by both intravenous and intracerebroventricular administration of the same pyrogen was examined and compared using another group of 11 rabbits. The variability in response to the intravenous route was similar to that found in the larger population, whereas the variation in response to the intracerebroventricular route was smaller, and all 11 animals had fevers that were greater than 1 degrees C. It is concluded that the variability of the febrile responses of rabbits to intravenous pyrogen was due to differences between individual sensitivities of animals to the intravenously administered pyrogen. This difference in sensitivity may be due to a difference in the amount of pyrogen that reaches the putative receptor sites, or to a difference in the density or effectiveness of receptor sites in translating the pyrogenic stimulus into a fever response.

Protection from pulmonary tissue damage associated with infection of cynomolgus macaques by highly pathogenic avian influenza virus (H5N1) by low dose natural human IFN-α administered to the buccal mucosa.

PubMed

Strayer, David R; Carter, William A; Stouch, Bruce C; Stittelaar, Koert J; Thoolen, Robert J M M; Osterhaus, Albert D M E; Mitchell, William M

2014-10-01

Using an established nonhuman primate model for H5N1 highly pathogenic influenza virus infection in humans, we have been able to demonstrate the prophylactic mitigation of the pulmonary damage characteristic of human fatal cases from primary influenza virus pneumonia with a low dose oral formulation of a commercially available parenteral natural human interferon alpha (Alferon N Injection®). At the highest oral dose (62.5IU/kg body weight) used there was a marked reduction in the alveolar inflammatory response with minor evidence of alveolar and interstitial edema in contrast to the hemorrhage and inflammatory response observed in the alveoli of control animals. The mitigation of severe damage to the lower pulmonary airway was observed without a parallel reduction in viral titers. Clinical trial data will be necessary to establish its prophylactic human efficacy for highly pathogenic influenza viruses. Copyright © 2014. Published by Elsevier B.V.

An Updated Comprehensive Risk Analysis for Radioisotopes Identified of High Risk to National Security in the Event of a Radiological Dispersion Device Scenario

NASA Astrophysics Data System (ADS)

Robinson, Alexandra R.

An updated global survey of radioisotope production and distribution was completed and subjected to a revised "down-selection methodology" to determine those radioisotopes that should be classified as potential national security risks based on availability and key physical characteristics that could be exploited in a hypothetical radiological dispersion device. The potential at-risk radioisotopes then were used in a modeling software suite known as Turbo FRMAC, developed by Sandia National Laboratories, to characterize plausible contamination maps known as Protective Action Guideline Zone Maps. This software also was used to calculate the whole body dose equivalent for exposed individuals based on various dispersion parameters and scenarios. Derived Response Levels then were determined for each radioisotope using: 1) target doses to members of the public provided by the U.S. EPA, and 2) occupational dose limits provided by the U.S. Nuclear Regulatory Commission. The limiting Derived Response Level for each radioisotope also was determined.

Changes in optically stimulated luminescent dosimeter (OSLD) dosimetric characteristics with accumulated dose

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

Jursinic, Paul A.

2010-01-15

Purpose: A new type of in vivo dosimeter, an optically stimulated luminescent dosimeter (OSLD), has now become commercially available for clinical use. The OSLD is a plastic disk infused with aluminum oxide doped with carbon (Al{sub 2}O{sub 3}:C). Crystals of Al{sub 2}O{sub 3}:C, when exposed to ionizing radiation, store energy that is released as luminescence (420 nm) when the OSLD is illuminated with stimulation light (540 nm). The intensity of the luminescence depends on the dose absorbed by the OSLD and the intensity of the stimulation light. The effects of accumulated dose on OSLD response were investigated. Methods: The OSLDsmore » used in this work were nanodot dosimeters, which were read with a MicroStar reader (Landauer, Inc., Glenwood, IL). Dose to the OSLDs was delivered by 6 MV x rays and gamma rays from Co-60 and Ir-192. The signal on the OSLDs after irradiation is removed by optical annealing with a 150 W tungsten-halogen lamp or a 14 W compact fluorescent lamp was investigated. Results: It was found that OSLD response to dose was supralinear and this response was altered with the amount of accumulated dose to the OSLD. The OSLD response can be modeled by a quadratic and an exponential equation. For accumulated doses up to 60 Gy, the OSLD sensitivity (counts/dose) decreases and the extent of supralinear increases. Above 60 Gy of accumulated dose the sensitivity increases and the extent of supralinearity decreases or reaches a plateau, depending on how the OSLDs were optically annealed. With preirradiation of OSLDs with greater than 1 kGy, it is found that the sensitivity reaches a plateau 2.5 folds greater than that of an OSLD with no accumulated dose and the supralinearity disappears. A regeneration of the luminescence signal in the dark after full optical annealing occurs with a half time of about two days. The extent of this regeneration signal depends on the amount of accumulated dose. Conclusions: For in vivo dosimetric measurements, a precision of {+-}0.5% can be achieved if the sensitivity and extent of supralinearity is established for each OSLD and use. Methods are presented for accomplishing this task.« less

Photo-Oxidation Products of Skin Surface Squalene Mediate Metabolic and Inflammatory Responses to Solar UV in Human Keratinocytes

PubMed Central

Kostyuk, Vladimir; Potapovich, Alla; Stancato, Andrea; De Luca, Chiara; Lulli, Daniela; Pastore, Saveria; Korkina, Liudmila

2012-01-01

The study aimed to identify endogenous lipid mediators of metabolic and inflammatory responses of human keratinocytes to solar UV irradiation. Physiologically relevant doses of solar simulated UVA+UVB were applied to human skin surface lipids (SSL) or to primary cultures of normal human epidermal keratinocytes (NHEK). The decay of photo-sensitive lipid-soluble components, alpha-tocopherol, squalene (Sq), and cholesterol in SSL was analysed and products of squalene photo-oxidation (SqPx) were quantitatively isolated from irradiated SSL. When administered directly to NHEK, low-dose solar UVA+UVB induced time-dependent inflammatory and metabolic responses. To mimic UVA+UVB action, NHEK were exposed to intact or photo-oxidised SSL, Sq or SqPx, 4-hydroxy-2-nonenal (4-HNE), and the product of tryptophan photo-oxidation 6-formylindolo[3,2-b]carbazole (FICZ). FICZ activated exclusively metabolic responses characteristic for UV, i.e. the aryl hydrocarbon receptor (AhR) machinery and downstream CYP1A1/CYP1B1 gene expression, while 4-HNE slightly stimulated inflammatory UV markers IL-6, COX-2, and iNOS genes. On contrast, SqPx induced the majority of metabolic and inflammatory responses characteristic for UVA+UVB, acting via AhR, EGFR, and G-protein-coupled arachidonic acid receptor (G2A). Conclusions/Significance Our findings indicate that Sq could be a primary sensor of solar UV irradiation in human SSL, and products of its photo-oxidation mediate/induce metabolic and inflammatory responses of keratinocytes to UVA+UVB, which could be relevant for skin inflammation in the sun-exposed oily skin. PMID:22952984

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

NASA Astrophysics Data System (ADS)

El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

2006-11-01

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

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.

Thermoluminescence characteristics of Israeli household salts for retrospective dosimetry in radiological events

NASA Astrophysics Data System (ADS)

Druzhyna, S.; Datz, H.; Horowitz, Y. S.; Oster, L.; Orion, I.

2016-06-01

Following a nuclear accident or terror attack involving the dispersal of radioactive substances, radiation dose assessment to first responders and the members of the public is essential. The need for a retrospective assessment of the radiation dose to those possibly affected is, therefore, obligatory. The present study examines the potential use of Israeli household salt as a retrospective dosimeter (RD). The experiments were carried out on Israeli salt samples (NaCl) following a Nielsen market track survey based on scanning data representing the barcoded market, including organized and independent retail chains and a sample of private minimarkets and supermarkets. The technique used was thermoluminescence (TL) dosimetry. Salt samples were exposed to levels of dose from 0.5 mGy to 300 Gy at the Israeli Secondary Standard Dosimetry Laboratory of the Soreq Nuclear Research Center using a calibrated 137Cs source. Our emphasis has been on a detailed investigation of the basic dosimetric characteristics of the salts including: (i) glow curve analysis (ii) individual glow peak dose response (iii) reproducibility (iv) estimation of minimal measurable dose (v) effect of nitrogen readout, (vi) influence of humidity during pre-irradiation storage and (vii) light induced fading. The results are sufficiently favorable to lead to the conclusion that the Israeli household salts can serve as a pragmatic potential candidate for RD under certain restricted conditions. Occasional pre-calibration of the major salt brands in a dedicated laboratory may be essential depending on the required accuracy in the estimation of dose and consequent clinical evaluation.

A chromogranin A ELISA absent of an apparent high-dose hook effect observed in other chromogranin A ELISAs.

PubMed

Erickson, J Alan; Grenache, David G

2016-01-15

Routine testing for chromogranin A (CgA) using an established commercial ELISA revealed an apparent high-dose hook effect in approximately 15% of specimens. Investigations found the same effect in two additional ELISAs. We hypothesized that a CgA derived peptide(s) at high concentrations was responsible but experiments were inconclusive. Here we describe the analytical performance characteristics of the Chromoa™ CgA ELISA that did not display the apparent high-dose hook effect. Performance characteristics of the Chromoa ELISA were assessed. The reference interval was established utilizing healthy volunteers. Specimens producing the apparent high-dose hook effect in other assays were evaluated using the Chromoa ELISA. The limit of detection was 8ng/ml. Linearity was acceptable (slope=1.04, intercept=18.1 and r(2)=0.997). CVs were ≤4.6 and ≤9.3% for repeatability and within-laboratory imprecision, respectively. CgA was stable at ambient and refrigerated temperatures for a minimum of two and 14days, respectively. An upper reference interval limit of 95ng/ml was established. Specimens demonstrating the apparent high-dose hook effect in other ELISAs did not exhibit the phenomenon using the Chromoa ELISA. The Chromoa ELISA demonstrates acceptable performance for quantifying serum CgA. The apparent high-dose hook effect exhibited in other ELISAs was absent using the Chromoa assay. Copyright © 2015 Elsevier B.V. All rights reserved.

Accurate dosimetry with GafChromic EBT film of a 6 MV photon beam in water: what level is achievable?

PubMed

van Battum, L J; Hoffmans, D; Piersma, H; Heukelom, S

2008-02-01

This paper focuses on the accuracy, in absolute dose measurements, with GafChromicTM EBT film achievable in water for a 6 MV photon beam up to a dose of 2.3 Gy. Motivation is to get an absolute dose detection system to measure up dose distributions in a (water) phantom, to check dose calculations. An Epson 1680 color (red green blue) transmission flatbed scanner has been used as film scanning system, where the response in the red color channel has been extracted and used for the analyses. The influence of the flatbed film scanner on the film based dose detection process was investigated. The scan procedure has been optimized; i.e. for instance a lateral correction curve was derived to correct the scan value, up to 10%, as a function of optical density and lateral position. Sensitometric curves of different film batches were evaluated in portrait and landscape scan mode. Between various batches important variations in sensitometric curve were observed. Energy dependence of the film is negligible, while a slight variation in dose response is observed for very large angles between film surface and incident photon beam. Improved accuracy in absolute dose detection can be obtained by repetition of a film measurement to tackle at least the inherent presence of film inhomogeneous construction. We state that the overall uncertainty is random in absolute EBT film dose detection and of the order of 1.3% (1 SD) under the condition that the film is scanned in a limited centered area on the scanner and at least two films have been applied. At last we advise to check a new film batch on its characteristics compared to available information, before using that batch for absolute dose measurements.

Determining the applicability of the Landauer nanoDot as a general public dosimeter in a research imaging facility.

PubMed

Charlton, Michael A; Thoreson, Kelly F; Cerecero, Jennifer A

2012-11-01

The Research Imaging Institute (RII) building at the University of Texas Health Science Center at San Antonio (UTHSCSA) houses two cyclotron particle accelerators, positron emission tomography (PET) machines, and a fluoroscopic unit. As part of the radiation protection program (RPP) and meeting the standard for achieving ALARA (as low as reasonably achievable), it is essential to minimize the ionizing radiation exposure to the general public through the use of controlled areas and area dose monitoring. Currently, thirty-four whole body Luxel+ dosimeters, manufactured by Landauer, are being used in various locations within the RII to monitor dose to the general public. The intent of this research was to determine if the nanoDot, a single point dosimeter, can be used as a general public dosimeter in a diagnostic facility. This was tested by first verifying characteristics of the nanoDot dosimeter including dose linearity, dose rate dependence, angular dependence, and energy dependence. Then, the response of the nanoDot dosimeter to the Luxel+ dosimeter when placed in a continuous, low dose environment was investigated. Finally, the nanoDot was checked for appropriate response in an acute, high dose environment. Based on the results, the current recommendation is that the nanoDot should not replace the Luxel+ dosimeter without further work to determine the energy spectra in the RII building and without considering the limitation of the microStar reader, portable on-site OSL reader, at doses below 0.1 mGy (10 mrad).

From ultraviolet to Prussian blue: a spectral response for the cyanotype process and a safe educational activity to explain UV exposure for all ages.

PubMed

Turner, J; Parisi, A V; Downs, N; Lynch, M

2014-12-01

Engaging students and the public in understanding UV radiation and its effects is achievable using the real time experiment that incorporates blueprint paper, an "educational toy" that is a safe and easy demonstration of the cyanotype chemical process. The cyanotype process works through the presence of UV radiation. The blueprint paper was investigated to be used as not only engagement in discussion for public outreach about UV radiation, but also as a practical way to introduce the exploration of measurement of UV radiation exposure and as a consequence, digital image analysis. Tests of print methods and experiments, dose response, spectral response and dark response were investigated. Two methods of image analysis for dose response calculation are provided using easy to access software and two methods of pixel count analysis were used to determine spectral response characteristics. Variation in manufacture of the blueprint paper product indicates some variance between measurements. Most importantly, as a result of this investigation, a preliminary spectral response range for the radiation required to produce the cyanotype reaction is presented here, which has until now been unknown.

Detection of calcification clusters in digital breast tomosynthesis slices at different dose levels utilizing a SRSAR reconstruction and JAFROC

NASA Astrophysics Data System (ADS)

Timberg, P.; Dustler, M.; Petersson, H.; Tingberg, A.; Zackrisson, S.

2015-03-01

Purpose: To investigate detection performance for calcification clusters in reconstructed digital breast tomosynthesis (DBT) slices at different dose levels using a Super Resolution and Statistical Artifact Reduction (SRSAR) reconstruction method. Method: Simulated calcifications with irregular profile (0.2 mm diameter) where combined to form clusters that were added to projection images (1-3 per abnormal image) acquired on a DBT system (Mammomat Inspiration, Siemens). The projection images were dose reduced by software to form 35 abnormal cases and 25 normal cases as if acquired at 100%, 75% and 50% dose level (AGD of approximately 1.6 mGy for a 53 mm standard breast, measured according to EUREF v0.15). A standard FBP and a SRSAR reconstruction method (utilizing IRIS (iterative reconstruction filters), and outlier detection using Maximum-Intensity Projections and Average-Intensity Projections) were used to reconstruct single central slices to be used in a Free-response task (60 images per observer and dose level). Six observers participated and their task was to detect the clusters and assign confidence rating in randomly presented images from the whole image set (balanced by dose level). Each trial was separated by one weeks to reduce possible memory bias. The outcome was analyzed for statistical differences using Jackknifed Alternative Free-response Receiver Operating Characteristics. Results: The results indicate that it is possible reduce the dose by 50% with SRSAR without jeopardizing cluster detection. Conclusions: The detection performance for clusters can be maintained at a lower dose level by using SRSAR reconstruction.

Reducing radiation dose to the female breast during conventional and dedicated breast computed tomography

NASA Astrophysics Data System (ADS)

Rupcich, Franco John

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

Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies.

PubMed

Alexander, Joe; Edwards, Roger A; Manca, Luigi; Grugni, Roberto; Bonfanti, Gianluca; Emir, Birol; Whalen, Edward; Watt, Stephen; Parsons, Bruce

2018-03-01

Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires adequate upward dose titration. Our goal was to identify relationships between titration and response to pregabalin in patients with pDPN. Data were integrated from nine randomized, placebo-controlled clinical trials as well as one 6-week open-label observational study conducted by 5808 physicians (2642 patients with pDPN) in standard outpatient settings in Germany. These studies evaluated pregabalin for treatment of pDPN. Using these data, we examined "what if" scenarios using a microsimulation platform that integrates data from randomized and observational sources as well as autoregressive-moving-average with exogenous inputs models that predict pain outcomes, taking into account weekly changes in pain, sleep interference, dose, and other patient characteristics that were unchanging. Final pain levels were significantly different depending on dose changes (P < 0.0001), with greater proportions improving with upward titration regardless of baseline pain severity. Altogether, 78.5% of patients with pDPN had 0-1 dose change, and 15.2% had ≥ 2 dose changes. Simulation demonstrated that the 4.8% of inadequately titrated patients who did not improve/very much improve their pain levels would have benefited from ≥ 2 dose changes. Patient satisfaction with tolerability (range 90.3-96.2%) was similar, regardless of baseline pain severity, number of titrations, or extent of improvement, suggesting that tolerability did not influence treatment response patterns. Upward dose titration reduced pain in patients with pDPN who actually received it. Simulation also predicted pain reduction in an inadequately titrated nonresponder subgroup of patients had they actually received adequate titration. The decision not to uptitrate must have been driven by factors other than tolerability. Pfizer, Inc.

Determination of the depth dose distribution of proton beam using PRESAGE TM dosimeter

NASA Astrophysics Data System (ADS)

Zhao, L.; Das, I. J.; Zhao, Q.; Thomas, A.; Adamovics, J.; Oldman, M.

2010-11-01

PRESAGETM dosimeter dosimeter has been proved useful for 3D dosimetry in conventional photon therapy and IMRT [1-5]. Our objective is to examine the use of PRESAGETM dosimeter for verification of depth dose distribution in proton beam therapy. Three PRESAGETM samples were irradiated with a 79 MeV un-modulated proton beam. Percent depth dose profile measured from the PRESAGETM dosimeter is compared with data obtained in a water phantom using a parallel plate Advanced Markus chamber. The Bragg-peak position determined from the PRESAGETM is within 2 mm compared to measurements in water. PRESAGETM shows a highly linear response to proton dose. However, PRESAGETM also reveals an underdosage around the Bragg peak position due to LET effects. Depth scaling factor and quenching correction factor need further investigation. Our initial result shows that PRESAGETM has promising dosimetric characteristics that could be suitable for proton beam dosimetry.

Dissecting Phosphite-Induced Priming in Arabidopsis Infected with Hyaloperonospora arabidopsidis1[W

PubMed Central

Massoud, Kamal; Barchietto, Thierry; Le Rudulier, Thomas; Pallandre, Laurane; Didierlaurent, Laure; Garmier, Marie; Ambard-Bretteville, Françoise; Seng, Jean-Marc; Saindrenan, Patrick

2012-01-01

Phosphite (Phi), a phloem-mobile oxyanion of phosphorous acid (H3PO3), protects plants against diseases caused by oomycetes. Its mode of action is unclear, as evidence indicates both direct antibiotic effects on pathogens as well as inhibition through enhanced plant defense responses, and its target(s) in the plants is unknown. Here, we demonstrate that the biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa) exhibits an unusual biphasic dose-dependent response to Phi after inoculation of Arabidopsis (Arabidopsis thaliana), with characteristics of indirect activity at low doses (10 mm or less) and direct inhibition at high doses (50 mm or greater). The effect of low doses of Phi on Hpa infection was nullified in salicylic acid (SA)-defective plants (sid2-1, NahG) and in a mutant impaired in SA signaling (npr1-1). Compromised jasmonate (jar1-1) and ethylene (ein2-1) signaling or abscisic acid (aba1-5) biosynthesis, reactive oxygen generation (atrbohD), or accumulation of the phytoalexins camalexin (pad3-1) and scopoletin (f6′h1-1) did not affect Phi activity. Low doses of Phi primed the accumulation of SA and Pathogenesis-Related protein1 transcripts and mobilized two essential components of basal resistance, Enhanced Disease Susceptibility1 and Phytoalexin Deficient4, following pathogen challenge. Compared with inoculated, Phi-untreated plants, the gene expression, accumulation, and phosphorylation of the mitogen-activated protein kinase MPK4, a negative regulator of SA-dependent defenses, were reduced in plants treated with low doses of Phi. We propose that Phi negatively regulates MPK4, thus priming SA-dependent defense responses following Hpa infection. PMID:22408091

Characteristics of optically stimulated luminescence dosimeters in the spread-out Bragg peak region of clinical proton beams

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

Kerns, James R.; Kry, Stephen F.; Sahoo, Narayan

Purpose: Optically stimulated luminescent detectors (OSLDs) have a number of advantages in radiation dosimetry making them excellent dosimeters for quality assurance and patient dose verification. Although the dosimeters have been investigated in several modalities, relatively little work has been done in examining the dosimeters for use in clinical proton beams. This study examined a number of characteristics of the response of the dosimeters in the spread-out Bragg peak (SOBP) region of clinical proton beams. Methods: Optically stimulated luminescence (OSL) dosimeters from Landauer, Inc., specifically the nanoDot dosimeter, were investigated. These dosimeters were placed in a special phantom with a recessmore » to fit the dosimeters without an air gap. Beams with nominal energies of 160, 200, and 250 MeV were used in the passively-scattered proton beam at the MD Anderson Cancer Center Proton Therapy Center. Dosimetric properties including linearity, field size dependence, energy dependence, residual signal as a function of cumulative dose, and postirradiation fading were investigated by taking measurements at the center of SOBPs. Results: The dosimeters showed 1% supralinearity at 200 cGy and 5% supralinearity at 1000 cGy. No noticeable field size dependence of the detector was found for field sizes from 2 x 2 cm{sup 2} to 18 x 18 cm{sup 2}. Residual signal as a function of cumulative dose showed a small increase for measurements up to 1000 cGy. Readout signal depletion of the dosimeters after consecutive readings showed a slightly larger depletion in protons for doses up to 500 cGy but not by a clinically significant amount. Within the center of various SOBP widths and proton energies the variation in response was less than 2%. An average beam quality factor of 1.089 with experimental standard deviation of 0.007 was determined and applied to the data such that the results were within 1.2% of ion chamber data. Conclusions: The nanoDot OSL dosimeter characteristics were studied in the SOBP region of clinical proton beams. To achieve accurate dosimetric readings, corrections to the dosimeter response were applied. Corrections tended to be minimal or broadly consistent. The nanoDot OSLD was found to be an acceptable dosimeter for measurement in the SOBP region for a range of clinical proton beams.« less

Characteristics of optically stimulated luminescence dosimeters in the spread-out Bragg peak region of clinical proton beams.

PubMed

Kerns, James R; Kry, Stephen F; Sahoo, Narayan

2012-04-01

Optically stimulated luminescent detectors (OSLDs) have a number of advantages in radiation dosimetry making them excellent dosimeters for quality assurance and patient dose verification. Although the dosimeters have been investigated in several modalities, relatively little work has been done in examining the dosimeters for use in clinical proton beams. This study examined a number of characteristics of the response of the dosimeters in the spread-out Bragg peak (SOBP) region of clinical proton beams. Optically stimulated luminescence (OSL) dosimeters from Landauer, Inc., specifically the nanoDot dosimeter, were investigated. These dosimeters were placed in a special phantom with a recess to fit the dosimeters without an air gap. Beams with nominal energies of 160, 200, and 250 MeV were used in the passively-scattered proton beam at the MD Anderson Cancer Center Proton Therapy Center. Dosimetric properties including linearity, field size dependence, energy dependence, residual signal as a function of cumulative dose, and postirradiation fading were investigated by taking measurements at the center of SOBPs. The dosimeters showed 1% supralinearity at 200 cGy and 5% supralinearity at 1000 cGy. No noticeable field size dependence of the detector was found for field sizes from 2 × 2 cm(2) to 18 × 18 cm(2). Residual signal as a function of cumulative dose showed a small increase for measurements up to 1000 cGy. Readout signal depletion of the dosimeters after consecutive readings showed a slightly larger depletion in protons for doses up to 500 cGy but not by a clinically significant amount. Within the center of various SOBP widths and proton energies the variation in response was less than 2%. An average beam quality factor of 1.089 with experimental standard deviation of 0.007 was determined and applied to the data such that the results were within 1.2% of ion chamber data. The nanoDot OSL dosimeter characteristics were studied in the SOBP region of clinical proton beams. To achieve accurate dosimetric readings, corrections to the dosimeter response were applied. Corrections tended to be minimal or broadly consistent. The nanoDot OSLD was found to be an acceptable dosimeter for measurement in the SOBP region for a range of clinical proton beams.

Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

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

CHARACTERISTICS OF THERMOLUMINESCENCE LiF:Mg,Cu,Ag NANOPHOSPHOR.

PubMed

Yahyaabadi, A; Torkzadeh, F; Rezaei-Ochbelagh, D

2018-04-23

A nanophosphor of LiF:Mg,Cu,Ag was prepared by planetary ball milling for the first time in the laboratory. The size and shape of the nanophosphor were confirmed by XRD and SEM, which showed that it was cubic in shape and ~53 nm in size. The thermoluminescence (TL) characteristics of this nanophosphor were then investigated. It was found that the optimum annealing condition was 250°C for 10 min. The TL sensitivity of the prepared nanopowder was less than that of its micropowder counterpart and the TL glow curve structure exhibited several peaks. The LiF:Mg,Cu,Ag nanophosphor exhibited a linear response over a range of doses from 1 Gy to ~10 kGy. From this study, it appears that LiF:Mg,Cu,Ag nanophosphor is a good candidate for dosimetry because of its linearity over a range of doses, low tendency to fade, good repeatability and simple glow curve structure.

Physiologic variability at the verge of systemic inflammation: multiscale entropy of heart rate variability is affected by very low doses of endotoxin.

PubMed

Herlitz, Georg N; Arlow, Renee L; Cheung, Nora H; Coyle, Susette M; Griffel, Benjamin; Macor, Marie A; Lowry, Stephen F; Calvano, Steve E; Gale, Stephen C

2015-02-01

Human injury or infection induces systemic inflammation with characteristic neuroendocrine responses. Fluctuations in autonomic function during inflammation are reflected by beat-to-beat variation in heart rate, termed heart rate variability (HRV). In the present study, we determine threshold doses of endotoxin needed to induce observable changes in markers of systemic inflammation, investigate whether metrics of HRV exhibit a differing threshold dose from other inflammatory markers, and investigate the size of data sets required for meaningful use of multiscale entropy (MSE) analysis of HRV. Healthy human volunteers (n = 25) were randomized to receive placebo (normal saline) or endotoxin/lipopolysaccharide (LPS): 0.1, 0.25, 0.5, 1.0, or 2.0 ng/kg administered intravenously. Vital signs were recorded every 30 min for 6 h and then at 9, 12, and 24 h after LPS. Blood samples were drawn at specific time points for cytokine measurements. Heart rate variability analysis was performed using electrocardiogram epochs of 5 min. Multiscale entropy for HRV was calculated for all dose groups to scale factor 40. The lowest significant threshold dose was noted in core temperature at 0.25 ng/kg. Endogenous tumor necrosis factor α and interleukin 6 were significantly responsive at the next dosage level (0.5 ng/kg) along with elevations in circulating leukocytes and heart rate. Responses were exaggerated at higher doses (1 and 2 ng/kg). Time domain and frequency domain HRV metrics similarly suggested a threshold dose, differing from placebo at 1.0 and 2.0 ng/kg, below which no clear pattern in response was evident. By applying repeated-measures analysis of variance across scale factors, a significant decrease in MSE was seen at 1.0 and 2.0 ng/kg by 2 h after exposure to LPS. Although not statistically significant below 1.0 ng/kg, MSE unexpectedly decreased across all groups in an orderly dose-response pattern not seen in the other outcomes. By using repeated-measures analysis of variance across scale factors, MSE can detect autonomic change after LPS challenge in a group of 25 subjects using electrocardiogram epochs of only 5 min and entropy analysis to scale factor of only 40, potentially facilitating MSE's wider use as a research tool or bedside monitor. Traditional markers of inflammation generally exhibit threshold dose behavior. In contrast, MSE's apparent continuous dose-response pattern, although not statistically verifiable in this study, suggests a potential subclinical harbinger of infectious or other insult. The possible derangement of autonomic complexity prior to or independent of the cytokine surge cannot be ruled out. Future investigation should focus on confirmation of overt inflammation following observed decreases in MSE in a clinical setting.

Physiologic variability at the verge of systemic inflammation: multi-scale entropy of heart rate variability is affected by very low doses of endotoxin

PubMed Central

Herlitz, Georg N.; Sanders, Renee L.; Cheung, Nora H.; Coyle, Susette M.; Griffel, Benjamin; Macor, Marie A.; Lowry, Stephen F.; Calvano, Steve E.; Gale, Stephen C.

2014-01-01

Introduction Human injury or infection induces systemic inflammation with characteristic neuro-endocrine responses. Fluctuations in autonomic function during inflammation are reflected by beat-to-beat variation in heart rate, termed heart rate variability (HRV). In the present study, we determine threshold doses of endotoxin needed to induce observable changes in markers of systemic inflammation, we investigate whether metrics of HRV exhibit a differing threshold dose from other inflammatory markers, and we investigate the size of data sets required for meaningful use of multi-scale entropy (MSE) analysis of HRV. Methods Healthy human volunteers (n=25) were randomized to receive placebo (normal saline) or endotoxin/lipopolysaccharide (LPS): 0.1, 0.25, 0.5, 1.0, or 2.0 ng/kg administered intravenously. Vital signs were recorded every 30 minutes for 6 hours and then at 9, 12, and 24 hours after LPS. Blood samples were drawn at specific time points for cytokine measurements. HRV analysis was performed using EKG epochs of 5 minutes. MSE for HRV was calculated for all dose groups to scale factor 40. Results The lowest significant threshold dose was noted in core temperature at 0.25ng/kg. Endogenous TNF-α and IL-6 were significantly responsive at the next dosage level (0.5ng/kg) along with elevations in circulating leukocytes and heart rate. Responses were exaggerated at higher doses (1 and 2 ng/kg). Time domain and frequency domain HRV metrics similarly suggested a threshold dose, differing from placebo at 1.0 and 2.0 ng/kg, below which no clear pattern in response was evident. By applying repeated-measures ANOVA across scale factors, a significant decrease in MSE was seen at 1.0 and 2.0 ng/kg by 2 hours post exposure to LPS. While not statistically significant below 1.0 ng/kg, MSE unexpectedly decreased across all groups in an orderly dose-response pattern not seen in the other outcomes. Conclusions By usingrANOVA across scale factors, MSE can detect autonomic change after LPS challenge in a group of 25 subjects using EKG epochs of only 5 minutes and entropy analysis to scale factor of only 40, potentially facilitating MSE’s wider use as a research tool or bedside monitor. Traditional markers of inflammation generally exhibit threshold dose behavior. In contrast, MSE’s apparent continuous dose-response pattern, while not statistically verifiable in this study, suggests a potential subclinical harbinger of infectious or other insult. The possible derangement of autonomic complexity prior to or independent of the cytokine surge cannot be ruled out. Future investigation should focus on confirmation of overt inflammation following observed decreases in MSE in a clinical setting. PMID:25526373

Low Dose Ionizing Radiation Modulates Immune Function

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

Nelson, Gregory A.

In order to examine the effects of low dose ionizing radiation on the immune system we chose to examine an amplified adaptive cellular immunity response. This response is Type IV delayed-type hypersensitivity also called contact hypersensitivity. The agent fluorescein isothiocyanate (FITC) is a low molecular weight, lipophilic, reactive, fluorescent molecule that can be applied to the skin where it (hapten) reacts with proteins (carriers) to become a complete antigen. Exposure to FITC leads to sensitization which is easily measured as a hypersensitivity inflammatory reaction following a subsequent exposure to the ear. Ear swelling, eosinophil infiltration, immunoglobulin E production and cytokinemore » secretion patterns characteristic of a “Th2 polarized” immune response are the components of the reaction. The reaction requires successful implementation of antigen processing and presentation by antigen presenting Langerhans cells, communication with naïve T lymphocytes in draining lymph nodes, expansion of activated T cell clones, migration of activated T cells to the circulation, and recruitment of memory T cells, macrophages and eosinophils to the site of the secondary challenge. Using this model our approach was to quantify system function rather than relying only on indirect biomarkers of cell. We measured the FITC-induced hypersensitivity reaction over a range of doses from 2 cGy to 2 Gy. Irradiations were performed during key events or prior to key events to deplete critical cell populations. In addition to quantifying the final inflammatory response, we assessed cell populations in peripheral blood and spleen, cytokine signatures, IgE levels and expression of genes associated with key processes in sensitization and elicitation/recall. We hypothesized that ionizing radiation would produce a biphasic effect on immune system function resulting in an enhancement at low doses and a depression at higher doses and suggested that this transition would occur in the dose range of 5 to 50 cGy.« less

SU-E-T-801: Verification of Dose Information Passed Through 3D-Printed Products

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

Jeong, S; Yoon, M; Kim, D

2015-06-15

Purpose: When quality assurance (QA) of patient treatment beam is performed, homogeneous water equivalent phantom which has different structure from patient’s internal structure is normally used. In these days, it is possible to make structures which have same shapes of human organs with commercialization of 3D-printer. As a Result, structures with same shape of human organs made by 3D-printer could be used to test qualification of treatment beam with greater accuracy than homogeneous water phantom. In this study, we estimated the dose response of 3D-printer materials to test the probability as a humanoid phantom or new generation of compensator tool.more » Methods: The rectangular products with variety densities (50%, 75% and 100%) were made to verify their characteristics. The products for experiment group and solid water phantom and air for control group with 125 cubic centimeters were put on solid water phantom with enough thickness. CT image of two products were acquired to know their HU values and to know about their radiologic characteristics. 6MV beams with 500MU were exposed for each experiment. Doses were measured behind the 3D-printed products. These measured doses were compared to the results taken by TPS. Results: Absorbed dose penetrated from empty air is normalized to 100%. Doses measured from 6MV photon beams penetrated from 50%, 75% and 100% products were 99%, 96% and 84%, respectively. HU values of 50%, 75% and 100% products are about −910, −860 and −10. Conclusion: 3D-printer can produce structures which have similar characteristics with human organ. These results would be used to make similar phantoms with patient information. This work was supported by the Nuclear Safety Research Program (Grant No. 1305033 and 1403019) of the Korea Radiation Safety Foundation and the Nuclear Safety and Security Commission and Radiation Technology Development Program (2013M2A2A4027117) of the Republic of Korea.« less

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

PubMed

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

2016-03-01

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

Studies on the mechanism of endogenous pyrogen production. III. Human blood monocytes.

PubMed

Bodel, P

1974-10-01

The characteristics of pyrogen production and release by human blood monocytes were investigated. A dose-response assay of monocyte pyrogen in rabbits indicated a linear relationship of temperature elevation to dose of pyrogen at lower doses. Monocytes did not contain pyrogen when first obtained, nor did they release it spontaneously even after 5 days of incubation in vitro. Pyrogen production was apparent 4 h after stimulation by endotoxin or phagocytosis, and continued for 24 h or more. Puromycin, an inhibitor of protein synthesis, prevented both initiation and continuation of pyrogen production and release. Pyrogen-containing supernates retained most pyrogenic activity during overnight incubation even in the presence of activated cells. Lymphocytes appeared to play no role in either initiation or continuation of pyrogen production in these studies.

Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions

PubMed Central

Nyquist, Michael D.; Schweizer, Michael T.; Balk, Stephen P.; Corey, Eva; Plymate, Stephen; Nelson, Peter S.; Mostaghel, Elahe A.

2017-01-01

Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs. From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses. Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations. Many questions regarding the biphasic response of PCa to androgen treatment remain, primarily regarding the mechanisms driving these responses and how best to exploit the biphasic phenomenon clinically. Here we review the preclinical and clinical data on high dose androgen growth repression and discuss cellular pathways and mechanisms likely to be involved in mediating this response. Although meaningful clinical responses have now been observed in men with PCa treated with high dose T, not all men respond, leading to questions regarding which tumor characteristics promote response or resistance, and highlighting the need for studies designed to determine the molecular mechanism(s) driving these responses and identify predictive biomarkers. PMID:29210989

Optically Stimulated Luminescence Response to Ionizing Radiation of Red Bricks (SiO2, Al2O3, and Fe2O3) Used as Building Materials

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

Bogard, James S; Espinosa Garcia, Guillermo

2007-01-01

Quartz is the most common mineral in our environment. It is found in granite, hydrothermal veins and volcanic rocks, as well as in sedimentary deposits derived from such solid materials. These sediments are also made into building materials, such as bricks and pottery. Thus the potential use of a dose reconstruction technique based on quartz grains is enormous, whether as a dating tool in archaeology and quaternary geology, or in nuclear accident dosimetry. This work describes the Optically Stimulated Luminescence (OSL) response of red brick to ionizing radiation. The bricks, from the state of Puebla, Mexico, represent another class ofmore » materials that can be used in retrospective dosimetry following nuclear or radiological incidents. The chemical composition of fifteen bricks (three samples from five different brick factories) was determined, using energy dispersive spectroscopy (EDS), be primarily SiO{sub 2}, Al{sub 2}O{sub 3} and Fe{sub 2}O{sub 3} and is believed to be representative for this common building material. Individual aliquots from these bricks were powdered in agate mortars and thermally annealed. Replicate samples of the aliquots were then irradiated with beta particles from a sealed source of {sup 90}Sr/{sup 90}Y. The OSL response was measured with a Daybreak Model 2200 High-Capacity OSL Reader System. We present here for this material the characteristic OSL response to beta particles; the reproducibility of the OSL response; the linearity of the response in the dose range 0.47 Gy to 47 Gy; and the fading characteristics.« less

Determining the use of prophylactic antibiotics in breast cancer surgeries: a survey of practice

PubMed Central

2012-01-01

Background Prophylactic antibiotics (PAs) are beneficial to breast cancer patients undergoing surgery because they prevent surgical site infection (SSI), but limited information regarding their use has been published. This study aims to determine the use of PAs prior to breast cancer surgery amongst breast surgeons in Colombia. Methods An online survey was distributed amongst the breast surgeon members of the Colombian Association of Mastology, the only breast surgery society of Colombia. The scope of the questions included demographics, clinical practice characteristics, PA prescription characteristics, and the use of PAs in common breast surgical procedures. Results The survey was distributed amongst eighty-eight breast surgeons of whom forty-seven responded (response rate: 53.4%). Forty surgeons (85.1%) reported using PAs prior to surgery of which >60% used PAs during mastectomy, axillary lymph node dissection, and/or breast reconstruction. Surgeons reported they targeted the use of PAs in cases in which patients had any of the following SSI risk factors: diabetes mellitus, drains in situ, obesity, and neoadjuvant therapy. The distribution of the self-reported PA dosing regimens was as follows: single pre-operative fixed-dose (27.7%), single preoperative dose followed by a second dose if the surgery was prolonged (44.7%), single preoperative dose followed by one or more postoperative doses for >24 hours (10.6%), and single preoperative weight-adjusted dose (2.1%). Conclusion Although this group of breast surgeons is aware of the importance of PAs in breast cancer surgery there is a discrepancy in how they use it, specifically with regards to prescription and timeliness of drug administration. Our findings call for targeted quality-improvement initiatives, such as standardized national guidelines, which can provide sufficient evidence for all stakeholders and therefore facilitate best practice medicine for breast cancer surgery. PMID:22937833

Determining the use of prophylactic antibiotics in breast cancer surgeries: a survey of practice.

PubMed

Acuna, Sergio A; Angarita, Fernando A; Escallon, Jaime; Tawil, Mauricio; Torregrosa, Lilian

2012-08-31

Prophylactic antibiotics (PAs) are beneficial to breast cancer patients undergoing surgery because they prevent surgical site infection (SSI), but limited information regarding their use has been published. This study aims to determine the use of PAs prior to breast cancer surgery amongst breast surgeons in Colombia. An online survey was distributed amongst the breast surgeon members of the Colombian Association of Mastology, the only breast surgery society of Colombia. The scope of the questions included demographics, clinical practice characteristics, PA prescription characteristics, and the use of PAs in common breast surgical procedures. The survey was distributed amongst eighty-eight breast surgeons of whom forty-seven responded (response rate: 53.4%). Forty surgeons (85.1%) reported using PAs prior to surgery of which >60% used PAs during mastectomy, axillary lymph node dissection, and/or breast reconstruction. Surgeons reported they targeted the use of PAs in cases in which patients had any of the following SSI risk factors: diabetes mellitus, drains in situ, obesity, and neoadjuvant therapy. The distribution of the self-reported PA dosing regimens was as follows: single pre-operative fixed-dose (27.7%), single preoperative dose followed by a second dose if the surgery was prolonged (44.7%), single preoperative dose followed by one or more postoperative doses for >24 hours (10.6%), and single preoperative weight-adjusted dose (2.1%). Although this group of breast surgeons is aware of the importance of PAs in breast cancer surgery there is a discrepancy in how they use it, specifically with regards to prescription and timeliness of drug administration. Our findings call for targeted quality-improvement initiatives, such as standardized national guidelines, which can provide sufficient evidence for all stakeholders and therefore facilitate best practice medicine for breast cancer surgery.

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

Medina, L; Adrada, A; Filipuzzi, M

Purpose: The purpose of this paper is to characterize EBT3 using two types of scanner, analyzing the factors of influence of each dosimetry system. Methods: The film used in this study was GAFCHROMIC EBT3, the films were exposed at a dose range between 0Gy a 9Gy in a solid water phantom, SSD=100cm, 5cm depth and perpendicularly to the 6MV photon beam generated by a Novalis TX linear accelerator equipped with an HDMLC. A Farmer type ion chamber TN30013 (PTW) was used to determine the dose delivered to the film. The films were digitized with a scanner EPSON expression 10000XL andmore » the VIDAR DosimetryPro Adventage RED. Software RIT113v6.1 was used for construction of the calibration curve and analysis. The film characteristics investigated were: response at different dose levels, sensitivity to orientation and side and resolution through the results of the spatial response function by analyzing a step pattern. Additionally, 20 IMRT treatment fields were measured with both scanner and compared with calculated dose using gamma index analysis (3%-3mm). Results: The OD obtained for dose level 2Gy in the orientation portrait of the film on the scanner EPSON is (0,222±0,19) and for Vidar RED (0,252±0,10) and landscape is for EPSON (0,211±0,25) and for Vidar RED (0,250±0,11) . The orientation dependence with respect to film side is about 0,09% for EPSON and about 0.03% for VIDAR. The spatial response function increase in response to the Gaussian function FWHM EPSON scanner (0.18mm) compared with VIDAR scanner function (less than 0.06mm) was observed. We analyzed 20 total plan dose distributions the number of pixels with gamma>1 (3%-3mm) was 0.7%±1.2 [0.1%; 2.82%] for EBT3-VIDAR y 2%±2.9 [0.2%; 3.5%] for EBT3-EPSON. Conclusion: VIDAR scanner shows better sensitivity. EBT3 film shows a different response between portrait and landscape orientation. Step pattern is better reproduce by VIDAR scanner.« less

Neurogenic Effects of Low-Dose Whole-Body HZE (Fe) Ion and Gamma Irradiation.

PubMed

Sweet, Tara B; Hurley, Sean D; Wu, Michael D; Olschowka, John A; Williams, Jacqueline P; O'Banion, M Kerry

2016-12-01

Understanding the dose-toxicity profile of radiation is critical when evaluating potential health risks associated with natural and man-made sources in our environment. The purpose of this study was to evaluate the effects of low-dose whole-body high-energy charged (HZE) iron (Fe) ions and low-energy gamma exposure on proliferation and differentiation of adult-born neurons within the dentate gyrus of the hippocampus, cells deemed to play a critical role in memory regulation. To determine the dose-response characteristics of the brain to whole-body Fe-ion vs. gamma-radiation exposure, C57BL/6J mice were irradiated with 1 GeV/n Fe ions or a static 137 Cs source (0.662 MeV) at doses ranging from 0 to 300 cGy. The neurogenesis was analyzed at 48 h and one month postirradiation. These experiments revealed that whole-body exposure to either Fe ions or gamma radiation leads to: 1. An acute decrease in cell division within the dentate gyrus of the hippocampus, detected at doses as low as 30 and 100 cGy for Fe ions and gamma radiation, respectively; and 2. A reduction in newly differentiated neurons (DCX immunoreactivity) at one month postirradiation, with significant decreases detected at doses as low as 100 cGy for both Fe ions and gamma rays. The data presented here contribute to our understanding of brain responses to whole-body Fe ions and gamma rays and may help inform health-risk evaluations related to systemic exposure during a medical or radiologic/nuclear event or as a result of prolonged space travel.

Effects of melatonin on 2-deoxy-(1-/sup 14/C)glucose uptake within rat suprachiasmatic nucleus

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

Cassone, V.M.; Roberts, M.H.; Moore, R.Y.

Previously, we have demonstrated that metabolic activity, shown by autoradiographic determination of 2-deoxy-(1-/sup 14/C)glucose (2-DG) uptake, within the rat hypothalamic suprachiasmatic nuclei (SCN) was inhibited by subcutaneous injection of 1 mg/kg melatonin. To determine whether this effect was specific to a particular time of day, the effects of melatonin on 2-DG uptake were studied in several hypothalamic areas, including the SCN, supraoptic nuclei (SON), lateral hypothalamic area (LHA), and anterior hypothalamic area (AHA) every 4 h throughout the circadian day. In a second experiment, the effects of different melatonin doses were studied at the time of day at which melatoninmore » had its maximal effect to determine the dose-response relationship of melatonin-induced inhibition of SCN 2-DG uptake. The data indicate that melatonin inhibited 2-DG uptake in the SCN alone at one time of day, primarily at circadian time (CT) 6 and CT10, 2-6 h before subjective dusk, and secondarily at CT22, just before subjective dawn. This effect was dose dependent with a 50% effective dose of 1.49 +/- 2.30 micrograms/kg. The temporal and dose-response characteristics of these effects are similar to those characterizing the entraining effects of melatonin on circadian patterns of locomotion and drinking.« less

Performance improvement of pentacosa-diynoic acid label dosimeter for radiation processing technology

NASA Astrophysics Data System (ADS)

Abdel-Fattah, A. A.; Soliman, Y. S.

2017-12-01

A radiation sensitive material, 10,12-pentacosa-diynoic acid (PCDA), was incorporated into polyvinyl butyral (PVB) films to develop indicators/dosimeters for blood and food irradiation. The present study aims to improve the dosimetric performance of these previously prepared dosimeters and to extend their shelf life by the combination of a radical scavenger, propyl gallate (PG), and a UV absorber, tinuvin-p (TP). The X-ray diffraction (XRD) patterns of the dosimeters were analysed and their dosimetric characteristics were investigated by specular reflectance in the visible spectrum range of 400-700 nm. Upon irradiation, the films turn blue exhibiting two main bands around 670 and 620 nm. Their dose-response functions were fitted by a double exponential growth, 5 parameters, equation. Irradiation temperature influences the dosimeter response at 670 nm without causing thermochromic transition up to 50 °C in poly-PCDA. The useful dose range is 5-4000 Gy depending on the wavelengths of analysis and PCDA content in the films. The overall uncertainty of dose measurement is less than 6% at 2σ.

Dosimetric characteristics of the University of Washington Clinical Neutron Therapy System

NASA Astrophysics Data System (ADS)

Moffitt, Gregory B.; Stewart, Robert D.; Sandison, George A.; Goorley, John T.; Argento, David C.; Jevremovic, Tatjana; Emery, Robert; Wootton, Landon S.; Parvathaneni, Upendra; Laramore, George E.

2018-05-01

The University of Washington (UW) Clinical Neutron Therapy System (CNTS), which generates high linear energy transfer fast neutrons through interactions of 50.5 MeV protons incident on a Be target, has depth-dose characteristics similar to 6 MV x-rays. In contrast to the fixed beam angles and primitive blocking used in early clinical trials of neutron therapy, the CNTS has a gantry with a full 360° of rotation, internal wedges, and a multi-leaf collimator (MLC). Since October of 1984, over 3178 patients have received conformal neutron therapy treatments using the UW CNTS. In this work, the physical and dosimetric characteristics of the CNTS are documented through comparisons of measurements and Monte Carlo simulations. A high resolution computed tomography scan of the model 17 ionization chamber (IC-17) has also been used to improve the accuracy of simulations of the absolute calibration geometry. The response of the IC-17 approximates well the kinetic energy released per unit mass (KERMA) in water for neutrons and photons for energies from a few tens of keV up to about 20 MeV. Above 20 MeV, the simulated model 17 ion chamber response is 20%–30% higher than the neutron KERMA in water. For CNTS neutrons, simulated on- and off-axis output factors in water match measured values within ~2%  ±  2% for rectangular and irregularly shaped field with equivalent square areas ranging in a side dimension from 2.8 cm to 30.7 cm. Wedge factors vary by less than 1.9% of the measured dose in water for clinically relevant field sizes. Simulated tissue maximum ratios in water match measured values within 3.3% at depths up to 20 cm. Although the absorbed dose for water and adipose tissue are within 2% at a depth of 1.7 cm, the absorbed dose in muscle and bone can be as much as 12 to 40% lower than the absorbed dose in water. The reported studies are significant from a historical perspective and as additional validation of a new tool for patient quality assurance and as an aid in ongoing efforts to clinically implement advanced treatment techniques, such as intensity modulated neutron therapy, at the UW.

Pharmacokinetic–pharmacodynamic modelling in anaesthesia

PubMed Central

Gambús, Pedro L; Trocóniz, Iñaki F

2015-01-01

Anaesthesiologists adjust drug dosing, administration system and kind of drug to the characteristics of the patient. They then observe the expected response and adjust dosing to the specific requirements according to the difference between observed response, expected response and the context of the surgery and the patient. The approach above can be achieved because on one hand quantification technology has made significant advances allowing the anaesthesiologist to measure almost any effect by using noninvasive, continuous measuring systems. On the other the knowledge on the relations between dosing, concentration, biophase dynamics and effect as well as detection of variability sources has been achieved as being the benchmark specialty for pharmacokinetic–pharmacodynamic (PKPD) modelling. The aim of the review is to revisit the most common PKPD models applied in the field of anaesthesia (i.e. effect compartmental, turnover, drug–receptor binding and drug interaction models) through representative examples. The effect compartmental model has been widely used in this field and there are multiple applications and examples. The use of turnover models has been limited mainly to describe respiratory effects. Similarly, cases in which the dissociation process of the drug–receptor complex is slow compared with other processes relevant to the time course of the anaesthetic effect are not frequent in anaesthesia, where in addition to a rapid onset, a fast offset of the response is required. With respect to the characterization of PD drug interactions different response surface models are discussed. Relevant applications that have changed the way modern anaesthesia is practiced are also provided. PMID:24251846

Predictions of Leukemia Risks to Astronauts from Solar Particle Events

NASA Technical Reports Server (NTRS)

Cucinotta, F. A.; Atwell, W.; Kim, M. Y.; George, K. A.; Ponomarev, A.; Nikjoo, H.; Wilson, J. W.

2006-01-01

Leukemias consisting of acute and chronic myeloid leukemia and acute lymphatic lymphomas represent the earliest cancers that appear after radiation exposure, have a high lethality fraction, and make up a significant fraction of the overall fatal cancer risk from radiation for adults. Several considerations impact the recommendation of a preferred model for the estimation of leukemia risks from solar particle events (SPE's): The BEIR VII report recommends several changes to the method of calculation of leukemia risk compared to the methods recommended by the NCRP Report No. 132 including the preference of a mixture model with additive and multiplicative components in BEIR VII compared to the additive transfer model recommended by NCRP Report No. 132. Proton fluences and doses vary considerably across marrow regions because of the characteristic spectra of primary solar protons making the use of an average dose suspect. Previous estimates of bone marrow doses from SPE's have used an average body-shielding distribution for marrow based on the computerized anatomical man model (CAM). We have developed an 82-point body-shielding distribution that faithfully reproduces the mean and variance of SPE doses in the active marrow regions (head and neck, chest, abdomen, pelvis and thighs) allowing for more accurate estimation of linear- and quadratic-dose components of the marrow response. SPE's have differential dose-rates and a pseudo-quadratic dose response term is possible in the peak-flux period of an event. Also, the mechanistic basis for leukemia risk continues to improve allowing for improved strategies in choosing dose-rate modulation factors and radiation quality descriptors. We make comparisons of the various choices of the components in leukemia risk estimates in formulating our preferred model. A major finding is that leukemia could be the dominant risk to astronauts for a major solar particle event.

Action spectra for photosynthetic inhibition

NASA Technical Reports Server (NTRS)

Caldwell, M. M.; Flint, S.; Camp, L. B.

1981-01-01

The ultraviolet action spectrum for photosynthesis inhibition was determined to fall between that of the general DNA action spectrum and the generalized plant action spectrum. The characteristics of this action spectrum suggest that a combination of pronounced increase in effectiveness with decreasing wavelength, substantial specificity for the UV-B waveband, and very diminished response in the UV-A waveband result in large radiation amplification factors when the action spectra are used as weighting functions. Attempted determination of dose/response relationships for leaf disc inhibition provided inconclusive data from which to deconvolute an action spectrum.

A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors.

PubMed

Aghajanian, Carol; Bell-McGuinn, Katherine M; Burris, Howard A; Siu, Lillian L; Stayner, Lee-Ann; Wheler, Jennifer J; Hong, David S; Kurkjian, Carla; Pant, Shubham; Santiago-Walker, Ademi; Gauvin, Jennifer L; Antal, Joyce M; Opalinska, Joanna B; Morris, Shannon R; Infante, Jeffrey R

2018-04-03

Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.

Functional Characterization of 5-HT1B Receptor Drugs in Nonhuman Primates Using Simultaneous PET-MR.

PubMed

Hansen, Hanne D; Mandeville, Joseph B; Sander, Christin Y; Hooker, Jacob M; Catana, Ciprian; Rosen, Bruce R; Knudsen, Gitte M

2017-11-01

In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT 1B receptor (5-HT 1B R) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates ( n = 3), we used positron emission tomography (PET) imaging with the radioligand [ 11 C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT 1B R occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT 1B R partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT 1B R occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT 1B R densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood-brain barrier-permeable 5-HT 1B R agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT 1B R cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT 1B R and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin. SIGNIFICANCE STATEMENT We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT 1B receptor binding and function and determined blood-brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial and temporal effects on brain hemodynamics provide information about pharmacologically driven downstream CNS drug effects; the brain hemodynamic response shows characteristic dose-related effects that differ depending on agonistic or antagonistic drug characteristics and on local 5-HT 1B receptor density. The technique lends itself to a comprehensive in vivo investigation and understanding of drugs' effects in the brain. Copyright © 2017 the authors 0270-6474/17/3710671-08$15.00/0.

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis.

PubMed

Senthivel, Vivek Raj; Sturrock, Marc; Piedrafita, Gabriel; Isalan, Mark

2016-12-16

Nonlinear responses to signals are widespread natural phenomena that affect various cellular processes. Nonlinearity can be a desirable characteristic for engineering living organisms because it can lead to more switch-like responses, similar to those underlying the wiring in electronics. Steeper functions are described as ultrasensitive, and can be applied in synthetic biology by using various techniques including receptor decoys, multiple co-operative binding sites, and sequential positive feedbacks. Here, we explore the inherent non-linearity of a biological signaling system to identify functions that can potentially be exploited using cell genome engineering. For this, we performed genome-wide transcription profiling to identify genes with ultrasensitive response functions to Hepatocyte Growth Factor (HGF). We identified 3,527 genes that react to increasing concentrations of HGF, in Madin-Darby canine kidney (MDCK) cells, grown as cysts in 3D collagen cell culture. By fitting a generic Hill function to the dose-responses of these genes we obtained a measure of the ultrasensitivity of HGF-responsive genes, identifying a subset with higher apparent Hill coefficients (e.g. MMP1, TIMP1, SNORD75, SNORD86 and ERRFI1). The regulatory regions of these genes are potential candidates for future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signalling.

Sensitivity of species to chemicals: dose-response characteristics for various test types (coldbloodedLC50, cold-blooded LR50 and warm-blooded LD50) and modes of action

EPA Science Inventory

While sensitivity of model species to common toxicants has been addressed, a systematic analysis of inter-species variability for different test types, modes of action and species is as yet lacking. Hence, the aim of the present study was to identify similarities and differences ...

Thermoluminescence characteristics of flat optical fiber in radiation dosimetry under different electron irradiation conditions

NASA Astrophysics Data System (ADS)

Alawiah, A.; Intan, A. M.; Bauk, S.; Abdul-Rashid, H. A.; Yusoff, Z.; Mokhtar, M. R.; Wan Abdullah, W. S.; Mat Sharif, K. A.; Mahdiraji, G. A.; Mahamd Adikan, F. R.; Tamchek, N.; Noor, N. M.; Bradley, D. A.

2013-05-01

Thermoluminescence (TL) flat optical fibers (FF) have been proposed as radiation sensor in medical dosimetry for both diagnostic and radiotherapy applications. A flat optical fiber with nominal dimensions of (3.226 × 3.417 × 0.980) mm3 contains pure silica SiO2 was selected for this research. The FF was annealed at 400°C for 1 h before irradiated. Kinetic parameters and dosimetric glow curve of TL response were studied in FF with respect to electron irradiation of 6 MeV, 15 MeV and 21 MeV using linear accelerator (LINAC) in the dose range of 2.0-10.0 Gy. The TL response was read using a TLD reader Harshaw Model 3500. The Time-Temperature-Profile (TTP) of the reader used includes; initial preheat temperature of 80°C, maximum readout temperature is 400°C and the heating rate of 30°Cs-1. The proposed FF shows excellent linear radiation response behavior within the clinical relevant dose range for all of these energies, good reproducibility, independence of radiation energy, independence of dose rate and exhibits a very low thermal fading. From these results, the proposed FF can be used as radiation dosimeter and favorably compares with the widely used of LiF:MgTi dosimeter in medical radiotherapy application.

Response of optically stimulated luminescence dosimeters subjected to X-rays in diagnostic energy range

NASA Astrophysics Data System (ADS)

Musa, Y.; Hashim, S.; Karim, M. K. A.; Bakar, K. A.; Ang, W. C.; Salehhon, N.

2017-05-01

The use of optically stimulated luminescence (OSL) for dosimetry applications has recently increased considerably due to availability of commercial OSL dosimeters (nanoDots) for clinical use. The OSL dosimeter has a great potential to be used in clinical dosimetry because of its prevailing advantages in both handling and application. However, utilising nanoDot OSLDs for dose measurement in diagnostic radiology can only be guaranteed when the performance and characteristics of the dosimeters are apposite. In the present work, we examined the response of commercially available nanoDot OSLD (Al2O3:C) subjected to X-rays in general radiography. The nanoDots response with respect to reproducibility, dose linearity and signal depletion were analysed using microStar reader (Landauer, Inc., Glenwood, IL). Irradiations were performed free-in-air using 70, 80 and 120 kV tube voltages and tube currents ranging from 10 - 100 mAs. The results showed that the nanoDots exhibit good linearity and reproducibility when subjected to diagnostic X-rays, with coefficient of variations (CV) ranging between 2.3% to 3.5% representing a good reproducibility. The results also indicated average of 1% signal reduction per readout. Hence, the nanoDots showed a promising potential for dose measurement in general X-ray procedure.

Characteristics of ethanol-induced behavioral sensitization in rats: Molecular mediators and cross-sensitization between ethanol and cocaine.

PubMed

Xu, Shijie; Kang, Ung Gu

2017-09-01

Repeated exposure to drugs of abuse can induce a progressive increase in locomotor activity, known as behavioral sensitization. However, little is known about behavioral sensitization to ethanol. We examined whether ethanol could induce behavioral sensitization and investigated several molecular changes accompanying sensitization. We also assessed whether "cross-sensitization" occurred between ethanol and cocaine, another abused drug. Ethanol-induced sensitization was examined in rats after ethanol treatment (0.5 or 2g/kg) for 15days. The biochemical effects of low- or high-dose ethanol were examined in terms of N-methyl-d-aspartate (NMDA) receptor subunit phosphorylation or expression. Neuronal activity after ethanol treatment was assessed by measuring the level of early growth response (Egr-1) expression. Ethanol-induced behavioral sensitization was observed at the low dose (0.5g/kg) but not the high dose (2g/kg). Although acute treatment with the sensitizing dose of ethanol robustly increased Egr-1 protein and mRNA levels, the expression and phosphorylation of NMDA receptor subunits were not affected. The biochemical responses to ethanol seemed to be enhanced in ethanol-sensitized animals. Cross-sensitization between ethanol and cocaine was observed, which supports the hypothesis that there are commonalities among substances in the pathophysiology of substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

[Therapeutic efficacy of nootropil different doses in attention deficit hyperactivity disorder].

PubMed

Zavadenko, N N; Suvorinova, S Iu

2004-01-01

Attention Deficit Hyperactivity Disorder (ADHD) is the most common cause of behavioral and learning problems in childhood. Therapeutic efficiency of nootropil (piracetam) in two different doses has been evaluated in the open control study of 80 children with ADHD, 70 boys and 10 girls, aged 6-11 years, being divided into 3 groups. Two groups received nootropil, as a monotherapy, for a month: 1st group (30 patients)--in the dosage of 70 mg/kg daily and 2nd group (30 patients)--40 mg/kg daily orally. The control group of 20 patients did not receive any treatment. All children were examined twice with one month interval. A procedure of assessment included of structured questionnaire to parents, neurological examination with scored evaluation of subtle signs and psychological testing. Nootropil therapy in ADHD children resulted in the improvement of behavioral characteristics, motor coordination as well as continuous, selective and divided attention. A response rate was 60% in patients received 70 mg/kg of nootropil and 43% for nootropil dosage of 40 mg/kg. The results of the study suggest more considerable positive therapeutic effects of nootropil higher dose on behavioral, motor and attention characteristics in children with ADHD.

Dose and dose rate effects of whole-body gamma-irradiation: II. Hematological variables and cytokines

NASA Technical Reports Server (NTRS)

Gridley, D. S.; Pecaut, M. J.; Miller, G. M.; Moyers, M. F.; Nelson, G. A.

2001-01-01

The goal of part II of this study was to evaluate the effects of gamma-radiation on circulating blood cells, functional characteristics of splenocytes, and cytokine expression after whole-body irradiation at varying total doses and at low- and high-dose-rates (LDR, HDR). Young adult C57BL/6 mice (n = 75) were irradiated with either 1 cGy/min or 80 cGy/min photons from a 60Co source to cumulative doses of 0.5, 1.5, and 3.0 Gy. The animals were euthanized at 4 days post-exposure for in vitro assays. Significant dose- (but not dose-rate-) dependent decreases were observed in erythrocyte and blood leukocyte counts, hemoglobin, hematocrit, lipopolysaccharide (LPS)-induced 3H-thymidine incorporation, and interleukin-2 (IL-2) secretion by activated spleen cells when compared to sham-irradiated controls (p < 0.05). Basal proliferation of leukocytes in the blood and spleen increased significantly with increasing dose (p < 0.05). Significant dose rate effects were observed only in thrombocyte counts. Plasma levels of transforming growth factor-beta 1 (TGF-beta 1) and splenocyte secretion of tumor necrosis factor-alpha (TNF-alpha) were not affected by either the dose or dose rate of radiation. The data demonstrate that the responses of blood and spleen were largely dependent upon the total dose of radiation employed and that an 80-fold difference in the dose rate was not a significant factor in the great majority of measurements.

Accurate EPR radiosensitivity calibration using small sample masses

NASA Astrophysics Data System (ADS)

Hayes, R. B.; Haskell, E. H.; Barrus, J. K.; Kenner, G. H.; Romanyukha, A. A.

2000-03-01

We demonstrate a procedure in retrospective EPR dosimetry which allows for virtually nondestructive sample evaluation in terms of sample irradiations. For this procedure to work, it is shown that corrections must be made for cavity response characteristics when using variable mass samples. Likewise, methods are employed to correct for empty tube signals, sample anisotropy and frequency drift while considering the effects of dose distribution optimization. A demonstration of the method's utility is given by comparing sample portions evaluated using both the described methodology and standard full sample additive dose techniques. The samples used in this study are tooth enamel from teeth removed during routine dental care. We show that by making all the recommended corrections, very small masses can be both accurately measured and correlated with measurements of other samples. Some issues relating to dose distribution optimization are also addressed.

Research design features and patient characteristics associated with the outcome of antidepressant clinical trials.

PubMed

Khan, Arif; Kolts, Russell L; Thase, Michael E; Krishnan, K Ranga Rama; Brown, Walter

2004-11-01

The authors examined which, if any, research design features and patient characteristics would significantly differ between successful and unsuccessful antidepressant trials. Clinical trial data were reviewed for nine antidepressants approved by the Food and Drug Administration between 1985 and 2000. From the antidepressant research programs on these medications, 52 clinical trials were included in the study. The authors evaluated trial design features, patient characteristics, and difference in response between placebo and antidepressant. Nine trial design features and patient characteristics were present in the research programs for all nine of the antidepressants. The severity of depressive symptoms before patient randomization, the dosing schedule (flexible versus fixed), the number of treatment arms, and the percentage of female patients were significantly associated with the difference in response to antidepressant and placebo. The duration of the antidepressant trial, number of patients per treatment arm, number of sites, and mean age of the patients were similar in successful trials (with a greater antidepressant-placebo difference) and less successful trials (with a smaller antidepressant-placebo difference). These findings may help in the design of future antidepressant trials.

On the development of a VIPARnd radiotherapy 3D polymer gel dosimeter

NASA Astrophysics Data System (ADS)

Kozicki, Marek; Jaszczak, Malwina; Maras, Piotr; Dudek, Mariusz; Cłapa, Marian

2017-02-01

This work presents an improvement of the VIPARnd (‘nd’ stands for ‘normoxic, double’, or VIP) polymer gel dosimeter. The gel composition was altered by increasing the concentration of the monomeric components, N-vinylpyrrolidone (NVP) and N,N‧-methylenebisacrylamide (MBA), in co-solvent solutions. The optimal composition (VIPARCT, where ‘CT’ stands for computed tomography, or VIC) comprised: 17% NVP, 8% MBA, 12% t-BuOH, 7.5% gelatine, 0.007% ascorbic acid, 0.0008% CuSO4  ×  5H2O and 0.02% hydroquinone. The following characteristics of VIC were achieved: (i) linear dose range of 0.9_30 Gy, (ii) saturation for radiation doses of over 50 Gy, (iii) threshold dose of about 0.5 Gy, (iv) dose sensitivity of 0.171 Gy-1 s-1, which is roughly 2.2 times higher than that of VIP (for nuclear magnetic resonance measurements). It was also found that VIC is dose- rate-independent, and its dose response does not alter if the radiation source is changed from electrons to photons for external beam radiotherapy. The gel responded similarly to irradiation with small changes in radiation energy but was sensitive to larger energy changes. The VIC gel retained temporal stability from 20 h until at least 10 d after irradiation, whereas spatial stability was retained from 20 h until at least 6 d after irradiation. The scheme adopted for VIC manufacturing yields repeatable gels in terms of radiation dose response. The VIC was also shown to perform better than VIP using x-ray computed tomography as a readout method; the dose sensitivity of VIC (0.397 HU Gy-1) was 1.5 times higher than that of VIP. Also, the dose resolution of VIC was better than that of VIP in the whole dose range examined.

Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C.

PubMed

Rodriguez-Torres, Maribel; Jeffers, Lennox J; Sheikh, Muhammad Y; Rossaro, Lorenzo; Ankoma-Sey, Victor; Hamzeh, Fayez M; Martin, Paul

2009-01-15

Race has been shown to be a factor in the response to therapy for hepatitis C virus (HCV) infection, and limited data suggest that ethnic group may be as well; however, Latinos and other ethnic subpopulations have been underrepresented in clinical trials. We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously. In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 microg per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded. Baseline characteristics were similar in the Latino and non-Latino groups, although higher proportions of Latino patients were 40 years of age or younger, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 27 or more than 30, and had cirrhosis. The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). The absence of HCV RNA in serum was more frequent in non-Latino whites at week 4 (P=0.045) and throughout the treatment period (P<0.001 for all other comparisons). Latino or non-Latino background was an independent predictor of the rate of sustained virologic response in an analysis adjusted for baseline differences in BMI, cirrhosis, and other characteristics. Adherence to treatment did not differ significantly between the two groups. The numbers of patients with adverse events and dose modifications were similar in the two groups, but fewer Latino patients discontinued therapy because of adverse events. Treatment with peginterferon alfa-2a and ribavirin for 48 weeks resulted in rates of sustained virologic response among patients infected with HCV genotype 1 that were lower among Latino whites than among non-Latino whites. Strategies to improve the sustained virologic response in Latinos are needed. (ClinicalTrials.gov number, NCT00107653.) 2009 Massachusetts Medical Society

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.

A phantom-based JAFROC observer study of two CT reconstruction methods: the search for optimisation of lesion detection and effective dose

NASA Astrophysics Data System (ADS)

Thompson, John D.; Chakraborty, Dev P.; Szczepura, Katy; Vamvakas, Ioannis; Tootell, Andrew; Manning, David J.; Hogg, Peter

2015-03-01

Purpose: To investigate the dose saving potential of iterative reconstruction (IR) in a computed tomography (CT) examination of the thorax. Materials and Methods: An anthropomorphic chest phantom containing various configurations of simulated lesions (5, 8, 10 and 12mm; +100, -630 and -800 Hounsfield Units, HU) was imaged on a modern CT system over a tube current range (20, 40, 60 and 80mA). Images were reconstructed with (IR) and filtered back projection (FBP). An ATOM 701D (CIRS, Norfolk, VA) dosimetry phantom was used to measure organ dose. Effective dose was calculated. Eleven observers (15.11+/-8.75 years of experience) completed a free response study, localizing lesions in 544 single CT image slices. A modified jackknife alternative free-response receiver operating characteristic (JAFROC) analysis was completed to look for a significant effect of two factors: reconstruction method and tube current. Alpha was set at 0.05 to control the Type I error in this study. Results: For modified JAFROC analysis of reconstruction method there was no statistically significant difference in lesion detection performance between FBP and IR when figures-of-merit were averaged over tube current (F(1,10)=0.08, p = 0.789). For tube current analysis, significant differences were revealed between multiple pairs of tube current settings (F(3,10) = 16.96, p<0.001) when averaged over image reconstruction method. Conclusion: The free-response study suggests that lesion detection can be optimized at 40mA in this phantom model, a measured effective dose of 0.97mSv. In high-contrast regions the diagnostic value of IR, compared to FBP, is less clear.

Retrospective analysis of bendamustine and rituximab use in indolent and mantle cell non-Hodgkin lymphoma based on initial starting dose.

PubMed

Bond, David A; Huang, Ying; Ruppert, Amy S; Walker, Alison R; Dotson, Emily K; Roddy, Julianna; Blum, Kristie A; Christian, Beth A

2017-07-01

The initial dose of bendamustine, an alkylating agent used in treating indolent lymphoma (iNHL) and mantle cell lymphoma, is variable in clinical practice. 134 patients treated with bendamustine and rituximab were evaluated for starting dosage, patient characteristics, toxicities, and clinical outcome. The starting dosage ranged from 50 to 90 mg/m 2 . Lower starting dosage (<90 mg/m 2 ) was associated with relapsed disease, increased age and worse performance status (PS), histologic subtype other than follicular lymphoma, baseline renal impairment, and cytopenias. No significant difference was observed in toxicities between patients treated with 90 mg/m 2 compared with lower doses. The starting dose of 90 mg/m 2 was associated with a higher complete response rate (56% vs. 29%) and longer progression free survival (PFS) (39.5 months vs. 19.7 months). However, in a multivariable model, the higher starting dose was not associated with longer PFS in those with similar age, histology, PS, and number of prior therapies.

Mobile phone use, school electromagnetic field levels and related symptoms: a cross-sectional survey among 2150 high school students in Izmir.

PubMed

Durusoy, Raika; Hassoy, Hür; Özkurt, Ahmet; Karababa, Ali Osman

2017-06-02

Health outcomes of electromagnetic fields (EMF) from mobile phones and their base stations are of concern. Conducting multidisciplinary research, targeting children and exploring dose-response are recommended. Our objectives were to describe the mobile phone usage characteristics of high school students and to explore the association between mobile phone usage characteristics, high school EMF levels and self-reported symptoms. This cross-sectional study's data were collected by a survey questionnaire and by measuring school EMF levels between November 2009 and April 2011. A sample size of 2530 was calculated from a total of 20,493 students in 26 high schools and 2150 (85.0%) were included in the analysis. The frequencies of 23 symptoms were questioned and analysed according to 16 different aspects of mobile phone use and school EMF levels, exploring also dose-response. School EMF levels were measured with Aaronia Spectran HF-4060 device. Chi square and trend tests were used for univariate and logistic regression was used for multivariate analyses. Among participants, 2021 (94.0%) were using mobile phones and 129 (6.0%) were not. Among users, 49.4% were speaking <10 min and 52.2% were sending/receiving 75 or more messages per day. Headache, fatigue and sleep disturbances were observed respectively 1.90 (95% CI 1.30-2.77), 1.78 (1.21-2.63) and 1.53 (1.05-2.21) times more among mobile phone users. Dose-response relationships were observed especially for the number of calls per day, total duration of calls per day, total number of text messages per day, position and status of mobile phone at night and making calls while charging as exposures and headache, concentration difficulties, fatigue and sleep disturbances as general symptoms and warming of the ear and flushing as local symptoms. We found an association between mobile phone use and especially headache, concentration difficulties, fatigue, sleep disturbances and warming of the ear showing also dose-response. We have found limited associations between vicinity to base stations and some general symptoms; however, we did not find any association with school EMF levels. Decreasing the numbers of calls and messages, decreasing the duration of calls, using earphones, keeping the phone away from the head and body and similar precautions might decrease the frequencies or prevalence of the symptoms.

Effect of Admission Oral Diuretic Dose on Response to Continuous versus Bolus Intravenous Diuretics in Acute Heart Failure: An Analysis from DOSE-AHF

PubMed Central

Shah, Ravi V.; McNulty, Steven; O'Connor, Christopher M.; Felker, G. Michael; Braunwald, Eugene; Givertz, Michael M.

2014-01-01

Background Results from the Diuretic Optimization Strategies in Acute Heart Failure (DOSE-AHF) study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in AHF. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function, and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. Methods DOSE-AHF randomized 308 patients within 24 hours of admission to high vs. low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs. continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n=177) versus low-dose (<120 mg furosemide equivalent, n=131) outpatient diuretics. Results Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P=.01), and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P=0.01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted HR=1.08 per 20-mg increment in dose, 95% CI 1.01–1.16, P=.03). Conclusions In acute HF, patients on higher diuretic doses have greater disease severity, and may benefit from an initial bolus strategy. PMID:23194486

Treatment Patterns and Early Outcomes of ALK-Positive Non-Small Cell Lung Cancer Patients Receiving Ceritinib: A Chart Review Study.

PubMed

Bendaly, Edmond; Dalal, Anand A; Culver, Kenneth; Galebach, Philip; Bocharova, Iryna; Foster, Rebekah; Sasane, Medha; Macalalad, Alexander R; Guérin, Annie

2017-05-01

This study aimed to provide the first real-world description of the characteristics, treatments, dosing patterns, and early outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC) who received ceritinib in US clinical practice. US oncologists provided data from medical charts of adult patients diagnosed with locally advanced or metastatic ALK-positive NSCLC who received ceritinib following crizotinib. Patient characteristics, treatment patterns, ceritinib dosing, early outcomes, and occurrence of gastrointestinal adverse events (AEs) by dose and instructions on food intake were assessed, and Kaplan-Meier analysis was used to describe clinician-defined progression-free survival (PFS) on ceritinib. Medical charts of 58 ALK-positive NSCLC patients treated with ceritinib were reviewed (median age 63 years; 41% male; 21% with prior chemotherapy experience). At ceritinib initiation, 44 patients had multiple distant metastases, most commonly in the liver (60%), bone (53%), and brain (38%). Initial ceritinib dose varied: 71% received 750 mg, 19% 600 mg, and 10% 450 mg. Although median follow-up after ceritinib initiation was short (3.8 months), most patients achieved either a complete or partial response (69%) on ceritinib, regardless of metastatic sites present at initiation or initial dose. Median PFS on ceritinib was 12.9 months. 17% of patients had a gastrointestinal AE reported during follow-up. The majority of events occurred in patients instructed to fast; no patients instructed to take a lower dose of ceritinib with food reported gastrointestinal AEs. These early findings of ceritinib use in clinical practice suggest that ceritinib is effective at treating crizotinib-experienced ALK-positive NSCLC patients, regardless of metastatic sites or initial dose, and dosing ceritinib with food may lead to fewer gastrointestinal AEs. Future studies with larger sample size and longer follow-up are warranted, including an ongoing randomized trial to assess the gastrointestinal tolerability of ceritinib 450 and 600 mg with low-fat meals. Novartis Pharmaceutical Corporation.

The effect of well-characterized, very low-dose x-ray radiation on fibroblasts

PubMed Central

Truong, Katelyn; Bradley, Suzanne; Baginski, Bryana; Wilson, Joseph R.; Medlin, Donald; Zheng, Leon; Wilson, R. Kevin; Rusin, Matthew; Takacs, Endre

2018-01-01

The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial “pause” in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature. PMID:29300773

SU-E-T-130: Dosimetric Evaluation of Tissue Equivalent Gel Dosimeter Using Saccharide in Radiotherapy System

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

Cho, Y; Lee, D; Jung, H

2014-06-01

Purpose: In this study, the dose responses of the MAGIC gel with various concentrations and type of saccharide are examined to clarify the roles of mono and disaccharide in the polymerization process. Then we focused on the tissue equivalence and dose sensitivity of MAGIC gel dosimeters. Methods: The gel is composed of HPLC, 8% gelatin, 2 × 10-3 M L-ascorbic acid, 1.8 × 10-2 M hydroquinone, 8 × 10-5 M copper(II)sulfate and 9% methacrylic acid, new polymer gels are synthesized by adding glucose(monosaccharide), sucrose(disaccharide) and urea in the concentration range of 5∼35%. For irradiation of the gel, cesium-137 gamma-ray irradiatormore » was used, radiation dose was delivered from 5∼50 Gy. MRI images of the gel were acquired by using a 3.0 T MRI system. Results: When saccharide and urea were added, the O/C, O/N and C/N ratios agreed with those of soft tissue with 1.7%. The dose-response of glucose and sucrose gel have slope-to-intercept ratio of 0.044 and 0.283 respectively. The slope-to-ratio is one important determinant of gel sensitivity. R-square values of glucose and sucrose gel dosimeters were 0.984 and 0.994 respectively. Moreover when urea were added, the slope-to-intercept ratio is 0.044 and 0.073 respectively. R-square values of mono and disaccharide gel were 0.973 and 0.989 respectively. When a saccharide is added into the MAGIC gel dosimeter, dose sensitivity is increased. However when urea were added, dose sensitivity is slightly decreased. Conclusion: In this study, it was possible to obtain the following conclusions by looking at the dose response characteristics after adding mono-, di-saccharide and urea to a MAGIC gel dosimeter. Saccharide was a tendency of increasing dose sensitivity with disaccharide. Sa.ccharide is cost effective, safe, soft tissue equivalent, and can be used under various experimental conditions, making it a suitable dosimeter for some radiotherapy applications.« less

Neurogenic Effects of Low-Dose Whole-Body HZE (Fe) Ion and Gamma Irradiation

PubMed Central

Sweet, Tara B.; Hurley, Sean D.; Wu, Michael D.; Olschowka, John A.; Williams, Jacqueline P.; O’Banion, M. Kerry

2017-01-01

Understanding the dose-toxicity profile of radiation is critical when evaluating potential health risks associated with natural and man-made sources in our environment. The purpose of this study was to evaluate the effects of low-dose whole-body high-energy charged (HZE) iron (Fe) ions and low-energy gamma exposure on proliferation and differentiation of adult-born neurons within the dentate gyrus of the hippocampus, cells deemed to play a critical role in memory regulation. To determine the dose-response characteristics of the brain to whole-body Fe-ion vs. gamma-radiation exposure, C57BL/6J mice were irradiated with 1 GeV/n Fe ions or a static 137Cs source (0.662 MeV) at doses ranging from 0 to 300 cGy. The neurogenesis was analyzed at 48 h and one month postirradiation. These experiments revealed that whole-body exposure to either Fe ions or gamma radiation leads to: 1. An acute decrease in cell division within the dentate gyrus of the hippocampus, detected at doses as low as 30 and 100 cGy for Fe ions and gamma radiation, respectively; and 2. A reduction in newly differentiated neurons (DCX immunoreactivity) at one month postirradiation, with significant decreases detected at doses as low as 100 cGy for both Fe ions and gamma rays. The data presented here contribute to our understanding of brain responses to whole-body Fe ions and gamma rays and may help inform health-risk evaluations related to systemic exposure during a medical or radiologic/nuclear event or as a result of prolonged space travel. PMID:27905869

Somatic cell mutations at the glycophorin A locus in erythrocytes of atomic bomb survivors: Implications for radiation carcinogenesis

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

Kyoizumi, Seishi; Akiyama, Mitoshi; Tanabe, Kazumi

To clarify the relationship between somatic cell mutations and radiation exposure, the frequency of hemizygous mutant erythrocytes at the glycophorin A (GPA) locus was measured by flow cytometry for 1,226 heterozygous atomic bomb (A-bomb) survivors in HIroshima and Nagasaki. For statistical analysis, both GPA mutant frequency and radiation dose were log-transformed to normalize skewed distributions of these variables. The GPA mutant frequency increased slightly but significantly with age at testing and with the number of cigarettes smoked. Also, mutant frequency was significantly higher in males than in females even with adjustment for smoking and was higher to Hiroshima than inmore » Nagasaki. These characteristics of background GPA mutant frequency are qualitatively similar to those of background solid cancer incidence or mortality obtained from previous epidemiological studies of survivors. An analysis of the mutant frequency dose response using a descriptive model showed that the doubling dose is about 1.20 Sv [95% confidence interval (CI): 0.95-1.56], whereas the minimum dose for detecting a significant increase in mutant frequency is about 0.24 Sv (95% CI: 0.041-0.51). No significant effects of sex, city or age at the time of exposure on the dose response were detected. Interestingly, the doubling dose of the GPA mutant frequency was similar to that of solid cancer incidence in A-bomb survivors. This observation is in line with the hypothesis that radiation-induced somatic cell mutations are the major cause of excess cancer risk after radiation. 49 refs., 6 figs., 2 tabs.« less

Single-hit mechanism of tumour cell killing by radiation.

PubMed

Chapman, J D

2003-02-01

To review the relative importance of the single-hit mechanism of radiation killing for tumour response to 1.8-2.0 Gy day(-1) fractions and to low dose-rate brachytherapy. Tumour cell killing by ionizing radiation is well described by the linear-quadratic equation that contains two independent components distinguished by dose kinetics. Analyses of tumour cell survival curves that contain six or more dose points usually provide good estimates of the alpha- and beta-inactivation coefficients. Superior estimates of tumour cell intrinsic radiosensitivity are obtained when synchronized populations are employed. The characteristics of single-hit inactivation of tumour cells are reviewed and compared with the characteristics of beta-inactivation. Potential molecular targets associated with single-hit inactivation are discussed along with strategies for potentiating cell killing by this mechanism. The single-hit mechanism of tumour cell killing shows no dependence on dose-rate and, consequently, no evidence of sublethal damage repair. It is uniquely potentiated by high linear-energy-transfer radiation, exhibits a smaller oxygen enhancement ratio and exhibits a larger indirect effect by hydroxyl radicals than the beta-mechanism. alpha-inactivation coefficients vary slightly throughout interphase but mitotic cells exhibit extremely high alpha-coefficients in the range of those observed for lymphocytes and some repair-deficient cells. Evidence is accumulating to suggest that chromatin in compacted form could be a radiation-hypersensitive target associated with single-hit radiation killing. Analyses of tumour cell survival curves demonstrate that it is the single-hit mechanism (alpha) that determines the majority of cell killing after doses of 2Gy and that this mechanism is highly variable between tumour cell lines. The characteristics of single-hit inactivation are qualitatively and quantitatively distinct from those of beta-inactivation. Compacted chromatin in tumour cells should be further investigated as a radiation-hypersensitive target that could be modulated for therapeutic advantage.

Study of L-aspartic acid for its possible use as a dosimeter in the interval of 3.4-20 kGy at different irradiation temperatures

NASA Astrophysics Data System (ADS)

Meléndez-López, Adriana; Negrón-Mendoza, Alicia; Gómez-Vidales, Virginia; Uribe, Roberto M.; Ramos-Bernal, Sergio

2014-11-01

Certain commercial applications of radiation processing increase the efficiency of chemical reactions at low temperatures to decrease the free radicals in the bulk material and avoid the synergistic effects of heat. Such applications have motivated the search for a reliable, low-temperature dosimeter for use under the conditions of the irradiation process. For this purpose, polycrystalline samples of L-aspartic acid (2-aminobutanedioic acid) were irradiated with gamma rays at low temperatures and doses in the kiloGray range (3.4-64 kGy). The potential use of the aspartic acid system as a chemical dosimeter is based on the formation of stable free radicals when the amino acid is exposed to ionizing radiation. These radicals can be studied and quantified using electron spin resonance (ESR). The response curves at different temperatures show that the intensity of the ESR spectra (the five characteristic lines) depends on the dose received. The response of the dosimeter increases with increasing temperature, and this relationship is linear up to 20 kGy at 298 K. The decay characteristics show that the change in the ESR signal over time is low and reproducible. In addition, the L-aspartic acid dosimeter is easy to handle and has low cost.

Thermoluminescence properties of Yb-Tb-doped SiO2 optical fiber subject to 6 and 10 MV photon irradiation

NASA Astrophysics Data System (ADS)

Sahini, M. H.; Wagiran, H.; Hossain, I.; Saeed, M. A.; Ali, H.

2014-08-01

This paper reports thermoluminescence characteristics of thermoluminescence dosimetry 100 chips and Yb-Tb-doped optical fibers irradiated with 6 and 10 MV photons. Thermoluminescence response of both dosimeters increases over a wide photon dose range from 0.5 to 4 Gy. Yb-Tb-doped optical fibers demonstrate useful thermoluminescence properties and represent a good candidate for thermoluminescence dosimetry application with ionizing radiation. The results of this fiber have been compared with those of commercially available standard thermoluminescence dosimetry-100 media. Commercially available Yb-Tb-doped optical fibers and said standard media are found to yield a linear relationship between dose- and thermoluminescence signal, although Yb-Tb-doped optical fibers provide only 10 % of the sensitivity of thermoluminescence dosimetry-100. With better thermoluminescence characteristics such as small size (125 μm diameter), high flexibility, easy of handling and low cost, as compared to other thermoluminescence materials, indicate that commercial Yb-Tb-doped optical fiber is a promising thermoluminescence material for variety of applications.

Neurosurgical applications of ion beams

NASA Astrophysics Data System (ADS)

Fabrikant, Jacob I.; Levy, Richard P.; Phillips, Mark H.; Frankel, Kenneth A.; Lyman, John T.

1989-04-01

The program at Donner Pavilion has applied nuclear medicine research to the diagnosis and radiosurgical treatment of life-threatening intracranial vascular disorders that affect more than half a million Americans. Stereotactic heavy-charged-particle Bragg peak radiosurgery, using narrow beams of heavy ions, demonstrates superior biological and physical characteristics in brain over X-and γ-rays, viz., improved dose distribution in the Bragg peak and sharp lateral and distal borders and less scattering of the beam. Examination of CNS tissue response and alteration of cerebral blood-flow dynamics related to heavy-ion Bragg peak radiosurgery is carried out using three-dimensional treatment planning and quantitative imaging utilizing cerebral angiography, computerized tomography (CT), magnetic resonance imaging (MRI), cine-CT, xenon X-ray CT and positron emission tomography (PET). Also under examination are the physical properties of narrow heavy-ion beams for improving methods of dose delivery and dose distribution and for establishing clinical RBE/LET and dose-response relationships for human CNS tissues. Based on the evaluation and treatment with stereotactically directed narrow beams of heavy charged particles of over 300 patients, with cerebral angiography, CT scanning and MRI and PET scanning of selected patients, plus extensive clinical and neuroradiological followup, it appears that Stereotactic charged-particle Bragg peak radiosurgery obliterates intracranial arteriovenous malformations or protects against rebleeding with reduced morbidity and no mortality. Discussion will include the method of evaluation, the clinical research protocol, the Stereotactic neuroradiological preparation, treatment planning, the radiosurgery procedure and the protocol for followup. Emphasis will be placed on the neurological results, including the neuroradiological and clinical response and early and late delayed injury in brain leading to complications (including vasogenic edema, arterial occlusion, venous thrombosis and radiation necrosis). Clinical results in both children and adults will be illustrated and health outcome will be related to the advantages of charged-particle treatment planning, the radiosurgical procedure, dose distribution and dose localization.

The thermoluminescence response of doped SiO2 optical fibres subjected to photon and electron irradiations.

PubMed

Hashim, S; Al-Ahbabi, S; Bradley, D A; Webb, M; Jeynes, C; Ramli, A T; Wagiran, H

2009-03-01

Modern linear accelerators, the predominant teletherapy machine in major radiotherapy centres worldwide, provide multiple electron and photon beam energies. To obtain reasonable treatment times, intense electron beam currents are achievable. In association with this capability, there is considerable demand to validate patient dose using systems of dosimetry offering characteristics that include good spatial resolution, high precision and accuracy. Present interest is in the thermoluminescence response and dosimetric utility of commercially available doped optical fibres. The important parameter for obtaining the highest TL yield during this study is to know the dopant concentration of the SiO2 fibre because during the production of the optical fibres, the dopants tend to diffuse. To achieve this aim, proton-induced X-ray emission (PIXE), which has no depth resolution but can unambiguously identify elements and analyse for trace elements with detection limits approaching microg/g, was used. For Al-doped fibres, the dopant concentration in the range 0.98-2.93 mol% have been estimated, with equivalent range for Ge-doped fibres being 0.53-0.71 mol%. In making central-axis irradiation measurements a solid water phantom was used. For 6-MV photons and electron energies in the range 6, 9 and 12 MeV, a source to surface distance of 100 cm was used, with a dose rate of 400 cGy/min for photons and electrons. The TL measurements show a linear dose-response over the delivered range of absorbed dose from 1 to 4 Gy. Fading was found to be minimal, less than 10% over five days subsequent to irradiation. The minimum detectable dose for 6-MV photons was found to be 4, 30 and 900 microGy for TLD-100 chips, Ge- and Al-doped fibres, respectively. For 6-, 9- and 12-MeV electron energies, the minimum detectable dose were in the range 3-5, 30-50 and 800-1400 microGy for TLD-100 chip, Ge-doped and Al-doped fibres, respectively.

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

PubMed

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

2004-02-01

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

Electroantennogram and behavioral responses of the imported fire ant, Solenopsis invicta Buren, to an alarm pheromone component and its analogues.

PubMed

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

2014-12-10

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

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

Kim, J; Park, S; Lee, H

Purpose: This work evaluated the characteristics of optically stimulated luminescence dosimeters (OSLDs) with fully filled deep electron/hole traps (OSLDfull) with the bleaching conditions according to the accumulated dose. Methods: The OSLDs were first pre-irradiated with a Co-60 gamma ray at more than 5 kGy, so as to fill the deep electron and hole traps. Using a 6-MV beam, the OSLDfull characteristics were investigated in terms of the full bleaching, fading, dose linearity, and dose sensitivity obtained in response to the accumulated dose values. To facilitate a comparison of the dose sensitivity, OSLDs with un-filled deep electron/hole traps (OSLDempty) were investigatedmore » in the same manner. A long-pass filter was used to exclude bleaching-source wavelengths of less than 520 nm. Various bleaching time and wavelength combinations were used in order to determine the optimal bleaching conditions for the OSLD full. Results: The fading for the OSLDfull exhibited stable signals after 8 min, for both 1- and 10-Gy. For 4-h bleaching time and an unfiltered bleaching device, the supralinear index values for the OSLDfull were 1.003, 1.002, 0.999, and 1.001 for doses of 2, 4, 7, and 10 Gy, respectively. For a 65-Gy accumulated dose with a 5-Gy fraction, no variation in dose sensitivity was obtained for the OSLDfull, within a standard deviation of 0.85%, whereas the OSLDempty dose sensitivity decreased by approximately 2.3% per 10 Gy. The filtered bleaching device yielded a highly stable sensitivity for OSLDfull, independent of bleaching time and within a standard deviation of 0.71%, whereas the OSLDempty dose sensitivity decreased by approximately 4.2% per 10 Gy for an accumulated dose of 25 Gy with a 5-Gy fraction. Conclusion: Under the bleaching conditions determined in this study, clinical dosimetry with OSLDfull is highly stable, having an accuracy of 1% with no change in dose sensitivity or linearity at clinical doses. This work was supported by a National Research Foundation of Korea (NRF) grant, funded by the Korea government (MISP) (No. 2014M2B2A4031164), and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3459).« less

Tumour response endpoints in the BA1112 rat sarcoma.

PubMed Central

Martin, D. F.; Moulder, J. E.; Fischer, J. J.

1980-01-01

The rat rhabdomyosarcoma BA1112 has a number of features which make it a useful model for the study of tumour response to radiation therapy. It is a transplantable tumour, isologous to an inbred line of WAG/Rij rats and it elicits no demonstrable host immune response. The tumour grows locally at the implantation site and rarely metastasizes. It is known to contain hypoxic cells which reoxygenate during a prolonged course of fractionated radiation therapy. The growth and radiation response characteristics of the tumour have remained stable for over 15 years. A newly developed in vitro assay for tumour cell clonogenicity greatly facilitates the measurement of radiation dose-response curves and the monitoring of cell response following in vivo treatment. The in vivo response of the tumour to fractionated radiation therapy is analysed in terms of cellular response, reoxygenation and cell proliferation. PMID:6932936

Analysis of Flow Cytometry DNA Damage Response Protein Activation Kinetics Following X-rays and High Energy Iron Nuclei Exposure

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

Universities Space Research Association; Chappell, Lori J.; Whalen, Mary K.

2010-12-15

We developed a mathematical method to analyze flow cytometry data to describe the kinetics of {gamma}H2AX and pATF2 phosphorylations ensuing various qualities of low dose radiation in normal human fibroblast cells. Previously reported flow cytometry kinetic results for these DSB repair phospho-proteins revealed that distributions of intensity were highly skewed, severely limiting the detection of differences in the very low dose range. Distributional analysis reveals significant differences between control and low dose samples when distributions are compared using the Kolmogorov-Smirnov test. Radiation quality differences are found in the distribution shapes and when a nonlinear model is used to relate dosemore » and time to the decay of the mean ratio of phosphoprotein intensities of irradiated samples to controls. We analyzed cell cycle phase and radiation quality dependent characteristic repair times and residual phospho-protein levels with these methods. Characteristic repair times for {gamma}H2AX were higher following Fe nuclei as compared to X-rays in G1 cells (4.5 {+-} 0.46 h vs 3.26 {+-} 0.76 h, respectively), and in S/G2 cells (5.51 {+-} 2.94 h vs 2.87 {+-} 0.45 h, respectively). The RBE in G1 cells for Fe nuclei relative to X-rays for {gamma}H2AX was 2.05 {+-} 0.61 and 5.02 {+-} 3.47, at 2 h and 24-h postirradiation, respectively. For pATF2, a saturation effect is observed with reduced expression at high doses, especially for Fe nuclei, with much slower characteristic repair times (>7 h) compared to X-rays. RBEs for pATF2 were 0.66 {+-} 0.13 and 1.66 {+-} 0.46 at 2 h and 24 h, respectively. Significant differences in {gamma}H2AX and pATF2 levels comparing irradiated samples to control were noted even at the lowest dose analyzed (0.05 Gy) using these methods of analysis. These results reveal that mathematical models can be applied to flow cytometry data to uncover important and subtle differences following exposure to various qualities of low dose radiation.« less

Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine.

PubMed

Czapla, M A; Gozal, D; Alea, O A; Beckerman, R C; Zadina, J E

2000-09-01

The novel endogenous mu-opioid receptor (MOR) agonists endomorphin 1 (EM1) and 2 (EM2) were tested for their cardiorespiratory effects in conscious, freely behaving rats. After systemic (intravenous) administration of EM1, EM2, or the selective MOR agonist DAMGO, analgesia, minute ventilation (V E), heart rate (HR) and mean arterial blood pressure (BP) were measured. The threshold dose for analgesia was similar for all 3 peptides ( approximately 900 nmol/kg). All 3 compounds elicited biphasic V E responses, with marked, short-lived V E depressions (4-6 s) followed by more sustained V E increases (10-12 min). However, compared with responses elicited by EM2 or DAMGO, EM1 decreased V E only at higher doses, and produced greater V E stimulation. Morphine produced a V E decrease, but no subsequent V E increase. EM2 and DAMGO decreased HR and BP, while EM1 decreased HR, but did not decrease BP in conscious rats at doses up to 9,600 nmol/kg. In anesthetized rats, all 3 peptides decreased HR and BP. The decreases in V E, HR, and BP were blocked by the MOR antagonist, naloxone HCI (NIx). Only the HR and BP responses, however, were blocked by naloxone-methiodide (MeNIx), indicating central mediation of V E responses and peripheral mediation of cardiovascular responses. We conclude that MOR-selective compounds vary in their cardiorespiratory response characteristics which could be linked to differential cellular actions. The results support the concept that the analgesic, respiratory, and cardiovascular effects of MOR agonists can be dissociated and that EM1-like compounds could provide the basis for novel, safer analgesics.

Radiation accident dosimetry on plastics by EPR spectrometry.

PubMed

Trompier, F; Bassinet, C; Clairand, I

2010-02-01

In case of acute exposure to ionizing radiation, the dose absorbed by the victims has to be rapidly and accurately assessed in order to choose an appropriate medical treatment. Tooth enamel and bone biopsies measured by EPR spectrometry are often used as dose indicators, due to the good radiation sensitivity and the stability of EPR radiation-sensitive signals. Nevertheless, the invasive sampling of teeth and bones limits the application of this technique to retrospective dosimetry. Therefore, we have investigated an alternative non-invasive methodology. We have surveyed with EPR spectrometry the dosimetric properties of the plastics that can be found in personal effects such as glasses (CR-39, polycarbonate), mobile phones (PMMA, polycarbonate), watches and buttons. Dose response, signal stability and effects of storage conditions were investigated. Significant signal fading limits the use for radiation accident dosimetry. Few plastics present the required characteristics to be used in case of a radiation accident.

Dose-Response Calculator for ArcGIS

USGS Publications Warehouse

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

2011-01-01

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

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.

Production of migration inhibitory factor in response to bacterial and fungal antigens in patients with untreated Graves' disease

PubMed Central

Wall, Jack R.; Ryan, E. Ann

1980-01-01

Tests for the production of migration inhibitory factor by peripheral blood leukocytes in response to ubiquitous bacterial and fungal antigens were carried out in patients with untreated Graves' disease and in healthy control subjects. Dose-response studies, tests for the production of this factor after 72 hours' stimulation with phytohemagglutinin as a test for reserve, and tests before and after 24 hours' preculture to deplete suppressor cells were also performed in some patients. The antigens used were Candida, Trichophyton-Oidiomyces-Epidermophyton, mumps live attenuated virus and purified protein derivative of tuberculin. The production of migration inhibitory factor was measured by the agarose microdroplet method. The production of migration inhibitory factor in response to all the antigens except mumps virus was slightly greater in the patients than in the control subjects, although the differences were not significant. The dose-response characteristics and the production of migration inhibitory factor after stimulation with phytohemagglutinin were similar in the two groups. The production of migration inhibitory factor in response to suboptimal concentrations of Candida, Trichophyton-Oidiomyces-Epidermophyton and mumps virus was not enhanced in either group after 24 hours' preculture apart from a slight increase in response to mumps virus in the patients. These results fail to support the suggestion that patients with Graves' disease have a deficiency of suppressor cells. PMID:6446374

Commissioning a p-type silicon diode for use in clinical electron beams.

PubMed

Eveling, J N; Morgan, A M; Pitchford, W G

1999-01-01

Commissioning measurements were carried out on a p-type silicon diode detector for use in patient monitoring in high energy electron beams. Characteristics specific to the diode were examined. The variation in diode sensitivity with dose per pulse was found to be less than 1% over a range 0.069-0.237 mGy/pulse. The diode exhibited a sensitivity variation with accumulated dose of 10% per kGy and a sensitivity variation with surface temperature of 0.26%/degree C. The dependence of the diode response on the direction of the incident electron beam was investigated. Results were found to exceed the manufacturer's specifications. Output factors measured with the diode agree to within 1.5% of those measured with an NACP-02 air ionization chamber. The detector showed a variation in response with energy of 0.8% over the energy range 4-15 MeV. Prior to introducing the diode into clinical use, an assessment of beam perturbation directly behind the diode was made. The maximum reduction in local dose directly behind the diode at a depth of 1.0 cm below the surface was approximately 13% at 4 and 15 MeV.

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

EPA Pesticide Factsheets

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

Modeling Rabbit Responses to Single and Multiple Aerosol ...

EPA Pesticide Factsheets

Journal Article Survival models are developed here to predict response and time-to-response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple dose dataset to predict the probability of death through specifying dose-response functions and the time between exposure and the time-to-death (TTD). Among the models developed, the best-fitting survival model (baseline model) has an exponential dose-response model with a Weibull TTD distribution. Alternative models assessed employ different underlying dose-response functions and use the assumption that, in a multiple dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this paper. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high-dose rabbit datasets. More accurate survival models depend upon future development of dose-response datasets specifically designed to assess potential multiple dose effects on response and time-to-response. The process used in this paper to dev

Patient characteristics associated with differences in radiation exposure from pediatric abdomen-pelvis CT scans: a quantile regression analysis.

PubMed

Cooper, Jennifer N; Lodwick, Daniel L; Adler, Brent; Lee, Choonsik; Minneci, Peter C; Deans, Katherine J

2017-06-01

Computed tomography (CT) is a widely used diagnostic tool in pediatric medicine. However, due to concerns regarding radiation exposure, it is essential to identify patient characteristics associated with higher radiation burden from CT imaging, in order to more effectively target efforts towards dose reduction. Our objective was to identify the effects of various demographic and clinical patient characteristics on radiation exposure from single abdomen/pelvis CT scans in children. CT scans performed at our institution between January 2013 and August 2015 in patients under 16 years of age were processed using a software tool that estimates patient-specific organ and effective doses and merges these estimates with data from the electronic health record and billing record. Quantile regression models at the 50th, 75th, and 90th percentiles were used to estimate the effects of patients' demographic and clinical characteristics on effective dose. 2390 abdomen/pelvis CT scans (median effective dose 1.52mSv) were included. Of all characteristics examined, only older age, female gender, higher BMI, and whether the scan was a multiphase exam or an exam that required repeating for movement were significant predictors of higher effective dose at each quantile examined (all p<0.05). The effects of obesity and multiphase or repeat scanning on effective dose were magnified in higher dose scans. Older age, female gender, obesity, and multiphase or repeat scanning are all associated with increased effective dose from abdomen/pelvis CT. Targeted efforts to reduce dose from abdominal CT in these groups should be undertaken. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia

PubMed Central

Liebman, Howard A.; Saleh, Mansoor N.; Bussel, James B.; Negrea, O. George; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2016-01-01

We compared two dosing schedules for subcutaneous injections of a low-dose humanized anti-CD20 antibody, veltuzumab, in immune thrombocytopenia. Fifty adults with primary immune thrombocytopenia, in whom one or more lines of standard therapy had failed and who had a platelet count <30×109/L but no major bleeding, initially received escalating 80, 160, or 320 mg doses of subcutaneous veltuzumab administered twice, 2 weeks apart; the last group received once-weekly doses of 320 mg for 4 weeks. In all dose groups, injection reactions were transient and mild to moderate; there were no other safety issues. Forty-seven response-evaluable patients had 23 (49%) objective responses (platelet counts ≥30×109/L and ≥2 × baseline) including 15 (32%) complete responses (platelets ≥100×109/L). Responses (including complete responses) and bleeding reduction occurred in all dose groups and were not dose-dependent. In contrast, response duration increased progressively with total dose, reaching a median of 2.7 years with the four once-weekly 320-mg doses. Among nine responders retreated at relapse, three at higher dose levels responded again, including one patient who was retreated four times. In all dose groups, B-cell depletion occurred after the first dose until recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with dose group according to total dose administered, but terminal half-life and clearance were comparable. Human anti-veltuzumab antibody titers developed without apparent dose dependence in nine patients, of whom six responded including five who had complete responses. Subcutaneous veltuzumab was convenient, well-tolerated, and active, without causing significant safety concerns. Platelet responses and bleeding reduction occurred in all dose groups, and response durability appeared to improve with higher doses. Clinicaltrials.gov identifier: NCT00547066 PMID:27515248

Therapeutic treatment with ascorbate rescues mice from heat stroke-induced death by attenuating systemic inflammatory response and hypothalamic neuronal damage.

PubMed

Chang, Chia-Yu; Chen, Jen-Yin; Chen, Sheng-Hsien; Cheng, Tain-Junn; Lin, Mao-Tsun; Hu, Miao-Lin

2016-04-01

The impact of ascorbate on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. However, recent evidence of the clinical benefit of parenteral vitamin C administration has emerged, especially in critical care. Heatstroke is defined as a form of excessive hyperthermia associated with a systemic inflammatory response that results in multiple organ dysfunctions in which central nervous system disorders such as delirium, convulsions, and coma are predominant. The thermoregulatory, immune, coagulation and tissue injury responses of heatstroke closely resemble those observed during sepsis and are likely mediated by similar cellular mechanisms. This study was performed by using the characteristic high lethality rate and sepsis-mimic systemic inflammatory response of a murine model of heat stroke to test our hypothesis that supra-physiological doses of ascorbate may have therapeutic use in critical care. We demonstrated that parenteral administration of ascorbate abrogated the lethality and thermoregulatory dysfunction in murine model of heat stroke by attenuating heat stroke-induced accelerated systemic inflammatory, coagulation responses and the resultant multiple organ injury, especially in hypothalamus. Overall, our findings support the hypothesis and notion that supra-physiological doses of ascorbate may have therapeutic use in critical care. Copyright © 2016. Published by Elsevier Inc.

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.

Humoral immune responses against gonadotropin releasing hormone elicited by immunization with phage-peptide constructs obtained via phage display.

PubMed

Samoylov, Alexandre; Cochran, Anna; Schemera, Bettina; Kutzler, Michelle; Donovan, Caitlin; Petrenko, Valery; Bartol, Frank; Samoylova, Tatiana

2015-12-20

Phage display is based on genetic engineering of phage coat proteins resulting in fusion peptides displayed on the surface of phage particles. The technology is widely used for generation of phages with novel characteristics for numerous applications in biomedicine and far beyond. The focus of this study was on development of phage-peptide constructs that stimulate production of antibodies against gonadotropin releasing hormone (GnRH). Phage-peptide constructs that elicit production of neutralizing GnRH antibodies can be used for anti-fertility and anti-cancer applications. Phage-GnRH constructs were generated via selection from a phage display library using several types of GnRH antibodies as selection targets. Such phage constructs were characterized for sequence similarities to GnRH peptide and frequency of their occurrence in the selection rounds. Five of the constructs with suitable characteristics were tested in mice as a single dose 5×10(11) virions (vir) vaccine and were found to be able to stimulate production of GnRH-specific antibodies, but not to suppress testosterone (indirect indicator of GnRH antibody neutralizing properties). Next, one of the constructs was tested at a higher dose of 2×10(12) vir per mouse in combination with a poly(lactide-co-glycolide) (PLGA)-based adjuvant. This resulted in multifold increase in GnRH antibody production and significant reduction of serum testosterone, indicating that antibodies produced in response to the phage-GnRH immunization possess neutralizing properties. To achieve optimal immune responses for desired applications, phage-GnRH constructs can be modified with respect to flanking sequences of GnRH-like peptides displayed on phage. Anticipated therapeutic effects also might be attained using optimized phage doses, a combination of several constructs in a single treatment, or application of adjuvants and advanced phage delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab

PubMed Central

2010-01-01

Background Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent. However, some clinical situations do not allow application of tumouricidal doses (i.e. re-irradiation) hence radiation sensitization by exploitation of high endothelial growth factor receptor (EGFR)-expression in ACC seems beneficial. This is a single-institution experience of combined radioimmunotherapy (RIT) with the EGFR-inhibitor cetuximab. Methods Between 2006 and 2010, 9 pts received RIT for advanced/recurrent ACC, 5/9 pts as re-irradiation. Baseline characteristics as well as treatment parameters were retrieved to evaluate efficacy and toxicity of the combination regimen were evaluated. Control rates (local/distant) and overall survival were calculated using Kaplan-Meier estimation. Results Median dose was 65 Gy, pts received a median of 6 cycles cetuximab. RIT was tolerated well with only one °III mucositis/dysphagia. Overall response/remission rates were high (77,8%); 2-year estimate of local control was 80% hence reaching local control levels comparable to high-dose RT. Progression-free survival (PFS) at 2 years and median overall survival were only 62,5% and 22,2 mo respectively. Conclusion While local control and treatment response in RIT seems promising, PFS and overall survival are still hampered by distant failure. The potential benefit of RIT with cetuximab warrants exploration in a prospective controlled clinical trial. PMID:21047402

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

PubMed

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

2017-08-01

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

[Regulation of the neuronal functional state by ultra low doses of different biologically active substances. Nonspecific effect ].

PubMed

Terekhova, S F; Grechenko, T N

2003-01-01

The role of biologically active substances in ultra-low doses (10(-15)-10(-27) mol/l) is discussed from the different points of view. The most detailed analysis of neurobiological effects produced by these doses can be studied on the preparate of completely isolated molluscan neurones. In this case the possibility arises to control the first modifications of action at the electrophysiological characteristics of neuronal activity. These changes of electrical activity can be regarded as a reaction to biologically active substance. The following characteristics were controlled: the level of membrane resting potential (MP), the electroexcitable membrane and pacemaker mechanism, chemical sensitivity of somatic membrane loci to neurotransmitter acetylcholine (Ach). Several substances were used in these experiments: two kinds of synthetic antioxidant, GABA, ethanol, serotonine, DSIP (delta-sleep inducing peptide), antibiotic ruboxil, nootrop GVS-111. The isolated neurones were placed into the special chamber. All these substances (0.35 ml) were added single dosing into this chamber with living physiological solution in concentration 10(-15)-10(-27) mol/l. The results demonstrated that all substances had initiated the development of prolonged neurophysiological responses. The intensities of neuronal reactions didn't depend in contact period on the concentration and on the type of substance. It is suggested that these data reveal the existence of unknown modes of regulation of neuronal functional states and presence of hidden channel for information transfer and receiving. This different way of regulation is extremely important influence living organisms.

CT image biomarkers to improve patient-specific prediction of radiation-induced xerostomia and sticky saliva.

PubMed

van Dijk, Lisanne V; Brouwer, Charlotte L; van der Schaaf, Arjen; Burgerhof, Johannes G M; Beukinga, Roelof J; Langendijk, Johannes A; Sijtsema, Nanna M; Steenbakkers, Roel J H M

2017-02-01

Current models for the prediction of late patient-rated moderate-to-severe xerostomia (XER 12m ) and sticky saliva (STIC 12m ) after radiotherapy are based on dose-volume parameters and baseline xerostomia (XER base ) or sticky saliva (STIC base ) scores. The purpose is to improve prediction of XER 12m and STIC 12m with patient-specific characteristics, based on CT image biomarkers (IBMs). Planning CT-scans and patient-rated outcome measures were prospectively collected for 249 head and neck cancer patients treated with definitive radiotherapy with or without systemic treatment. The potential IBMs represent geometric, CT intensity and textural characteristics of the parotid and submandibular glands. Lasso regularisation was used to create multivariable logistic regression models, which were internally validated by bootstrapping. The prediction of XER 12m could be improved significantly by adding the IBM "Short Run Emphasis" (SRE), which quantifies heterogeneity of parotid tissue, to a model with mean contra-lateral parotid gland dose and XER base . For STIC 12m , the IBM maximum CT intensity of the submandibular gland was selected in addition to STIC base and mean dose to submandibular glands. Prediction of XER 12m and STIC 12m was improved by including IBMs representing heterogeneity and density of the salivary glands, respectively. These IBMs could guide additional research to the patient-specific response of healthy tissue to radiation dose. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

The effects of hot carrier and swift heavy ion irradiation on electrical characteristics of advanced 200 GHz SiGe HBTs

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

Vinayakprasanna, N. H.; Praveen, K. C.; Prakash, A. P. Gnana, E-mail: gnanaprakash@physics.uni-mysore.ac.in

The 200 GHz SiGe HBTs were irradiated with 80 MeV Carbon ions up to a total dose of 100 Mrad to understand the degradation in electrical characteristics. The degradation in the electrical characteristics of SiGe HBTs was also studied by mixed mode electrical stress up to 10,000 s. The electrical characteristics were measured before and after every total dose and after fixed stress time. The normalized peak h{sub FE} of the stressed and irradiated SiGe HBTs are compared to estimate the equivalent stress time for a particular total dose. These correlations are drawn for the first time and the resultsmore » will establish a systematic relation between stress time and total dose.« less

Dose impact in radiographic lung injury following lung SBRT: Statistical analysis and geometric interpretation

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

Yu, Victoria; Kishan, Amar U.; Cao, Minsong

2014-03-15

Purpose: To demonstrate a new method of evaluating dose response of treatment-induced lung radiographic injury post-SBRT (stereotactic body radiotherapy) treatment and the discovery of bimodal dose behavior within clinically identified injury volumes. Methods: Follow-up CT scans at 3, 6, and 12 months were acquired from 24 patients treated with SBRT for stage-1 primary lung cancers or oligometastic lesions. Injury regions in these scans were propagated to the planning CT coordinates by performing deformable registration of the follow-ups to the planning CTs. A bimodal behavior was repeatedly observed from the probability distribution for dose values within the deformed injury regions. Basedmore » on a mixture-Gaussian assumption, an Expectation-Maximization (EM) algorithm was used to obtain characteristic parameters for such distribution. Geometric analysis was performed to interpret such parameters and infer the critical dose level that is potentially inductive of post-SBRT lung injury. Results: The Gaussian mixture obtained from the EM algorithm closely approximates the empirical dose histogram within the injury volume with good consistency. The average Kullback-Leibler divergence values between the empirical differential dose volume histogram and the EM-obtained Gaussian mixture distribution were calculated to be 0.069, 0.063, and 0.092 for the 3, 6, and 12 month follow-up groups, respectively. The lower Gaussian component was located at approximately 70% prescription dose (35 Gy) for all three follow-up time points. The higher Gaussian component, contributed by the dose received by planning target volume, was located at around 107% of the prescription dose. Geometrical analysis suggests the mean of the lower Gaussian component, located at 35 Gy, as a possible indicator for a critical dose that induces lung injury after SBRT. Conclusions: An innovative and improved method for analyzing the correspondence between lung radiographic injury and SBRT treatment dose has been demonstrated. Bimodal behavior was observed in the dose distribution of lung injury after SBRT. Novel statistical and geometrical analysis has shown that the systematically quantified low-dose peak at approximately 35 Gy, or 70% prescription dose, is a good indication of a critical dose for injury. The determined critical dose of 35 Gy resembles the critical dose volume limit of 30 Gy for ipsilateral bronchus in RTOG 0618 and results from previous studies. The authors seek to further extend this improved analysis method to a larger cohort to better understand the interpatient variation in radiographic lung injury dose response post-SBRT.« less

General radiographic attributes of optically stimulated luminescence dosimeters: A basic insight

NASA Astrophysics Data System (ADS)

Musa, Y.; Hashim, S.; Ghoshal, S. K.; Bradley, D. A.; Ahmad, N. E.; Karim, M. K. A.; Hashim, A.; Kadir, A. B. A.

2018-06-01

We report the ubiquitous radiographic characteristics of optically stimulated luminescence dosimeters (OSLD) so called nanoDot OSLDs (Landauer Inc., Glendwood, IL). The X-ray irradiations were performed in free air ambiance to inspect the repeatability, the reproducibility, the signal depletion, the element correction factors (ECFs), the dose response and the energy dependence. Repeatability of multiple readouts after single irradiation to 10 mGy revealed a coefficient of variation below 3%, while the reproducibility in repeated irradiation-readout-annealing cycles was above 2%. The OSL signal depletion for three nanoDots with simultaneous irradiation to 20 mGy and sequential readouts of 25 times displayed a consistent signal reduction ≈0.5% per readout with R2 values over 0.98. ECFs for individual OSLDs were varied from 0.97 to 1.03. In the entire dose range under 80 kV, a good linearity with an R2 exceeding 0.99 was achieved. Besides, the percentage difference between OSLD and ion-chamber dose was less than 5%, which was superior to TLD. The X-ray photon irradiated energy response factors (between 0.76 and 1.12) in the range of 40-150 kV (26.1-61.2 keV) exhibited significant energy dependence. Indeed, the nanoDot OSLDs disclosed good repeatability, reproducibility and linearity. The OSLDs measured doses were closer to ion-chamber doses than that of TLD. It can be further improved up to ≈3% by applying the individual dosimeter ECF. On top, the energy dependent uncertainties can be minimized using the energy correction factors. It is established that the studied nanoDot OSLDs are prospective for measuring entrance dose in general radiographic practices.

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

EPA Science Inventory

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

A MULTIMODEL APPROACH FOR CALCULATING BENCHMARK DOSE

EPA Science Inventory

A Multimodel Approach for Calculating Benchmark Dose
Ramon I. Garcia and R. Woodrow Setzer

In the assessment of dose response, a number of plausible dose- response models may give fits that are consistent with the data. If no dose response formulation had been speci...

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

PubMed

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

2014-08-01

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

Equivalence in Dose Fall-Off for Isocentric and Nonisocentric Intracranial Treatment Modalities and Its Impact on Dose Fractionation Schemes

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

Ma Lijun, E-mail: lijunma@radonc.ucsf.ed; Sahgal, Arjun; Descovich, Martina

2010-03-01

Purpose: To investigate whether dose fall-off characteristics would be significantly different among intracranial radiosurgery modalities and the influence of these characteristics on fractionation schemes in terms of normal tissue sparing. Methods and Materials: An analytic model was developed to measure dose fall-off characteristics near the target independent of treatment modalities. Variations in the peripheral dose fall-off characteristics were then examined and compared for intracranial tumors treated with Gamma Knife, Cyberknife, or Novalis LINAC-based system. Equivalent uniform biologic effective dose (EUBED) for the normal brain tissue was calculated. Functional dependence of the normal brain EUBED on varying numbers of fractions (1more » to 30) was studied for the three modalities. Results: The derived model fitted remarkably well for all the cases (R{sup 2} > 0.99). No statistically significant differences in the dose fall-off relationships were found between the three modalities. Based on the extent of variations in the dose fall-off curves, normal brain EUBED was found to decrease with increasing number of fractions for the targets, with alpha/beta ranging from 10 to 20. This decrease was most pronounced for hypofractionated treatments with fewer than 10 fractions. Additionally, EUBED was found to increase slightly with increasing number of fractions for targets with alpha/beta ranging from 2 to 5. Conclusion: Nearly identical dose fall-off characteristics were found for the Gamma Knife, Cyberknife, and Novalis systems. Based on EUBED calculations, normal brain sparing was found to favor hypofractionated treatments for fast-growing tumors with alpha/beta ranging from 10 to 20 and single fraction treatment for abnormal tissues with low alpha/beta values such as alpha/beta = 2.« less

SU-E-T-274: Does Atmospheric Oxygen Affect the PRESAGE Dosimeter?

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

Alqathami, M; Ibbott, G; Blencowe, A

Purpose: To experimentally determine the influence of atmospheric oxygen on the efficiency of the PRESAGE dosimeter and its reporting system. Methods: Batches of the reporting system – a mixture of chloroform and leuchomalachite green dye – and PRESAGE were prepared in aerobic and anaerobic conditions. For anaerobic batches, samples were deoxygenated by bubbling nitrogen through the dosimeter precursors or reporting system for 10 min. The dosimeters and reporting systems were prepared in spectrophotometric cuvettes and glass vials, respectively, and were irradiated with 6 MV photons to various radiation doses using a clinical linear accelerator. Changes in optical density of themore » dosimeters and reporting system before and after irradiation were measured using a spectrophotometer. In addition, the concentrations of dissolved oxygen were measured using a dissolved oxygen meter. Results: The experiments revealed that oxygen has little influence on the characteristics of PRESAGE, with the radical initiator oxidizing the leucomalachite green even in the presence of oxygen. However, deoxygenation of the reporting system leads to an increase in sensitivity to radiation dose by ∼ 30% when compared to the non-deoxygenated system. A slight improvement in sensitivity (∼ 5%) was also achieved by deoxygenating the PRESAGE precursor prior to casting. Measurement of the dissolved oxygen revealed low levels (0.4 ppm) in the polyurethane precursor used to fabricate the dosimeters, as compared to water (8.6 ppm). In addition, deoxygenation had no effect on the retention of the post-response absorption value of the PRESAGE dosimeter. Conclusion: The results suggest that the presence of oxygen does not inhibit the radiochromic properties of the PRESAGE system. In addition, there were no observed changes in the dose linearity, absorption spectrum and post-response photofading characteristics of the PRESAGE under the conditions investigated.« less

Thermoluminescence response of K{sub 2}Ca{sub 2}(SO{sub 4}){sub 3} nanophosphor Co-doped with Eu and Ce for gamma ray dosimetry

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

Patil, B. J.; Bhadane, Mahesh S.; Dahiwale, S. S.

2015-06-24

K{sub 2}Ca{sub 2}(SO{sub 4}){sub 3} nanophosphors co-doped with Eu and Ce were synthesized by the chemical co-precipitation method. These samples were further annealed at 700 °C structural reformation. The structural and morphological characteristics were studied using XRD and TEM techniques. The particle size calculated from XRD spectra was around 35 nm. The as synthesized sample shows cubic structure annealed at 700 °C. The as synthesized and annealed sample of K{sub 2}Ca{sub 2}(SO{sub 4}){sub 3}: EuCe were irradiated with Co{sup 60} gamma rays for the doses from 2Gy to 1kGy. The TL characteristic sample of co-doped were studied for the dosimetric applicationmore » by gamma radiation. The TL spectrum of annealed sample has single peaked at 160 °C. The Eu doped sample has a high TL sensitivity than Ce doped sample. But after co-doping with Eu and Ce, TL intensity observed to be decreased. The decrees in TL peak intensity of the phosphor on co-doping of Eu and Ce gives an insight into the emission mechanism of the phosphor which involves energy transfer from Eu to Ce. The TL response of all the samples were found to be linear for the dose from 2 Gy to 1 KGy. Therefore, K{sub 2}Ca{sub 2}(SO{sub 4}){sub 3}: EuCe nanophosphor can be used for the measurement of high dose of gamma radiation.« less

Task-based detectability comparison of exponential transformation of free-response operating characteristic (EFROC) curve and channelized Hotelling observer (CHO)

NASA Astrophysics Data System (ADS)

Khobragade, P.; Fan, Jiahua; Rupcich, Franco; Crotty, Dominic J.; Gilat Schmidt, Taly

2016-03-01

This study quantitatively evaluated the performance of the exponential transformation of the free-response operating characteristic curve (EFROC) metric, with the Channelized Hotelling Observer (CHO) as a reference. The CHO has been used for image quality assessment of reconstruction algorithms and imaging systems and often it is applied to study the signal-location-known cases. The CHO also requires a large set of images to estimate the covariance matrix. In terms of clinical applications, this assumption and requirement may be unrealistic. The newly developed location-unknown EFROC detectability metric is estimated from the confidence scores reported by a model observer. Unlike the CHO, EFROC does not require a channelization step and is a non-parametric detectability metric. There are few quantitative studies available on application of the EFROC metric, most of which are based on simulation data. This study investigated the EFROC metric using experimental CT data. A phantom with four low contrast objects: 3mm (14 HU), 5mm (7HU), 7mm (5 HU) and 10 mm (3 HU) was scanned at dose levels ranging from 25 mAs to 270 mAs and reconstructed using filtered backprojection. The area under the curve values for CHO (AUC) and EFROC (AFE) were plotted with respect to different dose levels. The number of images required to estimate the non-parametric AFE metric was calculated for varying tasks and found to be less than the number of images required for parametric CHO estimation. The AFE metric was found to be more sensitive to changes in dose than the CHO metric. This increased sensitivity and the assumption of unknown signal location may be useful for investigating and optimizing CT imaging methods. Future work is required to validate the AFE metric against human observers.

Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins.

PubMed

Ternant, David; Paintaud, Gilles

2005-09-01

Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell's receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration-effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration-effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose-response relationships must be studied by PK-PD modelling.

Increasing food deprivation relative to baseline influences D-amphetamine dose-response gradients.

PubMed

Lotfizadeh, Amin D; Zimmermann, Zachary J; Watkins, Erin E; Edwards, Timothy L; Poling, Alan

2014-10-01

Several studies using non-pharmacological discriminative stimuli have found that stimulus control, as evident in generalization gradients, changes when motivation for (i.e., deprivation of) the relevant reinforcer is altered. Drug-discrimination studies, however, have not consistently revealed such an effect. A procedural detail that may account for the lack of a reliable effect in drug-discrimination studies is that motivation was characteristically reduced relative to the training condition in these studies. The present experiment examined how substantially increasing motivation affects D-amphetamine discrimination. Rats initially were trained to discriminate D-amphetamine (1.0 mg/kg) from vehicle (0 mg/kg) injections under 22-h food deprivation conditions. Dose-response gradients were then obtained under 22-h and 46-h deprivation levels. The ED50 was significantly higher with greater deprivation. This finding suggests that increasing motivation relative to the training condition may reduce stimulus control by drugs, while decreasing it may sharpen stimulus control. Copyright © 2014. Published by Elsevier Inc.

Analysis of sheltering and evacuation strategies for an urban nuclear detonation scenario.

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

Yoshimura, Ann S.; Brandt, Larry D.

2009-05-01

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

Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease - algorithm for practical management.

PubMed

Ding, N S; Hart, A; De Cruz, P

2016-01-01

Nonresponse and loss of response to anti-TNF therapies in Crohn's disease represent significant clinical problems for which clear management guidelines are lacking. To review the incidence, mechanisms and predictors of primary nonresponse and secondary loss of response to formulate practical clinical algorithms to guide management. Through a systematic literature review, 503 articles were identified which fit the inclusion criteria. Primary nonresponse to anti-TNF treatment affects 13-40% of patients. Secondary loss of response to anti-TNF occurs in 23-46% of patients when determined according to dose intensification, and 5-13% of patients when gauged by drug discontinuation rates. Recent evidence suggests that the mechanisms underlying primary nonresponse and secondary loss of response are multifactorial and include disease characteristics (phenotype, location, severity); drug (pharmacokinetic, pharmacodynamic or immunogenicity) and treatment strategy (dosing regimen) related factors. Clinical algorithms that employ therapeutic drug monitoring (using anti-TNF tough levels and anti-drug antibody levels) may be used to determine the underlying cause of primary nonresponse and secondary loss of response respectively and guide clinicians as to which patients are most likely to respond to anti-TNF therapy and help optimise drug therapy for those who are losing response to anti-TNF therapy. Nonresponse or loss of response to anti-TNF occurs commonly in Crohn's disease. Clinical algorithms utilising therapeutic drug monitoring may establish the mechanisms for treatment failure and help guide the subsequent therapeutic approach. © 2015 John Wiley & Sons Ltd.

Dosimetric evaluation of a MOSFET detector for clinical application in photon therapy.

PubMed

Kohno, Ryosuke; Hirano, Eriko; Nishio, Teiji; Miyagishi, Tomoko; Goka, Tomonori; Kawashima, Mitsuhiko; Ogino, Takashi

2008-01-01

Dosimetric characteristics of a metal oxide-silicon semiconductor field effect transistor (MOSFET) detector are studied with megavoltage photon beams for patient dose verification. The major advantages of this detector are its size, which makes it a point dosimeter, and its ease of use. In order to use the MOSFET detector for dose verification of intensity-modulated radiation therapy (IMRT) and in-vivo dosimetry for radiation therapy, we need to evaluate the dosimetric properties of the MOSFET detector. Therefore, we investigated the reproducibility, dose-rate effect, accumulated-dose effect, angular dependence, and accuracy in tissue-maximum ratio measurements. Then, as it takes about 20 min in actual IMRT for the patient, we evaluated fading effect of MOSFET response. When the MOSFETs were read-out 20 min after irradiation, we observed a fading effect of 0.9% with 0.9% standard error of the mean. Further, we applied the MOSFET to the measurement of small field total scatter factor. The MOSFET for dose measurements of small field sizes was better than the reference pinpoint chamber with vertical direction. In conclusion, we assessed the accuracy, reliability, and usefulness of the MOSFET detector in clinical applications such as pinpoint absolute dosimetry for small fields.

Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

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

Appelt, Ane L., E-mail: ane.lindegaard.appelt@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

2013-01-01

Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from themore » histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D{sub 50,i}, and the normalized dose-response gradient, {gamma}{sub 50,i}. Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D{sub 50,TRG1} = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), {gamma}{sub 50,TRG1} = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D{sub 50,TRG1} and {sub 2} = 72.1 Gy (CI 65.3-94.0 Gy), {gamma}{sub 50,TRG1} and {sub 2} = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.« less

A study on comparison of Gafchromic EBT2 film response under single and cumulative exposure conditions

PubMed Central

Ganapathy, K.; Kurup, P.G.G.; Murali, V.; Muthukumaran, M.; Velmurugan, J.

2013-01-01

Gafchromic films are used as dosimeter for in vivo and in phantom dose measurements. The dose response of Gafchromic EBT2 film under single and repeated exposure conditions is compared in this study to analyze the usability of Gafchromic EBT2 films in cumulative dose measurements. The post-irradiation change in response of the film is studied for up to 4 days after irradiation. The effect of repeated exposure to scanner light on the response of the film is also studied. To check usability of Gafchromic EBT2 films in cumulative dose measurements, three EBT2 films were exposed to a daily fraction dose of 100 cGy, 150 cGy and 200 cGy, respectively, for 4 days. The dose response of the films exposed to cumulative irradiation was compared with the dose measured from films exposed to the same dose but in a single exposure. It is observed that the post-irradiation darkening of the film does not saturate and continue to take place even 4 days after irradiation. The dose measured from the EBT2 films after 4 days from irradiation was around 2% higher than the dose measured from the same films at 24 hours post-irradiation. It was also observed that the repeated exposure to scanner light does not produce any significant change in the film response. The dose response of films exposed to cumulative irradiation agrees with the dose response of films exposed to the same dose in a single irradiation with less than 3% difference. Gafchromic EBT2 films can be used to measure the cumulative dose delivered over multiple fractions, when the delivered dose is uniform across the film. PMID:24672151

Comparative Analysis of AhR-Mediated TCDD-Elicited Gene Expression in Human Liver Adult Stem Cells

PubMed Central

Kim, Suntae; Dere, Edward; Burgoon, Lyle D.; Chang, Chia-Cheng; Zacharewski, Timothy R.

2009-01-01

Time course and dose-response studies were conducted in HL1-1 cells, a human liver cell line with stem cell–like characteristics, to assess the differential gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compared with other established models. Cells were treated with 0.001, 0.01, 0.1, 1, 10, or 100nM TCDD or dimethyl sulfoxide vehicle control for 12 h for the dose-response study, or with 10nM TCDD or vehicle for 1, 2, 4, 8, 12, 24, or 48 h for the time course study. Elicited changes were monitored using a human cDNA microarray with 6995 represented genes. Empirical Bayes analysis identified 144 genes differentially expressed at one or more time points following treatment. Most genes exhibited dose-dependent responses including CYP1A1, CYP1B1, ALDH1A3, and SLC7A5 genes. Comparative analysis of HL1-1 differential gene expression to human HepG2 data identified 74 genes with comparable temporal expression profiles including 12 putative primary responses. HL1-1–specific changes were related to lipid metabolism and immune responses, consistent with effects elicited in vivo. Furthermore, comparative analysis of HL1-1 cells with mouse Hepa1c1c7 hepatoma cell lines and C57BL/6 hepatic tissue identified 18 and 32 commonly regulated orthologous genes, respectively, with functions associated with signal transduction, transcriptional regulation, metabolism and transport. Although some common pathways are affected, the results suggest that TCDD elicits species- and model-specific gene expression profiles. PMID:19684285

Characterization of a new commercial single crystal diamond detector for photon- and proton-beam dosimetry.

PubMed

Akino, Yuichi; Gautam, Archana; Coutinho, Len; Würfel, Jan; Das, Indra J

2015-11-01

A synthetic single crystal diamond detector (SCDD) is commercially available and is characterized for radiation dosimetry in various radiation beams in this study. The characteristics of the commercial SCDD model 60019 (PTW) with 6- and 15-MV photon beams, and 208-MeV proton beams, were investigated and compared with the pre-characterized detectors: Semiflex (model 31010) and PinPoint (model 31006) ionization chambers (PTW), the EDGE diode detector (Sun Nuclear Corp) and the SFD Stereotactic Dosimetry Diode Detector (IBA). To evaluate the effects of the pre-irradiation, the diamond detector, which had not been irradiated on the day, was set up in the water tank, and the response to 100 MU was measured every 20 s. The depth-dose and profiles data were collected for various field sizes and depths. For all radiation types and field sizes, the depth-dose data of the diamond chamber showed identical curves to those of the ionization chambers. The profile of the diamond detector was very similar to those of the EDGE and SFD detectors, although the Semiflex and PinPoint chambers showed volume-averaging effects in the penumbrae region. The temperature dependency was within 0.7% in the range of 4-41°C. A dose of 900 cGy and 1200 cGy was needed to stabilize the chamber to the level within 0.5% and 0.2%, respectively. The PTW type 60019 SCDD detector showed suitable characteristics for radiation dosimetry, for relative dose, depth-dose and profile measurements for a wide range of field sizes. However, at least 1000 cGy of pre-irradiation will be needed for accurate measurements. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

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

EPA Science Inventory

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

Research pressure instrumentation for NASA Space Shuttle main engine, modification no. 5

NASA Technical Reports Server (NTRS)

Anderson, P. J.; Nussbaum, P.; Gustafson, G.

1984-01-01

The objective of the research project described is to define and demonstrate methods to advance the state of the art of pressure sensors for the space shuttle main engine (SSME). Silicon piezoresistive technology was utilized in completing tasks: generation and testing of three transducer design concepts for solid state applications; silicon resistor characterization at cryogenic temperatures; experimental chip mounting characterization; frequency response optimization and prototype design and fabrication. Excellent silicon sensor performance was demonstrated at liquid nitrogen temperature. A silicon resistor ion implant dose was customized for SSME temperature requirements. A basic acoustic modeling software program was developed as a design tool to evaluate frequency response characteristics.

Cosmetic Use of AbobotulinumtoxinA in Men: Considerations Regarding Anatomical Differences and Product Characteristics.

PubMed

Bloom, Jason D; Green, Jeremy B; Bowe, Whitney; von Grote, Erika; Nogueira, Alessandra

2016-09-01

The proportion of men seeking facial rejuvenation with botulinum neurotoxin type A (BoNTA) products is increasing. The number of male patients treated in the 5-year period between 2009 and 2014 grew by 25%. There is little clinical data supporting gender-specific efficacy with regard to dosing and injection placement in men. To nurture the confidence associated with treatment of male patients, clinicians are in need of more informational materials to develop their evaluation and treatment strategies. Three BoNTA products are currently available in the United States (US) for treatment of the upper face. The varying potency of the different BoNTA formulations is reflected by disparate dose-response characteristics, meaning they are not interchangeable for injection purposes. Clinicians who are familiar with the characteristics of all the BoNTA options will be equipped with the necessary tools to provide their male patients with a desired outcome.
Among the product options available in the US, Dysport^® (abobotulinumtoxinA) (Galderma Laboratories, L.P., Fort Worth, Texas) is unique in that its recommendations for reconstitution provide the clinician with 2 different final product concentrations. The flexibility provided by a variable dose may be a valuable tool for tailoring treatments to male patient-specific needs, which may include a more conservative outcome, maintaining a certain degree of muscle activity and expressivity. Achieving a conservative outcome may be the key to a positive experience for the male patient.

J Drugs Dermatol. 2016;15(9):1056-1062.

THE DEPRESSANT EFFECT OF CONTINUOUS COBALT-60 RADIATION ON THE SECONDARY TETANUS ANTITOXIN RESPONSE IN MICE

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

Stoner, R.D.; Hale, W.M.

1958-05-01

The radiosensitivity of the secondary tetanus antitoxin response in mice was demonstrated after rather low doses of continuous gamma -radiation given at a dose rate of 4 rep/hr. Accumulated doses of 48 to 288 rep depressed antitoxin formation. Comparable doses of acute gamma radiation did not depress antitoxin production. Acute doses of 350 to 650 rep sharply depressed the secondary antibody response, however. Extended periods of continuous gamma -radiation from 10 to 28 days to accumulated doses of 960 to 2688 rep markedly depressed the secondary antibody response. An accumulated dose of 2688 rep was needed to depress antitoxin formationmore » to the level observed after an acute dose of 650 rep. When the secondary stimulus of fluid tetanus toxoid was given prior to 10 days of continuous exposure to an accumulated dose of 860 rep, the secondary antibody respense was not depressed. Irradiated mice recovered the ability to produce a normal secondary antitoxin response during the second week after an accumulated dose of 1248 rep. The secondary antitoxin response was depressed in mice given long-continued gamma -radiation at a dose rate of 1 rep/hr. (auth)« less

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

PubMed

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

2005-06-01

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

Functional Data Analysis Applied to Modeling of Severe Acute Mucositis and Dysphagia Resulting From Head and Neck Radiation Therapy

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

Dean, Jamie A., E-mail: jamie.dean@icr.ac.uk; Wong, Kee H.; Gay, Hiram

Purpose: Current normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue–sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation. Methods and Materials: FDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis were used for dimensionality reduction of the dose-volume histogrammore » data. The reduced dose data were input into functional logistic regression models (functional partial least squares–logistic regression [FPLS-LR] and functional principal component–logistic regression [FPC-LR]) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate–response associations, assessed using bootstrapping. Results: The area under the receiver operating characteristic curve for the PLR, FPC-LR, and FPLS-LR models was 0.65, 0.69, and 0.67, respectively, for mucositis (internal validation) and 0.81, 0.83, and 0.83, respectively, for dysphagia (external validation). The calibration slopes/intercepts for the PLR, FPC-LR, and FPLS-LR models were 1.6/−0.67, 0.45/0.47, and 0.40/0.49, respectively, for mucositis (internal validation) and 2.5/−0.96, 0.79/−0.04, and 0.79/0.00, respectively, for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models. Conclusions: FPLS and functional principal component analysis marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in normal tissue complication probability modeling.« less

Functional Data Analysis Applied to Modeling of Severe Acute Mucositis and Dysphagia Resulting From Head and Neck Radiation Therapy.

PubMed

Dean, Jamie A; Wong, Kee H; Gay, Hiram; Welsh, Liam C; Jones, Ann-Britt; Schick, Ulrike; Oh, Jung Hun; Apte, Aditya; Newbold, Kate L; Bhide, Shreerang A; Harrington, Kevin J; Deasy, Joseph O; Nutting, Christopher M; Gulliford, Sarah L

2016-11-15

Current normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue-sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation. FDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis were used for dimensionality reduction of the dose-volume histogram data. The reduced dose data were input into functional logistic regression models (functional partial least squares-logistic regression [FPLS-LR] and functional principal component-logistic regression [FPC-LR]) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate-response associations, assessed using bootstrapping. The area under the receiver operating characteristic curve for the PLR, FPC-LR, and FPLS-LR models was 0.65, 0.69, and 0.67, respectively, for mucositis (internal validation) and 0.81, 0.83, and 0.83, respectively, for dysphagia (external validation). The calibration slopes/intercepts for the PLR, FPC-LR, and FPLS-LR models were 1.6/-0.67, 0.45/0.47, and 0.40/0.49, respectively, for mucositis (internal validation) and 2.5/-0.96, 0.79/-0.04, and 0.79/0.00, respectively, for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models. FPLS and functional principal component analysis marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in normal tissue complication probability modeling. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Dose-Response Relationship between Inorganic Arsenic Exposure and Lung Cancer among Arseniasis Residents with Low Methylation Capacity.

PubMed

Hsu, Kuang-Hung; Tsui, Ke-Hung; Hsu, Ling-I; Chiou, Hung-Yi; Chen, Chien-Jen

2017-05-01

Background: Exposure to inorganic arsenic (InAs) has been documented as a risk factor for lung cancer. This study examined the association between InAs exposure, its metabolism, and lung cancer occurrence. Methods: We followed 1,300 residents from an arseniasis area in Taiwan, determined urinary InAs metabolites, and identified 39 lung cancer cases. Cox proportional hazards model was performed. Results: The results demonstrated that participants with either the primary methylation index [monomethylarsonic acid (MMA)/InAs] or the secondary methylation index [dimethylarsenic acid (DMA)/MMA] lower than their respective median values were at a higher risk of lung cancer (HRs from 3.41 to 4.66) than those with high methylation capacity. The incidence density of lung cancer increased from 79.9/100,000 (year -1 ) to 467.4/100,000 (year -1 ) for residents with low methylation capacity and from 0 to 158.5/100,000 (year -1 ) for residents with high methylation capacity when the arsenic exposure dose increased from 2 to 10 ppb to ≥200 ppb, respectively. The analyses revealed a dose-response relationship between lung cancer occurrence and increasing arsenic concentrations in drinking water as well as cumulative arsenic exposure (monotonic trend test; P < 0.05 and P < 0.05, respectively) among the residents with low methylation capacity. The relationship between arsenic exposure and lung cancer among high methylators was not statistically significant. Conclusions: Hypomethylation responses to InAs exposure may dose dependently increase lung cancer occurrence. Impact: The high-risk characteristics observed among those exposed should be considered in future preventive medicine and research on arsenic carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(5); 756-61. ©2016 AACR . ©2016 American Association for Cancer Research.

High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features

PubMed Central

Arjunan, Ananth; Wang, Hong; Saul, Melissa; Davar, Diwakar; Appleman, Leonard J.; Friedland, David; Parikh, Rahul A.

2017-01-01

Background High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12–20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10–15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. Methods Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer′s exact test and Wilcoxon rank sum test. Results Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0–21.3). Median OS was 30.5 months (95% CI 13.3–57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3–35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4–10.2). Conclusion In patients with mRCC with sarcomatoid features, use of HD IL-2 was associated with a modest ORR and a higher survival compared to historical controls (patients with mRCC and sarcomatoid features). Thus, HD IL-2 may have a role in treating selected patients with mRCC with sarcomatoid features. PMID:29261796

High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features.

PubMed

Achkar, Tala; Arjunan, Ananth; Wang, Hong; Saul, Melissa; Davar, Diwakar; Appleman, Leonard J; Friedland, David; Parikh, Rahul A

2017-01-01

High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12-20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10-15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer's exact test and Wilcoxon rank sum test. Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0-21.3). Median OS was 30.5 months (95% CI 13.3-57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3-35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4-10.2). In patients with mRCC with sarcomatoid features, use of HD IL-2 was associated with a modest ORR and a higher survival compared to historical controls (patients with mRCC and sarcomatoid features). Thus, HD IL-2 may have a role in treating selected patients with mRCC with sarcomatoid features.

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

Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy.

PubMed

Kanai, T; Endo, M; Minohara, S; Miyahara, N; Koyama-ito, H; Tomura, H; Matsufuji, N; Futami, Y; Fukumura, A; Hiraoka, T; Furusawa, Y; Ando, K; Suzuki, M; Soga, F; Kawachi, K

1999-04-01

The irradiation system and biophysical characteristics of carbon beams are examined regarding radiation therapy. An irradiation system was developed for heavy-ion radiotherapy. Wobbler magnets and a scatterer were used for flattening the radiation field. A patient-positioning system using X ray and image intensifiers was also installed in the irradiation system. The depth-dose distributions of the carbon beams were modified to make a spread-out Bragg peak, which was designed based on the biophysical characteristics of monoenergetic beams. A dosimetry system for heavy-ion radiotherapy was established to deliver heavy-ion doses safely to the patients according to the treatment planning. A carbon beam of 80 keV/microm in the spread-out Bragg peak was found to be equivalent in biological responses to the neutron beam that is produced at cyclotron facility in National Institute Radiological Sciences (NIRS) by bombarding 30-MeV deuteron beam on beryllium target. The fractionation schedule of the NIRS neutron therapy was adapted for the first clinical trials using carbon beams. Carbon beams, 290, 350, and 400 MeV/u, were used for a clinical trial from June of 1994. Over 300 patients have already been treated by this irradiation system by the end of 1997.

[The predictive value of dynamic arterial elastance in arterial pressure response after norepinephrine dosage reduction in patients with septic shock].

PubMed

Liang, F M; Yang, T; Dong, L; Hui, J J; Yan, J

2017-05-01

Objective: To assess whether dynamic arterial elastance(Ea(dyn))can be used to predict the reduction of arterial pressure after decreasing norepinephrine (NE) dosage in patients with septic shock. Methods: A prospective observational cohort study was conducted. Thirty-two patients with septic shock and mechanical ventilationwere enrolledfrom January 2014 to December 2015 in ICU of Wuxi People's Hospital of Nanjing Medical University. Hemodynamic parameters were recorded by pulse contour cardiac output(PiCCO)monitoring technology before and after decreasing norepinephrine dosage. Ea(dyn) was defined as the ratio of pulse pressure variation (PPV) to stroke volume variation (SVV). Mean arterial pressure(MAP) variation was calculated after decreasing the dose of NE. Response was defined as a ≥15% decrease of MAP. AUC was plotted to assess the value of Ea(dyn) in predicting MAP response. Results: A total of 32 patients were enrolled in our study, with 13 responding to NE dose decrease where as the other 19 did not. Ea(dyn) was lower in responders than in nonresponders (0.77±0.13 vs 1.09±0.31, P <0.05). Baseline Ea(dyn) was positively correlated with systolic blood pressure variation, diastolic blood pressure variation, systemic vascular resistance variation and MAP variation( r =0.621, P =0.000; r =0.735, P =0.000; r =0.756, P =0.000; r =0.568, P =0.000 respectively). However, stoke volume variation, baseline level of systemic vascular resistance and NE baseline dose were not correlated with Ea(dyn) baseline value( r =0.264, P =0.076; r =0.078, P =0.545; r =0.002, P =0.987 respectively). Ea(dyn)≤0.97 predicted a decrease of MAP when decreasing NE dose, with an area under the receiver-operating characteristic curve of 0.85.The sensitivity was 100.0% and specificity was 73.7%. Conclusions: In septic shock patients treated with NE, Ea(dyn) is an index to predict the decrease of arterial pressure in response to NE dose reduction.

The developing framework of marine ecotoxicology: Pollutants as a variable in marine ecosystems?

USGS Publications Warehouse

Luoma, Samuel N.

1996-01-01

Marine ecosystems include a subset in which at least some interrelated geochemical, biochemical, physiological, population and community characteristics are changed by pollutants. Moderate contamination is relatively widespread in coastal and estuarine ecosystems, so the subset of ecosystems with at least some processes affected could be relatively large. Pollutant influences have changed and will probably continue to change on time scales of decades. Biological exposures and dose in such ecosystems are species-specific and determined by how the species is exposed to different environmental media and the geochemistry of individual pollutants within those media. Bioaccumulation models offer significant promise for interpreting such exposures. Biological responses to pollutants need to be more directly linked to exposure and dose. At the level of the individual this might be improved by better understanding relationships between tissue concentrations of pollutants and responses to pollutants. Multi-discipline field and laboratory studies combined with advanced understanding of some basic processes have reduced the ambiguities in interpreting a few physiological/organismic responses to pollutants in nature. Recognition of pollutant-induced patterns in population responses could lead to similar advances. A rational framework for ecotoxicology is developing, but its further advance is dependent upon better integration of ecotoxicology with basic marine ecology and biology.

A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: A case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.

PubMed

Sun, Haoyu; Calabrese, Edward J; Zheng, Min; Wang, Dali; Pan, Yongzheng; Lin, Zhifen; Liu, Ying

2018-08-01

Hormesis occurs frequently in broadly ranging biological areas (e.g. plant biology, microbiology, biogerontology), toxicology, pharmacology and medicine. While numerous mechanisms (e.g. receptor and pathway mediated pathway responses) account for stimulatory and inhibitory features of hormetic dose responses, the vast majority emphasizes the inclusion of many doses but only one timepoint or use of a single optimized dose that is assessed over a broad range of timepoints. In this paper, a toxicity study was designed using a large number of properly spaced doses with responses determined over a large number of timepoints, which could help us reveal the underlying mechanism of hormesis. We present the results of a dose-time-response study on hormesis using five antibacterial chemicals on the bioluminescence of Aliivibrio fischeri, measuring expression of protein mRNA based on quorum sensing, simulating bioluminescent reaction and analyzing toxic actions of test chemicals. The findings show dose-time-dependent responses conforming to the hormetic dose-response model, while revealing unique response dynamics between agent induced stimulatory and inhibitory effects within bacterial growth phase dynamics. These dynamic dose-time features reveal a type of biological seesaw model that integrates stimulatory and inhibitory responses within unique growth phase, dose and time features, which has faultlessly explained the time-dependent hormetic phenomenon induced by five antibacterial chemicals (characterized by low-dose stimulation and high-dose inhibition). This study offers advances in understanding cellular dynamics, the biological integration of diverse and opposing responses and their role in evolutionary adaptive strategies to chemicals, which can provide new insight into the mechanistic investigation of hormesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

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.

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.

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

PubMed

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

2016-07-01

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

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

Field, Kevin G.; Yang, Ying; Busby, Jeremy T.

Radiation induced segregation (RIS) is a well-studied phenomena which occurs in many structurally relevant nuclear materials including austenitic stainless steels. RIS occurs due to solute atoms preferentially coupling to mobile point defect fluxes that migrate and interact with defect sinks. Here, a 304 stainless steel was neutron irradiated up to 47.1 dpa at 320 °C. Investigations into the RIS response at specific grain boundary types were utilized to determine the sink characteristics of different boundary types as a function of irradiation dose. A rate theory model built on the foundation of the modified inverse Kirkendall (MIK) model is proposed andmore » benchmarked to the experimental results. This model, termed the GiMIK model, includes alterations in the boundary conditions based on grain boundary structure and includes expressions for interstitial binding. This investigation, through experiment and modeling, found specific grain boundary structures exhibit unique defect sink characteristics depending on their local structure. Furthermore, such interactions were found to be consistent across all doses investigated and had larger global implications including precipitation of Ni-Si clusters near different grain boundary types.« less

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

Field, Kevin G.; Yang, Ying; Allen, Todd R.

Radiation induced segregation (RIS) is a well-studied phenomena which occurs in many structurally relevant nuclear materials including austenitic stainless steels. RIS occurs due to solute atoms preferentially coupling to mobile point defect fluxes that migrate and interact with defect sinks. Here, a 304 stainless steel was neutron irradiated up to 47.1 dpa at 320 °C. Investigations into the RIS response at specific grain boundary types were utilized to determine the sink characteristics of different boundary types as a function of irradiation dose. A rate theory model built on the foundation of the modified inverse Kirkendall (MIK) model is proposed andmore » benchmarked to the experimental results. This model, termed the GiMIK model, includes alterations in the boundary conditions based on grain boundary structure and includes expressions for interstitial binding. This investigation, through experiment and modeling, found specific grain boundary structures exhibit unique defect sink characteristics depending on their local structure. Such interactions were found to be consistent across all doses investigated and had larger global implications including precipitation of Ni-Si clusters near different grain boundary types.« less

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

Characterization of a new unshielded diode for small field dosimetry under flattening filter free beams.

PubMed

Reggiori, Giacomo; Mancosu, Pietro; Suchowerska, Natalka; Lobefalo, Francesca; Stravato, Antonella; Tomatis, Stefano; Scorsetti, Marta

2016-02-01

To characterize the performance of a new unshielded silicon diode (Razor-IBA) for dose measurements in small flattening filter free beams. The Razor has an active volume of 0.6 mm in diameter and 20 µm in length. The detector response stability in measured dose, dose rate, dose per pulse, and dark current were evaluated. The detector response in square fields (0.6-5.0 cm) was determined using PDD curves, axial beam profiles and output ratios. The performances were compared to that of the previously available SFD-IBA and PFD-IBA diodes. The Razor short term stability relative to the SFD was much improved (<±0.1% after 1.2 kGy). The linearity was <±1% (0.05-30 Gy range) and the dose rate dependence was <±0.5% (4-24 Gy/min range). The dose per pulse dependence was <±0.7% (0.08-0.21 cGy/pulse range). The PDDs measured with Razor and PFD differed <1%. A larger dark current was observed with increase in dose (0.0025 pA/Gy) compared to the SFD (0.0002 pA/Gy). This characteristic is attributed to an increased concentration of recombination centers. The beam profile showed good agreement with the SFD. Penumbra differences were <±0.3 mm relative to PFD, with a slight overestimation of the tails (<1%), due to the absence of diode shielding. Output ratios were in good agreement for fields up to 5 × 5 cm(2) (<1%). The Razor diode has the same spatial resolution and performance reliability as its predecessor (SFD), but exhibits the additional advantage of improved stability. These features make the Razor diode detector a good candidate for small field dosimetry. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Dosing of Intravenous Tocilizumab in a Real-World Setting of Rheumatoid Arthritis: Analyses from the Corrona Registry.

PubMed

Pappas, Dimitrios A; John, Ani; Curtis, Jeffrey R; Reed, George W; Karki, Chitra; Magner, Robert; Kremer, Joel M; Shewade, Ashwini; Greenberg, Jeffrey D

2016-06-01

In the United States, the recommended starting dose of intravenous tocilizumab (TCZ) is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response for patients with moderate to severe rheumatoid arthritis; however, data on how TCZ dose is escalated in real life are missing. The objective of this analysis was to describe patterns of early intravenous TCZ dose escalation in a real-world setting using data from the Corrona registry. All patients enrolled in the comparative effectiveness substudy (CERTAIN) nested within Corrona who initiated TCZ and completed 3- and 6-month study visits were eligible for inclusion. Patients who initiated TCZ 4 mg/kg were categorized into 1 of 2 groups: those who remained on TCZ 4 mg/kg at 3 months (Group 1) and those who escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Changes in clinical disease activity measures were provided. Of the 213 patients who were eligible for analysis, 86 (40.4%) remained on their initial dose of TCZ 4 mg/kg (Group 1) and 110 (51.6%) were escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Baseline demographic and clinical characteristics were similar between the 2 groups; except in Group 2, patients were older (58.3 vs. 54.0 years) and a lower proportion was female (75.5% vs. 89.4%) than in Group 1. Significant improvements in disease activity measures were observed at 3 and 6 months in both groups, with the majority of patients in both groups achieving moderate or good European League Against Rheumatism response. Real-world data demonstrated that physicians escalate TCZ dose at varying frequencies. The ability to administer TCZ in varying doses allows physicians to tailor TCZ therapy to disease activity. ClinicalTrials.gov identifier, NCT01625650.

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

PubMed

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

2009-06-01

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

Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

PubMed Central

Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Yoo, Yeonjoo; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.

2015-01-01

Experimental Data Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t>60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t<60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult. Mathematical Modeling We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods. PMID:25993564

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

PubMed

Jiang, Xiaoqi; Kopp-Schneider, Annette

2015-11-01

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

Discrimination and common mental disorders of undergraduate students of the Universidade Federal de Santa Catarina.

PubMed

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

2015-01-01

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

Specific issues in small animal dosimetry and irradiator calibration

PubMed Central

Yoshizumi, Terry; Brady, Samuel L.; Robbins, Mike E.; Bourland, J. Daniel

2013-01-01

Purpose In response to the increased risk of radiological terrorist attack, a network of Centers for Medical Countermeasures against Radiation (CMCR) has been established in the United States, focusing on evaluating animal model responses to uniform, relatively homogenous whole- or partial-body radiation exposures at relatively high dose rates. The success of such studies is dependent not only on robust animal models but on accurate and reproducible dosimetry within and across CMCR. To address this issue, the Education and Training Core of the Duke University School of Medicine CMCR organised a one-day workshop on small animal dosimetry. Topics included accuracy in animal dosimetry accuracy, characteristics and differences of cesium-137 and X-ray irradiators, methods for dose measurement, and design of experimental irradiation geometries for uniform dose distributions. This paper summarises the information presented and discussed. Conclusions Without ensuring accurate and reproducible dosimetry the development and assessment of the efficacy of putative countermeasures will not prove successful. Radiation physics support is needed, but is often the weakest link in the small animal dosimetry chain. We recommend: (i) A user training program for new irradiator users, (ii) subsequent training updates, and (iii) the establishment of a national small animal dosimetry center for all CMCR members. PMID:21961967

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

Hobbs, R; Le, Y; Armour, E

Purpose: Dose-response studies in radiation therapy are typically using single response values for tumors across ensembles of tumors. Using the high dose rate (HDR) treatment plan dose grid and pre- and post-therapy FDG-PET images, we look for correlations between voxelized dose and FDG uptake response in individual tumors. Methods: Fifteen patients were treated for localized rectal cancer using 192Ir HDR brachytherapy in conjunction with surgery. FDG-PET images were acquired before HDR therapy and 6–8 weeks after treatment (prior to surgery). Treatment planning was done on a commercial workstation and the dose grid was calculated. The two PETs and the treatmentmore » dose grid were registered to each other using non-rigid registration. The difference in PET SUV values before and after HDR was plotted versus absorbed radiation dose for each voxel. The voxels were then separated into bins for every 400 cGy of absorbed dose and the bin average values plotted similarly. Results: Individual voxel doses did not correlate with PET response; however, when group into tumor subregions corresponding to dose bins, eighty percent of the patients showed a significant positive correlation (R2 > 0) between PET uptake difference in the targeted region and the absorbed dose. Conclusion: By considering larger ensembles of voxels, such as organ average absorbed dose or the dose bins considered here, valuable information may be obtained. The dose-response correlations as measured by FDG-PET difference potentially underlines the importance of FDG-PET as a measure of response, as well as the value of voxelized information.« less

Characteristics of Mononuclear Phagocytes Mediating Antilisterial Resistance in Splenectomized Mice

PubMed Central

Pietrangeli, Carolynn; Pang, King C.; Skamene, Emil; Kongshavn, Patricia A. L.

1983-01-01

The characteristics of mononuclear phagocytes mediating resistance to infection with Listeria monocytogenes during the early phase (up to 48 h) of the response were investigated in mice of the A strain that had undergone splenectomy. Although irradiation in the sham-operated host had no effect on its antilisterial response when administered immediately before infection, it markedly reduced the ability of the splenectomized host to resist listerial challenge. This effect of radiation was demonstrable in the high-dose range (600 r) and could not be reversed immediately by repopulation with 20 × 106 syngeneic nucleated bone marrow cells. Administration of silica 24 h before infection profoundly enhanced the growth of L. monocytogenes in the liver of splenectomized mice. Shielding of the liver, but not the bone marrow, protected the splenectomized host against the effects of radiation, indicating that the cell population responsible for mediating the enhanced antilisterial resistance resides in the liver. The enhanced antilisterial resistance of splenectomized mice was specifically because of the absence of the spleen and not merely because of the removal of a favorable replicating environment for listeria organisms. PMID:6299948

The modified unified interaction model: incorporation of dose-dependent localised recombination.

PubMed

Lavon, A; Eliyahu, I; Oster, L; Horowitz, Y S

2015-02-01

The unified interaction model (UNIM) was developed to simulate thermoluminescence (TL) linear/supralinear dose-response and the dependence of the supralinearity on ionisation density, i.e. particle type and energy. Before the development of the UNIM, this behaviour had eluded all types of TL modelling including conduction band/valence band (CB/VB) kinetic models. The dependence of the supralinearity on photon energy was explained in the UNIM as due to the increasing role of geminate (localised recombination) with decreasing photon/electron energy. Recently, the Ben Gurion University group has incorporated the concept of trapping centre/luminescent centre (TC/LC) spatially correlated complexes and localised/delocalised recombination into the CB/VB kinetic modelling of the LiF:Mg,Ti system. Track structure considerations are used to describe the relative population of the TC/LC complexes by an electron-hole or by an electron-only as a function of both photon/electron energy and dose. The latter dependence was not included in the original UNIM formulation, a significant over-simplification that is herein corrected. The modified version, the M-UNIM, is then applied to the simulation of the linear/supralinear dose-response characteristics of composite peak 5 in the TL glow curve of LiF:Mg,Ti at two representative average photon/electron energies of 500 and 8 keV. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Low-Dose Involved-Field Radiation in the Treatment of Non-Hodgkin Lymphoma: Predictors of Response and Treatment Failure

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

Russo, Andrea L., E-mail: alrusso@partners.org; Chen, Yu-Hui; Martin, Neil E.

Purpose: To investigate clinical and pathologic factors significant in predicting local response and time to further treatment after low-dose involved-field radiation therapy (LD-IFRT) for non-Hodgkin lymphoma (NHL). Methods and Materials: Records of NHL patients treated at a single institution between April 2004 and September 2011 were retrospectively reviewed. Low-dose involved-field radiation therapy was given as 4 Gy in 2 fractions over 2 consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination. A generalized estimating equation model was used to assess the effect of tumor and patient characteristics on disease response. A Cox proportional hazardsmore » regression model was used to assess time to further treatment. Results: We treated a total of 187 sites in 127 patients with LD-IFRT. Histologies included 66% follicular, 9% chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, 10% marginal zone, 6% mantle cell lymphoma (MCL), and 8% other. Median follow-up time was 23.4 months (range, 0.03-92.2 months). The complete response, partial response, and overall response rates were 57%, 25%, and 82%, respectively. A CLL histology was associated with a lower response rate (odds ratio 0.2, 95% confidence interval 0.1-0.5, P=.02). Tumor size, site, age at diagnosis, and prior systemic therapy were not associated with response. The median time to first recurrence was 13.6 months. Those with CLL and age ≤50 years at diagnosis had a shorter time to further treatment for local failures (hazard ratio [HR] 3.63, P=.01 and HR 5.50, P=.02, respectively). Those with CLL and MCL had a shorter time to further treatment for distant failures (HR 11.1 and 16.3, respectively, P<.0001). Conclusions: High local response rates were achieved with LD-IFRT across most histologies. Chronic lymphocytic leukemia and MCL histologies and age ≤50 years at diagnosis had a shorter time to further treatment after LD-IFRT.« less

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

Exploring Multilevel Factors for Family Engagement in Home Visiting Across Two National Models.

PubMed

Latimore, Amanda D; Burrell, Lori; Crowne, Sarah; Ojo, Kristen; Cluxton-Keller, Fallon; Gustin, Sunday; Kruse, Lakota; Hellman, Daniela; Scott, Lenore; Riordan, Annette; Duggan, Anne

2017-07-01

The associations of family, home visitor and site characteristics with family engagement within the first 6 months were examined. The variation in family engagement was also explored. Home visiting program participants were drawn from 21 Healthy Families America sites (1707 families) and 9 Nurse-Family Partnership sites (650 families) in New Jersey. Three-level nested generalized linear mixed models assessed the associations of family, home visitor and site characteristics with family receipt of a high dose of services in the first 6 months of enrollment. A family was considered to have received a high dose of service in the first 6 months of enrollment if they were active at 6 months and had received at least 50% of their expected visits in the first 6 months. In general, both home visiting programs engaged, at a relatively high level (Healthy Families America (HFA) 59%, Nurse-Family Partnership (NFP) 64%), with families demonstrating high-risk characteristics such as lower maternal education, maternal smoking, and maternal mental health need. Home visitor characteristics explained more of the variation (87%) in the receipt of services for HFA, while family characteristics explained more of the variation (75%) in the receipt of services for NFP. At the family level, NFP may improve the consistency with which they engage families by increasing retention efforts among mothers with lower education and smoking mothers. HFA sites seeking to improve engagement consistency should consider increasing the flexible in home visitor job responsibilities and examining the current expected-visit policies followed by home visitors on difficult-to-engage families.

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.

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...

Accuracy of micro powder dosing via a vibratory sieve-chute system.

PubMed

Besenhard, M O; Faulhammer, E; Fathollahi, S; Reif, G; Calzolari, V; Biserni, S; Ferrari, A; Lawrence, S M; Llusa, M; Khinast, J G

2015-08-01

This paper describes a powder dosing system with a vibratory sieve mounted on a chute that doses particles into a capsule. Vertical vibration occurred with a broad range of frequencies and amplitudes. During dosing events, the fill weight was accurately recorded via a capacitance sensor, covering the capsules and making it possible to analyze filling characteristics, that is, the fill rates and their robustness. The range of frequencies and amplitudes was screened for settings that facilitated reasonable (no blocking, no spilling) fill rates for three lactose powders. The filling characteristics were studied within this operating space. The results reveal similar operating spaces for all investigated powders. The fill rate robustness varied distinctly in the operating space, which is of prime importance for selecting the settings for continuous feeding applications. In addition, we present accurate dosing studies utilizing the knowledge about the filling characteristics of each powder. Copyright © 2015 Elsevier B.V. All rights reserved.

Dedicated multichannel readout ASIC coupled with single crystal diamond for dosimeter application

NASA Astrophysics Data System (ADS)

Fabbri, A.; Falco, M. D.; De Notaristefani, F.; Galasso, M.; Marinelli, M.; Orsolini Cencelli, V.; Tortora, L.; Verona, C.; Verona Rinati, G.

2013-02-01

This paper reports on the tests of a low-noise, multi-channel readout integrated circuit used as a readout electronic front-end for a diamond multi-pixel dosimeter. The system is developed for dose distribution measurement in radiotherapy applications. The first 10-channel prototype chip was designed and fabricated in a 0.18 um CMOS process. Every channel includes a charge integrator with a 10 pF capacitor and a double slope A/D converter. The diamond multi-pixel detector, based on CVD synthetic single crystal diamond Schottky diodes, is made by a 3 × 3 sensor matrix. The overall device has been tested under irradiation with 6 MeV radio therapeutic photon beams at the Policlinico ``Tor Vergata'' (PTV) hospital. Measurements show a 20 fA RMS leakage current from the front-end input stage and a negligible dark current from the diamond detector, a stable temporal response and a good linear behaviour as a function of both dose and dose rate. These characteristics were common to each tested channel.

The Ellipta® in asthma and chronic obstructive pulmonary disease: device characteristics and patient acceptability.

PubMed

Jones, Thomas L; Neville, Daniel M; Chauhan, Anoop J

2018-02-01

Asthma and chronic obstructive pulmonary disease are primarily treated with inhaled medication, but delivery of that medication to its site of action is problematic; patients' ability to use inhalers will affect therapeutic response. Multiple inhaler devices are available but they are variably easy to use with consequent effects on compliance, intentional or otherwise. The Ellipta ® device is a novel blister strip dry powder inhaler with medium resistance and a consistent delivered dose across a range of inspiratory flow rates. The Ellipta has proven easy to use and is preferred by patients across several evaluations and compared with other inhaler devices. The Ellipta is used to administer multiple inhaled medications, all in single daily-dose regimens, making it ideal for patients who struggle with complex inhaled therapy regimens.

Blister formation at subcritical doses in tungsten irradiated by MeV protons

NASA Astrophysics Data System (ADS)

Gavish Segev, I.; Yahel, E.; Silverman, I.; Makov, G.

2017-12-01

The material response of tungsten to irradiation by MeV protons has been studied experimentally, in particular with respect to bubble and blister formation. Tungsten samples were irradiated by 2.2 MeV protons at the Soreq Applied Research Accelerator Facility (SARAF) to doses of the order of 1017 protons/cm2 which are below the reported critical threshold for blister formation derived from keV range irradiation studies. Large, well-developed blisters are observed indicating that for MeV range protons the critical threshold is at least an order of magnitude lower than the lowest value reported previously. The effects of fluence, flux, and corresponding temperature on the distribution and characteristics of the obtained blisters were studied. FIB cross sections of several blisters exposed their depth and structure.

Obstetric therapeutics-how pharmacogenetics may inform drug therapy for pregnant women in the future.

PubMed

Haas, David M

2013-09-01

Most pregnant women take prescription medications. There are many factors related to pregnancy that make finding the most effective and safe dose of a therapeutic drug difficult for providers. Genetic differences in drug-metabolizing enzymes, transporters, and receptors may also account for some of the differences in drug response. Single-nucleotide polymorphisms in drug-metabolizing enzymes, such as the cytochrome P450 families, have been studied in relation to drugs used in pregnancy. Combining clinical characteristics, physiologic parameters in pregnancy, and possibly pharmacogenetic models may allow for providers to individualize pharmacotherapy in pregnancy and get to the most effective and safe dose of medication more quickly than in the current practice model. This article discusses these issues along with helpful Web sites and references for providers.

Nonparametric estimation of benchmark doses in environmental risk assessment

PubMed Central

Piegorsch, Walter W.; Xiong, Hui; Bhattacharya, Rabi N.; Lin, Lizhen

2013-01-01

Summary An important statistical objective in environmental risk analysis is estimation of minimum exposure levels, called benchmark doses (BMDs), that induce a pre-specified benchmark response in a dose-response experiment. In such settings, representations of the risk are traditionally based on a parametric dose-response model. It is a well-known concern, however, that if the chosen parametric form is misspecified, inaccurate and possibly unsafe low-dose inferences can result. We apply a nonparametric approach for calculating benchmark doses, based on an isotonic regression method for dose-response estimation with quantal-response data (Bhattacharya and Kong, 2007). We determine the large-sample properties of the estimator, develop bootstrap-based confidence limits on the BMDs, and explore the confidence limits’ small-sample properties via a short simulation study. An example from cancer risk assessment illustrates the calculations. PMID:23914133

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

PubMed

King, Christopher R

2016-11-01

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

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

MedlinePlus

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

Enhancement of dissolution rate through eutectic mixture and solid solution of posaconazole and benznidazole.

PubMed

Figueirêdo, Camila Bezerra Melo; Nadvorny, Daniela; de Medeiros Vieira, Amanda Carla Quintas; Soares Sobrinho, José Lamartine; Rolim Neto, Pedro José; Lee, Ping I; de La Roca Soares, Monica Felts

2017-06-15

Benznidazole (BNZ), the only commercialized antichagasic drug, and the antifungal compound posaconazole (PCZ) have shown synergistic action in the therapy of Chagas disease, however both active pharmaceutical ingredients (APIs) exhibit low aqueous solubility potentially limiting their bioavailability and therapeutic efficacy. In this paper, we report for the first time the formation of a eutectic mixture as well as an amorphous solid solution of PCZ and BNZ (at the same characteristic ratio of 80:20wt%), which provided enhanced solubility and dissolution rate for both APIs. This eutectic system was characterized by DSC and the melting points obtained were used for the construction of a phase diagram. The preservation of the characteristic PXRD patterns and the IR spectra of the parent APIs, and the visualization of a characteristic eutectic lamellar crystalline microstructure using Confocal Raman Microscopy confirm this system as a true eutectic mixture. The PXRD result also confirms the amorphous nature of the prepared solid solution. Theoretical chemical analyses indicate the predominance of π-stacking interactions in the amorphous solid solution, whereas an electrostatic interaction between the APIs is responsible for maintaining the alternating lamellar crystalline microstructure in the eutectic mixture. Both the eutectic mixture and the amorphous solid solution happen to have a characteristic PCZ to BNZ ratio similar to that of their pharmacological doses for treating Chagas disease, thus providing a unique therapeutic combination dose with enhanced apparent solubility and dissolution rate. Copyright © 2017 Elsevier B.V. All rights reserved.

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

EPA Science Inventory

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

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

EPA Science Inventory

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

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

PubMed

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

2016-05-01

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

Effect of 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

A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

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

Palma, Giuseppe; Monti, Serena; D'Avino, Vittoria

Purpose: To apply a voxel-based (VB) approach aimed at exploring local dose differences associated with late radiation-induced lung damage (RILD). Methods and Materials: An interinstitutional database of 98 patients who were Hodgkin lymphoma (HL) survivors treated with postchemotherapy supradiaphragmatic radiation therapy was analyzed in the study. Eighteen patients experienced late RILD, classified according to the Radiation Therapy Oncology Group scoring system. Each patient's computed tomographic (CT) scan was normalized to a single reference case anatomy (common coordinate system, CCS) through a log-diffeomorphic approach. The obtained deformation fields were used to map the dose of each patient into the CCS. Themore » coregistration robustness and the dose mapping accuracy were evaluated by geometric and dose scores. Two different statistical mapping schemes for nonparametric multiple permutation inference on dose maps were applied, and the corresponding P<.05 significance lung subregions were generated. A receiver operating characteristic (ROC)-based test was performed on the mean dose extracted from each subregion. Results: The coregistration process resulted in a geometrically robust and accurate dose warping. A significantly higher dose was consistently delivered to RILD patients in voxel clusters near the peripheral medial-basal portion of the lungs. The area under the ROC curves (AUC) from the mean dose of the voxel clusters was higher than the corresponding AUC derived from the total lung mean dose. Conclusions: We implemented a framework including a robust registration process and a VB approach accounting for the multiple comparison problem in dose-response modeling, and applied it to a cohort of HL survivors to explore a local dose–RILD relationship in the lungs. Patients with RILD received a significantly greater dose in parenchymal regions where low doses (∼6 Gy) were delivered. Interestingly, the relation between differences in the high-dose range and RILD seems to lack a clear spatial signature.« less

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.

Characteristics and Dose Levels for Spent Reactor Fuels

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

Coates, Cameron W

2007-01-01

Current guidance considers highly radioactive special nuclear materials to be those materials that, unshielded, emit a radiation dose [rate] measured at 1 m which exceeds 100 rem/h. Smaller, less massive fuel assemblies from research reactors can present a challenge from the point of view of self protection because of their size (lower dose, easier to handle) and the desirability of higher enrichments; however, a follow-on study to cross-compare dose trends of research reactors and power reactors was deemed useful to confirm/verify these trends. This paper summarizes the characteristics and dose levels of spent reactor fuels for both research reactors andmore » power reactors and extends previous studies aimed at quantifying expected dose rates from research reactor fuels worldwide.« less

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...

In utero exposure to iodine-131 from Chernobyl fallout and anthropometric characteristics in adolescence.

PubMed

Neta, Gila; Hatch, Maureen; Kitahara, Cari M; Ostroumova, Evgenia; Bolshova, Elena V; Tereschenko, Valery P; Tronko, Mykola D; Brenner, Alina V

2014-03-01

Prenatal exposure to external radiation has been linked to growth retardation among atomic bomb survivors in adolescence. It is unclear from previous studies whether in utero exposure to internal radiation such as iodine-131 (I-131), which concentrates in the thyroid gland, has an effect on physical growth. We examined the associations between estimated thyroid gland dose from prenatal exposure to I-131 and self-reported height and weight in a cohort of 2,460 individuals exposed to radioactive fallout from the 1986 Chernobyl nuclear accident [mean I-131 dose = 72 (mGy)] and screened for thyroid diseases in adolescence. Using multivariable linear regression models, we estimated the mean differences in height, weight and body mass index (BMI) per unit increase in dose (100 mGy) in models adjusted for gender, age at examination, type of residence (rural/urban) and presence of thyroid disease diagnosed at screening. All of the adjustment factors as well as the trimester of exposure were evaluated as potential modifiers of the dose response. Overall, no significant dose response was found for height (P = 0.29), weight (P = 0.14) or BMI (P = 0.16). We found significant modification of the dose response for weight and BMI by presence/absence of thyroid disease (P = 0.02 and P = 0.03, respectively), but not for other factors. In individuals without thyroid disease (n = 1,856), there was a weak, significant association between I-131 thyroid dose and higher weight (210 g per 100 mGy, P = 0.02) or BMI (70 g/m² per 100 mGy, P = 0.02) that depended on individuals (n = 52) exposed to ≥500 mGy. In individuals with thyroid disease (n = 579, 67.4% with simple diffuse goiter) no significant association with I-131 for weight (P = 0.14) or BMI (P = 0.14) was found. These results do not support the hypothesis that in utero exposure to I-131 at levels experienced by a majority of study subjects may be associated with meaningful differences in adolescent anthropometry. However, additional studies are needed to clarify whether in utero exposure to I-131 at levels > = 500 mGy may be associated with increases in weight/BMI and to evaluate the confounding or modifying role of thyroid disease, past iodine deficiency, maternal and prenatal/postnatal factors.

The Development of a Beta-Gamma Personnel Dosimeter

NASA Astrophysics Data System (ADS)

Tsakeres, Frank Steven

The assessment of absorbed dose in mixed beta and gamma radiation fields is an extremely complex task. For many years, the assessment of the absorbed dose to tissue from the weakly penetrating components of a radiation field (i.e., beta particles, electrons) has been largely ignored. Beta radiation fields are encountered routinely in a nuclear facility and may represent the major radiation component under certain accident or emergency conditions. Many attempts have been made to develop an accurate mixed field personnel dosimeter. However, all of these dosimeters have exhibited numerous response problems which have limited their usefulness for personnel dose assessment. Consequently, the determination of the absorbed dose at the epidermal depth (i.e., 7 mg/cm('2)) has been difficult to measure accurately. The objective of this research project was to design, build, and test a sensitive and accurate personnel dosimeter for mixed field applications. The selection of the various dosimeter elements were determined by evaluating several types of phosphors, filters, and backscatter materials. After evaluating the various response characteristics of the badge components, a prototype dosimeter, the CHEMM (CaF(,2):Dy Highly Efficient Multiple Element Multiple Filter) personnel dosimeter, was developed and tested at Georgia Tech, Emory University and the National Bureau of Standards. This dosimeter was comprised of four large CaF(,2):Dy (TLD-200) TLD's and a standard LiF (TLD-100) chip. The weakly penetrating and penetrating components of a radiation field were separated using a series of TLD/filter combinations and a new dose assessment algorithm. The large TLD-200 chips, along with a series of tissue-equivalent filters, were used to determine the absorbed dose due to the weakly penetrating radiation while a LiF/filter combination was used to measure the penetrating component. In addition, a new backscatter material was included in the badge design to better simulate a tissue-equivalent response. The CHEMM personnel dosimeter performance tests were conducted to simulate actual mixed radiation field environments. This dosimeter provided a high degree of sensitivity with accuracies well within the ANSI recommended performance standards for personnel dosimeters. In addition, it was concluded that the CHEMM dosimetry system provided a practical dosimeter alternative with a higher dose assessment accuracy and measurement sensitivity than the personnel dosimetry systems presently used in the nuclear power industry.

In Utero Exposure to Iodine-131 from Chernobyl Fallout and Anthropometric Characteristics in Adolescence

PubMed Central

Neta, Gila; Hatch, Maureen; Kitahara, Cari M.; Ostroumova, Evgenia; Bolshova, Elena V.; Tereschenko, Valery P.; Tronko, Mykola D.; Brenner, Alina V.

2014-01-01

Prenatal exposure to external radiation has been linked to growth retardation among atomic bomb survivors in adolescence. It is unclear from previous studies whether in utero exposure to internal radiation such as iodine-131 (I-131), which concentrates in the thyroid gland, has an effect on physical growth. We examined the associations between estimated thyroid gland dose from prenatal exposure to I-131 and self-reported height and weight in a cohort of 2,460 individuals exposed to radioactive fallout from the 1986 Chernobyl nuclear accident [mean I-131 dose = 72 (mGy)] and screened for thyroid diseases in adolescence. Using multivariable linear regression models, we estimated the mean differences in height, weight and body mass index (BMI) per unit increase in dose (100 mGy) in models adjusted for gender, age at examination, type of residence (rural/urban) and presence of thyroid disease diagnosed at screening. All of the adjustment factors as well as the trimester of exposure were evaluated as potential modifiers of the dose response. Overall, no significant dose response was found for height (P = 0.29), weight (P = 0.14) or BMI (P = 0.16). We found significant modification of the dose response for weight and BMI by presence/absence of thyroid disease (P = 0.02 and P = 0.03, respectively), but not for other factors. In individuals without thyroid disease (n = 1,856), there was a weak, significant association between I-131 thyroid dose and higher weight (210 g per 100 mGy, P = 0.02) or BMI (70 g/m2 per 100 mGy, P = 0.02) that depended on individuals (n = 52) exposed to ≥500 mGy. In individuals with thyroid disease (n = 579, 67.4% with simple diffuse goiter) no significant association with I-131 for weight (P = 0.14) or BMI (P = 0.14) was found. These results do not support the hypothesis that in utero exposure to I-131 at levels experienced by a majority of study subjects may be associated with meaningful differences in adolescent anthropometry. However, additional studies are needed to clarify whether in utero exposure to I-131 at levels > = 500 mGy may be associated with increases in weight/BMI and to evaluate the confounding or modifying role of thyroid disease, past iodine deficiency, maternal and prenatal/postnatal factors. PMID:24611659

Exfoliated graphite with graphene flakes as potential candidates for TL dosimeters at high gamma doses.

PubMed

Ortiz-Morales, A; López-González, E; Rueda-Morales, G; Ortega-Cervantez, G; Ortiz-Lopez, J

2018-06-06

Graphite powder (GP) subjected to microwave radiation (MWG) results in exfoliation of graphite particles into few-layered graphene flakes (GF) intermixed with partially exfoliated graphite particles (PEG). Characterization of MWG by Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM) and Raman spectroscopy reveal few-layer GF with sizes ranging from 0.2 to 5 µm. Raman D, G, and 2D (G') bands characteristic of graphitic structures include evidence of the presence of bilayered graphene. The thermoluminescent (TL) dosimetric properties of MWG are evaluated and can be characterized as a gamma-ray sensitive and dose-resistant material with kinetic parameters (activation energy for the main peak located at 400 and 408 K is 0.69 and 0.72 eV) and threshold dose (~1 kGy and 5 kGy respectively). MWG is a low-Z material (Z eff = 6) with a wide linear range of TL dose-response (0.170-2.5 kGy) tested at doses in the 1-20 kGy range with promising results for applications in gamma-ray dosimetry. Results obtained in gamma irradiated MWG are compared with those obtained in graphite powder samples (GP) without microwave treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Characterization of the exradin W1 plastic scintillation detector for small field applications in proton therapy.

PubMed

Hoehr, C; Lindsay, C; Beaudry, J; Penner, C; Strgar, V; Lee, R; Duzenli, C

2018-05-04

Accurate dosimetry in small field proton therapy is challenging, particularly for applications such as ocular therapy, and suitable detectors for this purpose are sought. The Exradin W1 plastic scintillating fibre detector is known to out-perform most other detectors for determining relative dose factors for small megavoltage photon beams used in radiotherapy but its potential in small proton beams has been relatively unexplored in the literature. The 1 mm diameter cylindrical geometry and near water equivalence of the W1 makes it an attractive alternative to other detectors. This study examines the dosimetric performance of the W1 in a 74 MeV proton therapy beam with particular focus on detector response characteristics relevant to relative dose measurement in small fields suitable for ocular therapy. Quenching of the scintillation signal is characterized and demonstrated not to impede relative dose measurements at a fixed depth. The background cable-only (Čerenkov and radio-fluorescence) signal is 4 orders of magnitude less than the scintillation signal, greatly simplifying relative dose measurements. Comparison with other detectors and Monte Carlo simulations indicate that the W1 is useful for measuring relative dose factors for field sizes down to 5 mm diameter and shallow spread out Bragg peaks down to 6 mm in depth.

Characterization of the exradin W1 plastic scintillation detector for small field applications in proton therapy

NASA Astrophysics Data System (ADS)

Hoehr, C.; Lindsay, C.; Beaudry, J.; Penner, C.; Strgar, V.; Lee, R.; Duzenli, C.

2018-05-01

Accurate dosimetry in small field proton therapy is challenging, particularly for applications such as ocular therapy, and suitable detectors for this purpose are sought. The Exradin W1 plastic scintillating fibre detector is known to out-perform most other detectors for determining relative dose factors for small megavoltage photon beams used in radiotherapy but its potential in small proton beams has been relatively unexplored in the literature. The 1 mm diameter cylindrical geometry and near water equivalence of the W1 makes it an attractive alternative to other detectors. This study examines the dosimetric performance of the W1 in a 74 MeV proton therapy beam with particular focus on detector response characteristics relevant to relative dose measurement in small fields suitable for ocular therapy. Quenching of the scintillation signal is characterized and demonstrated not to impede relative dose measurements at a fixed depth. The background cable-only (Čerenkov and radio-fluorescence) signal is 4 orders of magnitude less than the scintillation signal, greatly simplifying relative dose measurements. Comparison with other detectors and Monte Carlo simulations indicate that the W1 is useful for measuring relative dose factors for field sizes down to 5 mm diameter and shallow spread out Bragg peaks down to 6 mm in depth.

Individualized Radiation Dose Escalation Based on the Decrease in Tumor FDG Uptake and Normal Tissue Constraints Improve Survival in Patients With Esophageal Carcinoma.

PubMed

Ma, Jinbo; Wang, Zhaoyang; Wang, Chengde; Chen, Ercheng; Dong, Yaozong; Song, Yipeng; Wang, Wei; You, Dong; Jiang, Wei; Zang, Rukun

2017-02-01

To determine whether individualized radiation dose escalation after planned chemoradiation based on the decrease in tumor and normal tissue constraints can improve survival in patients with esophageal carcinoma. From August 2005 to December 2010, 112 patients with squamous esophageal carcinoma were treated with radical concurrent chemoradiation. Patients received positron emission tomography-computer tomography scan twice, before radiation and after radiation dose of 50.4 Gy. All patients were noncomplete metabolic response groups according to the Response Evaluation Criteria in solid tumors. Only 52 patients with noncomplete metabolic response received individualized dose escalation based on tumor and normal tissue constraints. Survival and treatment failure were observed and analyzed using SPSS (13.0). The rate of complete metabolic response for patients with noncomplete metabolic response after dose escalation reached 17.3% (9 of 52). The 2-year overall survival rates for patients with noncomplete metabolic response in the conventional and dose-escalation groups were 20.5% and 42.8%, respectively( P = .001). The 2-year local control rates for patients were 35.7% and 76.2%, respectively ( P = .002). When patients were classified into partial metabolic response and no metabolic response, 2-year overall survival rates for patients with partial metabolic response were significantly different in conventional and dose-escalation groups (33.8% vs 78.4%; P = .000). The 2-year overall survival rates for patients with no metabolic response in two groups (8.6% vs 15.1%) did not significantly differ ( P = .917). Individualized radiation dose escalation has the potential to improve survival in patients with esophageal carcinoma according to increased rate of complete metabolic response. However, further trials are needed to confirm this and to identify patients who may benefit from dose escalation.

VKORC1 and VKORC1L1 have distinctly different oral anticoagulant dose-response characteristics and binding sites

PubMed Central

Czogalla, Katrin J.; Liphardt, Kerstin; Höning, Klara; Hornung, Veit; Biswas, Arijit; Watzka, Matthias

2018-01-01

Vitamin K reduction is catalyzed by 2 enzymes in vitro: the vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) and its isozyme VKORC1-like1 (VKORC1L1). In vivo, VKORC1 reduces vitamin K to sustain γ-carboxylation of vitamin K-dependent proteins, including coagulation factors. Inhibition of VKORC1 by oral anticoagulants (OACs) is clinically used in therapy and in prevention of thrombosis. However, OACs also inhibit VKORC1L1, which was previously shown to play a role in intracellular redox homeostasis in vitro. Here, we report data for the first time on specific inhibition of both VKOR enzymes for various OACs and rodenticides examined in a cell-based assay. Effects on endogenous VKORC1 and VKORC1L1 were independently investigated in genetically engineered HEK 293T cells that were knocked out for the respective genes by CRISPR/Cas9 technology. In general, dose-responses for 4-hydroxycoumarins and 1,3-indandiones were enzyme-dependent, with lower susceptibility for VKORC1L1 compared with VKORC1. In contrast, rodenticides exhibited nearly identical dose-responses for both enzymes. To explain the distinct inhibition pattern, we performed in silico modeling suggesting different warfarin binding sites for VKORC1 and VKORC1L1. We identified arginine residues at positions 38, 42, and 68 in the endoplasmatic reticulum luminal loop of VKORC1L1 responsible for charge-stabilized warfarin binding, resulting in a binding pocket that is diametrically opposite to that of VKORC1. In conclusion, our findings provide insight into structural and molecular drug binding on VKORC1, and especially on VKORC1L1. PMID:29581108

Dexmedetomidine in Attenuation of Haemodynamic Response and Dose Sparing Effect on Opioid and Anaesthetic Agents in Patients undergoing Laparoscopic Cholecystectomy- A Randomized Study

PubMed Central

Bhagat, Nandlal; Karim, Habib Md Reazaul; Hajong, Ranendra; Bhattacharyya, Prithwis; Singh, Manorama

2016-01-01

Introduction Perioperative procedures are stressful and lead to haemodynamic instability with potentially devastating consequences. Dexmedetomidine is found to have many of the desired characteristics that are required in perioperative period. Aim To evaluate the ability of pre and intraoperative dexmedetomidine to attenuate stress induced haemodynamic responses, quantifying the anaesthetic agents sparing as well as its cost-effectiveness in patients undergoing laparoscopic cholecystectomy. Materials and Methods The present single blind randomized study was conducted with 120 ASA I and II consented patients who underwent laparoscopic cholecystectomy. Patients were randomly divided into 2 groups (i.e., group D and group N). Prior to induction, group D received 1 μg/kg of Dexmedetomidine and group N received Normal saline infusion over 20 minutes. Group D also received maintenance Dexmedetomidine intraoperatively. Bispectral index and minimum alveolar concentration monitoring was done in both the groups. Haemodynamic parameters were noted till 100 minutes post laryngoscopy. Opioid and anaesthetic agent consumptions were also noted and cost analysis was done. Medcalc–Version 12.5.0.0 software was used for statistics and p <0.05 was considered significant. Results Dexmedetomidine attenuated the stress induced haemodynamics responses and produced stable, relatively non fluctuating haemodynamics throughout. The Minimum Alveolar Concentration (MAC) requirement and the consumptions of Fentanyl and Isoflurane were significantly less in the Dexmedetomidine group (p<0.0001). However, despite anaesthetic dose sparing effect the anaesthetic technique was not cost-effective. Conclusion Dexmedetomidine is effective in attenuating haemodynamic responses in laparoscopic surgery and having dose sparing effect on Fentanyl, Propofol and Isoflurane. However, overall this technique is not cost-effective. PMID:28050479

Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

PubMed Central

Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

2012-01-01

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

Effect of 3 Different Doses of Intrathecal Dexmedetomidine (2.5µg, 5µg, and 10 µg) on Subarachnoid Block Characteristics: A Prospective Randomized Double Blind Dose-Response Trial.

PubMed

Gupta, Mayank; Gupta, Priyanka; Singh, Dhananjay Kumar

2016-03-01

The extended analgesic efficacy of intrathecal dexmedetomidine (ITD) has been investigated in a few clinical trials; however, there is a lack of conclusive evidence upon its ideal dosage. To elucidate the dose-response relationship between ITD and subarachnoid block characteristics, particularly the duration of analgesia and differential analgesia (DA: defined as time difference from the offset of motor blockade to the first analgesic requirement on numerical rating scale = 4.0). Prospective, randomized double blind active control trial. Medical college teaching hospital. Ninety adult (18 - 60 years) patients undergoing elective lower abdominal and lower limb surgeries were randomized into 3 groups to receive intrathecal 0.5% bupivacaine 3 mL with 2.5 µg (group BD2.5), 5µg (group BD5), or 10 µg (group BD10) dexmedetomidine in 0.5 mL normal saline. The 2 segment sensory regression times (TSSRT), duration of motor blockade analgesia, DA, and perioperative adverse effects were assessed. The primary outcome was duration of analgesia and DA. ANOVA, Kruskal Wallis test, Chi-square (x2), and Fisher's exact test, significance: P < 0.05. The onset of sensory block was significantly earlier in group BD10 compared with group BD5 (P = 0.035) and BD2.5 (P = 0.010) while the onset of motor block was significantly earlier in group BD10 compared with BD2.5 (P = 0.020). There was a significant and dose-dependent prolongation of the duration of sensory block (127.50, 149.17, and 187.50 minutes; P < 0.001), motor block (258.50, 331, and 365 minutes; P < 0.001), analgesia (306.17, 396.50, and 512 minutes; P < 0.001), and DA (47.67, 65.50, and147 minutes; P < 0.001) with escalating doses of ITD, respectively. Group BD10 required significantly fewer rescue analgesics compared with other 2 groups (P = 0.001). Except for mild sedation which was significantly higher in group BD10; all the groups were comparable with respect to hemodynamic and other adverse effects. Lack of placebo group, exclusion of higher doses (15µg) of ITD, and short duration of postoperative follow-up. The addition of 10 µg compared with 2.5 µg or 5µg ITD to 0.5% hyperbaric bupivacaine is associated with significantly earlier onset of sensory and motor block as well as prolonged duration of sensory block, motor block, analgesia, and DA with a comparable adverse effect profile.

Feasibility Study of Glass Dosimeter for In Vivo Measurement: Dosimetric Characterization and Clinical Application in Proton Beams

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

Rah, Jeong-Eun; Oh, Do Hoon; Kim, Jong Won

Purpose: To evaluate the suitability of the GD-301 glass dosimeter for in vivo dose verification in proton therapy. Methods and Materials: The glass dosimeter was analyzed for its dosimetrics characteristic in proton beam. Dosimeters were calibrated in a water phantom using a stairlike holder specially designed for this study. To determine the accuracy of the glass dosimeter in proton dose measurements, we compared the glass dosimeter and thermoluminescent dosimeter (TLD) dose measurements using a cylindrical phantom. We investigated the feasibility of the glass dosimeter for the measurement of dose distributions near the superficial region for proton therapy plans with amore » varying separation between the target volume and the surface of 6 patients. Results and Discussion: Uniformity was within 1.5%. The dose-response has good linearity. Dose-rate, fading, and energy dependence were found to be within 3%. The beam profile measured using the glass dosimeter was in good agreement with the profile obtained from the ionization chamber. Depth-dose distributions in nonmodulated and modulated proton beams obtained with the glass dosimeter were estimated to be within 3%, which was lower than those with the ionization chamber. In the phantom study, the difference of isocenter dose between the delivery dose calculated by the treatment planning system and that measured by the glass dosimeter was within 5%. With in vivo dosimetry, the calculated surface doses overestimated measurements by 4%-16% using glass dosimeter and TLD. Conclusion: It is recommended that bolus be added for these clinical cases. We also believe that the glass dosimeter has considerable potential for use with in vivo patient proton dosimetry.« less

Feasibility study of glass dosimeter for in vivo measurement: dosimetric characterization and clinical application in proton beams.

PubMed

Rah, Jeong-Eun; Oh, Do Hoon; Kim, Jong Won; Kim, Dae-Hyun; Suh, Tae-Suk; Ji, Young Hoon; Shin, Dongho; Lee, Se Byeong; Kim, Dae Yong; Park, Sung Yong

2012-10-01

To evaluate the suitability of the GD-301 glass dosimeter for in vivo dose verification in proton therapy. The glass dosimeter was analyzed for its dosimetrics characteristic in proton beam. Dosimeters were calibrated in a water phantom using a stairlike holder specially designed for this study. To determine the accuracy of the glass dosimeter in proton dose measurements, we compared the glass dosimeter and thermoluminescent dosimeter (TLD) dose measurements using a cylindrical phantom. We investigated the feasibility of the glass dosimeter for the measurement of dose distributions near the superficial region for proton therapy plans with a varying separation between the target volume and the surface of 6 patients. Uniformity was within 1.5%. The dose-response has good linearity. Dose-rate, fading, and energy dependence were found to be within 3%. The beam profile measured using the glass dosimeter was in good agreement with the profile obtained from the ionization chamber. Depth-dose distributions in nonmodulated and modulated proton beams obtained with the glass dosimeter were estimated to be within 3%, which was lower than those with the ionization chamber. In the phantom study, the difference of isocenter dose between the delivery dose calculated by the treatment planning system and that measured by the glass dosimeter was within 5%. With in vivo dosimetry, the calculated surface doses overestimated measurements by 4%-16% using glass dosimeter and TLD. It is recommended that bolus be added for these clinical cases. We also believe that the glass dosimeter has considerable potential for use with in vivo patient proton dosimetry. Copyright © 2012 Elsevier Inc. All rights reserved.

SU-E-T-139: Feasibility Study of Glass Dosimeter for in Vivo Measurement: Dosimetric Characterization and Clinical Application in Proton Beams.

PubMed

Lah, J; Kim, D; Park, S

2012-06-01

To evaluate the suitability of the GD-301 glass dosimeter for use in in vivo dose verification in proton therapy. The glass dosimeter was analyzed for its dosimetric characteristic in proton beam. Dosimeters were calibrated in a water phantom using a stair-like holder specially designed for this study. To determine the accuracy of the glass dosimeter in proton dose measurements, we compared the glass dosimeter and TLD dose measurements of plan delivery using a cylindrical phantom. We investigated the feasibility of the glass dosimeter for the measurement of dose distributions near the superficial region for proton therapy plans with a varying separation between the target volume and the surface of 6 patients. Uniformity was within 1.5%. The dose-response has a good linear. Dose-rate, fading, and energy dependence were found to be within 3%. The beam profile measured using the glass dosimeter was in good agreement with the profile obtained from the ionization chamber. Depth-dose distributions in non-modulated and modulated proton beams obtained with the glass dosimeter were estimated to be within 3%, which was lower than those with the ionization chamber. In the phantom study, the difference of isocenter dose between the delivery dose calculated by the Eclipse and that of the measured by the glass dosimeter was within 5%. In vivo dosimetry of patients, given the results of the glass dosimeter and TLD measurements, calculated doses on the surface of the patient are typically overestimated between 4% and 16%. As such, it is recommended that bolus be added for these clinical cases. We also believe that the glass dosimeter has considerable potential to be used for in vivo patient proton dosimetry. © 2012 American Association of Physicists in Medicine.

Anastomotic Complications After Ivor Lewis Esophagectomy in Patients Treated With Neoadjuvant Chemoradiation Are Related to Radiation Dose to the Gastric Fundus

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

Vande Walle, Caroline; Ceelen, Wim P., E-mail: wim.ceelen@ugent.be; Boterberg, Tom

2012-03-01

Purpose: Neoadjuvant chemoradiation (CRT) is increasingly used in locally advanced esophageal cancer. Some studies have suggested that CRT results in increased surgical morbidity. We assessed the influence of CRT on anastomotic complications in a cohort of patients who underwent CRT followed by Ivor Lewis esophagectomy. Patients and Methods: Clinical and pathologic data were collected from all patients treated with neoadjuvant CRT (36 Gy combined with 5-fluorouracil and cisplatin) followed by Ivor Lewis esophagectomy. On the radiotherapy (RT) planning computed tomography scans, normal tissue volumes were drawn encompassing the proximal esophageal region and the gastric fundus. Within these volumes, dose-volume histogramsmore » were analyzed to generate the total dose to 50% of the volume (D{sub 50}). We studied the ability of the D{sub 50} to predict anastomotic complications (leakage, ischemia, or stenosis). Dose limits were derived using receiver operating characteristics analysis. Results: Fifty-four patients were available for analysis. RT resulted in either T or N downstaging in 51% of patients; complete pathologic response was achieved in 11%. In-hospital mortality was 5.4%, and major morbidity occurred in 36% of patients. Anastomotic complications (AC) developed in 7 patients (13%). No significant influence of the D{sub 50} on the proximal esophagus was noted on the anastomotic complication rate. The median D{sub 50} on the gastric fundus, however, was 33 Gy in patients with AC and 18 Gy in patients without AC (p = 0.024). Using receiver operating characteristics analysis, the D{sub 50} limit on the gastric fundus was defined as 29 Gy. Conclusions: In patients undergoing neoadjuvant CRT followed by Ivor Lewis esophagectomy, the incidence of AC is related to the RT dose on the gastric fundus but not to the dose received by the proximal esophagus. When planning preoperative RT, efforts should be made to limit the median dose on the gastric fundus to 29 Gy with a V{sub 30} below 40%.« less

Statistical analysis of nonmonotonic dose-response relationships: research design and analysis of nasal cell proliferation in rats exposed to formaldehyde.

PubMed

Gaylor, David W; Lutz, Werner K; Conolly, Rory B

2004-01-01

Statistical analyses of nonmonotonic dose-response curves are proposed, experimental designs to detect low-dose effects of J-shaped curves are suggested, and sample sizes are provided. For quantal data such as cancer incidence rates, much larger numbers of animals are required than for continuous data such as biomarker measurements. For example, 155 animals per dose group are required to have at least an 80% chance of detecting a decrease from a 20% incidence in controls to an incidence of 10% at a low dose. For a continuous measurement, only 14 animals per group are required to have at least an 80% chance of detecting a change of the mean by one standard deviation of the control group. Experimental designs based on three dose groups plus controls are discussed to detect nonmonotonicity or to estimate the zero equivalent dose (ZED), i.e., the dose that produces a response equal to the average response in the controls. Cell proliferation data in the nasal respiratory epithelium of rats exposed to formaldehyde by inhalation are used to illustrate the statistical procedures. Statistically significant departures from a monotonic dose response were obtained for time-weighted average labeling indices with an estimated ZED at a formaldehyde dose of 5.4 ppm, with a lower 95% confidence limit of 2.7 ppm. It is concluded that demonstration of a statistically significant bi-phasic dose-response curve, together with estimation of the resulting ZED, could serve as a point-of departure in establishing a reference dose for low-dose risk assessment.

Experimental verification of bremsstrahlung production and dosimetry predictions for 15.5 MeV electrons

NASA Astrophysics Data System (ADS)

Sanford, T. W. L.; Beutler, D. E.; Halbleib, J. A.; Knott, D. P.

1991-12-01

The radiation produced by a 15.5-MeV monoenergetic electron beam incident on optimized and nonoptimized bremsstrahlung targets is characterized using the ITS Monte Carlo code and measurements with equilibrated and nonequilibrated TLD dosimetry. Comparisons between calculations and measurements verify the calculations and demonstrate that the code can be used to predict both bremsstrahlung production and TLD response for radiation fields that are characteristic of those produced by pulsed simulators of gamma rays. The comparisons provide independent confirmation of the validity of the TLD calibration for photon fields characteristic of gamma-ray simulators. The empirical Martin equation, which is often used to calculate radiation dose from optimized bremsstrahlung targets, is examined, and its range of validity is established.

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...

The two-dimensional Monte Carlo: a new methodologic paradigm for dose reconstruction for epidemiological studies.

PubMed

Simon, Steven L; Hoffman, F Owen; Hofer, Eduard

2015-01-01

Retrospective dose estimation, particularly dose reconstruction that supports epidemiological investigations of health risk, relies on various strategies that include models of physical processes and exposure conditions with detail ranging from simple to complex. Quantification of dose uncertainty is an essential component of assessments for health risk studies since, as is well understood, it is impossible to retrospectively determine the true dose for each person. To address uncertainty in dose estimation, numerical simulation tools have become commonplace and there is now an increased understanding about the needs and what is required for models used to estimate cohort doses (in the absence of direct measurement) to evaluate dose response. It now appears that for dose-response algorithms to derive the best, unbiased estimate of health risk, we need to understand the type, magnitude and interrelationships of the uncertainties of model assumptions, parameters and input data used in the associated dose estimation models. Heretofore, uncertainty analysis of dose estimates did not always properly distinguish between categories of errors, e.g., uncertainty that is specific to each subject (i.e., unshared error), and uncertainty of doses from a lack of understanding and knowledge about parameter values that are shared to varying degrees by numbers of subsets of the cohort. While mathematical propagation of errors by Monte Carlo simulation methods has been used for years to estimate the uncertainty of an individual subject's dose, it was almost always conducted without consideration of dependencies between subjects. In retrospect, these types of simple analyses are not suitable for studies with complex dose models, particularly when important input data are missing or otherwise not available. The dose estimation strategy presented here is a simulation method that corrects the previous deficiencies of analytical or simple Monte Carlo error propagation methods and is termed, due to its capability to maintain separation between shared and unshared errors, the two-dimensional Monte Carlo (2DMC) procedure. Simply put, the 2DMC method simulates alternative, possibly true, sets (or vectors) of doses for an entire cohort rather than a single set that emerges when each individual's dose is estimated independently from other subjects. Moreover, estimated doses within each simulated vector maintain proper inter-relationships such that the estimated doses for members of a cohort subgroup that share common lifestyle attributes and sources of uncertainty are properly correlated. The 2DMC procedure simulates inter-individual variability of possibly true doses within each dose vector and captures the influence of uncertainty in the values of dosimetric parameters across multiple realizations of possibly true vectors of cohort doses. The primary characteristic of the 2DMC approach, as well as its strength, are defined by the proper separation between uncertainties shared by members of the entire cohort or members of defined cohort subsets, and uncertainties that are individual-specific and therefore unshared.

Animal and human dose-response models for Brucella species.

PubMed

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

2011-10-01

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

Gafchromic EBT-XD film: Dosimetry characterization in high-dose, volumetric-modulated arc therapy.

PubMed

Miura, Hideharu; Ozawa, Shuichi; Hosono, Fumika; Sumida, Naoki; Okazue, Toshiya; Yamada, Kiyoshi; Nagata, Yasushi

2016-11-08

Radiochromic films are important tools for assessing complex dose distributions. Gafchromic EBT-XD films have been designed for optimal performance in the 40-4,000 cGy dose range. We investigated the dosimetric characteristics of these films, including their dose-response, postexposure density growth, and dependence on scanner orientation, beam energy, and dose rate with applications to high-dose volumetric-modulated arc therapy (VMAT) verification. A 10 MV beam from a TrueBeam STx linear accelerator was used to irradiate the films with doses in the 0-4,000 cGy range. Postexposure coloration was analyzed at postirradiation times ranging from several minutes to 48 h. The films were also irradiated with 6 MV (dose rate (DR): 600 MU/min), 6 MV flattening filter-free (FFF) (DR: 1,400 MU/ min), and 10 MV FFF (DR: 2,400 MU/min) beams to determine the energy and dose-rate dependence. For clinical examinations, we compared the dose distribu-tion measured with EBT-XD films and calculated by the planning system for four VMAT cases. The red channel of the EBT-XD film exhibited a wider dynamic range than the green and blue channels. Scanner orientation yielded a variation of ~ 3% in the net optical density (OD). The difference between the film front and back scan orientations was negligible, with variation of ~ 1.3% in the net OD. The net OD increased sharply within the first 6 hrs after irradiation and gradually afterwards. No significant difference was observed for the beam energy and dose rate, with a variation of ~ 1.5% in the net OD. The gamma passing rates (at 3%, 3 mm) between the film- measured and treatment planning system (TPS)-calculated dose distributions under a high dose VMAT plan in the absolute dose mode were more than 98.9%. © 2016 The Authors.

Impact of Nagasaki atomic bomb exposure on myelodysplastic syndrome patients who are treated with azacitidine.

PubMed

Jo, Tatsuro; Horio, Kensuke; Shigematsu, Kazuto

2015-05-01

High-dose radiation exposure greatly increases the risk of myelodysplastic syndromes (MDS), however the clinical characteristics of MDS among atomic bomb survivors have not been thoroughly investigated to date. We designed this study to identify these characteristics. We retrospectively evaluated data from 13 atomic bomb survivors with MDS and 15 elderly patients with de novo MDS who were diagnosed between April 2011 and April 2013 at the Nagasaki Genbaku Hospital. All patients were treated with azacitidine (AZA; a hypomethylating agent) and overall survival rates were estimated. No clear difference was observed in the clinical response to AZA between the two groups. However, atomic bomb survivors had a survival disadvantage, independent of their karyotype. Minute genetic alterations caused by exposure to atomic radiation can adversely affect the response to AZA, even 66 years after the exposure. Further studies are required to clarify the mechanisms underlying this phenomenon. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Comparative transcriptome analysis of rice seedlings induced by different doses of heavy ion radiation

NASA Astrophysics Data System (ADS)

Zhao, Qian; Sun, Yeqing; Wang, Wei

2016-07-01

Highly ionizing radiation (HZE) in space is considered as a main factor causing biological effects on plant seeds. To investigate the different effects on genome-wide gene expression of low-dose and high-dose ion radiation, we carried out ground-base carbon particle HZE experiments with different cumulative doses (0Gy, 0.2Gy, 2Gy) to rice seeds and then performed comparative transcriptome analysis of the rice seedlings. We identified a total of 2551 and 1464 differentially expressed genes (DEGs) in low-dose and high-dose radiation groups, respectively. Gene ontology analyses indicated that low-dose and high-dose ion radiation both led to multiple physiological and biochemical activities changes in rice. By Gene Ontology analyses, the results showed that only one process-oxidation reduction process was enriched in the biological process category after high-dose ion radiation, while more processes such as response to biotic stimulus, heme binding, tetrapyrrole binding, oxidoreductase activity, catalytic activity and oxidoreductase activity were significantly enriched after low-dose ion radiation. The results indicated that the rice plants only focused on the process of oxidation reduction to response to high-dose ion radiation, whereas it was a coordination of multiple biological processes to response to low-dose ion radiation. To elucidate the transcriptional regulation of radiation stress-responsive genes, we identified several DEGs-encoding TFs. AP2/EREBP, bHLH, C2H2, MYB and WRKY TF families were altered significantly in response to ion radiation. Mapman analysis speculated that the biological effects on rice seedlings caused by the radiation stress might share similar mechanisms with the biotic stress. Our findings highlight important alterations in the expression of radiation response genes, metabolic pathways, and TF-encoding genes in rice seedlings exposed to low-dose and high-dose ion radiation.

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

EPA Science Inventory

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

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

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

Niedzielski, J; Martel, M; Tucker, S

2014-06-15

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

Afterglow based detection and dosimetry of beta particle irradiated ZrO2.

PubMed

Salas-Juárez, Ch J; Cruz-Vázquez, C; Avilés-Monreal, R; Bernal, R

2018-08-01

In this work, we report on the afterglow (AG) response characterization of commercially available ZrO 2 . Pellet shaped samples previously annealed in air at 1000°C during 24h were exposed to beta particle irradiation in the dose range from 0.5 up to 128Gy and their AG decay curves recorded during 600s after irradiation exposure. The characteristic glow curves of beta particle irradiated ZrO 2 show two maxima located around 80°C and 150°C. The first one rapidly vanishes at room temperature, giving rise to AG. The integrated AG signal increases as dose increases from 0.5 to 128Gy, with a linear dependence from 0.5 up to ca. 32Gy. Excellent reproducibility of the AG response was observed in 10 irradiation - AG readout cycles, showing that the studied ZrO 2 samples are reusable. The results here presented show that ZrO 2 is a promising material for use as a radiation dosimeter based on the AG phenomenon. Copyright © 2017 Elsevier Ltd. All rights reserved.

Investigation of dosimetric characteristics of a core-shell quantum dots nano composite (CdTe/CdS/PMMA): fabrication of a new gamma sensor

NASA Astrophysics Data System (ADS)

Feizi, Shahzad; Zare, Hakimeh; Hoseinpour, Masoumeh

2018-06-01

CdTe/CdS-PMMA nanocomposite was prepared using dispersion of CdTe/CdS core-shell quantum dots (QDs) in poly methyl methacrylate (PMMA) polymer matrix. High-quality CdTe/CdS core/shell quantum dots were synthesized in aqueous solution and were transferred from water to chloroform using ligand-exchange process in the presence of 1-dodecanethiol (1-DDT). Transmission electron microscopy analysis reveals that the obtained nano-particles are highly crystalline nature with mean diameter of 3.6 nm. To prepare an ohmic contact detector, a conductive cell with two silver coated walls was designed and fabricated for exploring gamma detecting properties of the nano composite. New detector was assessed for the linearity of doserate response, angular dependence, sensitivity and repeatability. The results show that the dose rate response of the prepared sensor is linear in the dose rate range of 50-145 mGy/min. So this nanocomposite can be utilized as a potential gamma sensor in the medical radiation device design.

Wearable glass beads for in vivo dosimetry of total skin electron irradiation treatments

NASA Astrophysics Data System (ADS)

Nabankema, S. K.; Jafari, S. M.; Peet, S. C.; Binny, D.; Sylvander, S. R.; Crowe, S. B.

2017-11-01

Glass beads have recently been proposed for use as radiation therapy dosimeters. Glass beads have a number of characteristics that make them suitable for in vivo skin dose measurements, including an ability to be worn on a string, and therefore avoid possible patient discomfort that may result from the use of adhesives. In this study, their use for in vivo dose measurements in total skin electron irradiation treatments has been tested. First, the dosimetric properties of cylindrical beads with a 3 mm diameter were characterised using electron fields produced by a linear accelerator. The mean individual bead reproducibility was demonstrated to be within 3%; and a batch variation of 7% was observed. The beads were shown to have a linear dose response, and both dose rate and beam energy independence, within the measurement uncertainty. Phantom measurements were then performed for a total skin electron irradiation beam arrangement, and results compared against optically stimulated luminescent dosimeters at five anatomical sites. For a majority of measurement locations, agreement within 3% was observed between the two dosimetry techniques, demonstrating the feasibility of glass beads as in vivo dosimeters for total skin electron irradiation; though further investigation may be needed to minimise uncertainty in results.

Biological properties and response to x-rays of first-generation transplants of spontaneous mammary carcinomas in C3H mice.

PubMed

Fowler, J F; Sheldon, P W; Begg, A C; Hill, S A; Smith, A M

1975-05-01

First-generation transplants of spontaneous mouse mammary carcinomas have been used extensively for radiobiological investigations of fractionated irradiation schedules, r.b.e. of fast neutrons and effectiveness of radiosensitizers, as reported elsewhere. The present work investigates the growth characteristics of the tumours; the criteria for the choice of end-points used in the definition of 'local control' of irradiated tumours; the reason for a decrease of 30 per cent in X-ray dose required to control tumours in females as compared with male mice; the proportion of hypoxic cells and its variation with time (reoxygenation) after a single dose of 1500 rad of X-rays; and the repair capacity of tumour cells within 24 hours after a substantial first dose of X-rays. Evidence is presented that the male-female difference was due to a higher proportion of hypoxic cells in tumours in male than in female mice. The repair of sub-lethal injury in tumour cells made hypoxic was slightly less than in skin made hypoxic but not significantly so. In the two-dose experiments on clamped tumours, no evidence of induced synchrony was found.

Emergency Dosimetry Using Ceramic Components in Personal Electronic Devices

NASA Astrophysics Data System (ADS)

Kouroukla, E. C.; Bailiff, I. K.; Terry, I.

2014-02-01

The rapid assessment of radiation dose to members of the public exposed to significant levels of ionizing radiation during a radiological incident presents a significant difficulty in the absence of planned radiation monitoring. However, within most personal electronic devices components such as resistors with alumina substrates can be found that have potentially suitable properties as solid state dosimeters using luminescence measurement techniques. The suitability of several types of ceramic-based components (e.g., resonators, inductors and resistors) has been previously examined using optically stimulated luminescence (OSL) and thermoluminescence (TL) techniques to establish their basic characteristics for the retrospective determination of absorbed dose. In this paper, we present results obtained with aluminum oxide surface mount resistors extracted from mobile phones that further extend this work. Very encouraging results have been obtained related to the measurement of luminescence sensitivity, dose response, reusability, limit of detection, signal reproducibility and known-dose recovery. However, the alumina exhibits a rapid loss of the latent luminescence signal with time following irradiation attributed to athermal (or anomalous) fading. The issues related to obtaining a reliable correction protocol for this loss and the detailed examinations required of the fading behavior are discussed.

The use of ionisation chambers for dose rate measurements at industrial irradiation plants

NASA Astrophysics Data System (ADS)

Sephton, J. P.; Sharpe, P. H. G.; Chu, R. D. H.

2002-03-01

The use of ionisation chambers to measure dose rate at industrial irradiation plants has been studied as part of a wider project on real time dosimetry. The characteristics required of such a chamber are discussed. These include the ability to withstand operation at high cumulative doses (up to 5 MGy) and dose rates of up to about 150 kGy h -1. Other desirable features are water equivalence and immunity to environmental conditions such as temperature, pressure and humidity. A number of chambers have been assessed experimentally and a suitable chamber selected. The dosimetric characteristics of the chosen chamber have been assessed by comparison with absorbed dose measurements made using chemical dosimeters.

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...

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

NASA Astrophysics Data System (ADS)

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

2006-07-01

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

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2015-09-23

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

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

PubMed

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

2017-10-02

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

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

PubMed

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

2011-10-01

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

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

PubMed

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

2015-07-31

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

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

PubMed

Leonard, Bobby E

2008-02-27

Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type (125)I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite primary unresolved questions regarding adaptive response behavior and bystander behavior. The five features of major significance provided by the Microdose Model so far are 1. Single Specific Energy Hits initiate Adaptive Response. 2. Mammogram and diagnostic X-rays induce a protective Bystander Effect as well as Adaptive Response radio-protection. 3. For mammogram X-rays the Adaptive Response protection is retained at high primer dose levels. 4. The dose range of the AR protection depends on the value of the Specific Energy per Hit, 1 >. 5. Alpha particle induced deleterious Bystander damage is modulated by low LET radiation.

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.

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

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

EPA Science Inventory

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

Immunogenicity and safety of a combined measles, mumps, rubella and varicella live vaccine (ProQuad ®) administered concomitantly with a booster dose of a hexavalent vaccine in 12-23-month-old infants.

PubMed

Deichmann, Klaus A; Ferrera, Giuseppe; Tran, Clément; Thomas, Stéphane; Eymin, Cécile; Baudin, Martine

2015-05-11

Concomitant administration of vaccines can facilitate vaccination uptake, provided that no clinically significant effect on either vaccine is identified. We investigated the concomitant administration, during the second year of life, of one dose of the combined measles, mumps, rubella and varicella vaccine (ProQuad(®)) with a booster dose of a hexavalent vaccine. In this multicentre, open-label study, participants were randomized to 3 groups: Group 1, concomitant administration of one dose of ProQuad(®) and a booster of hexavalent vaccine; Group 2, one dose of ProQuad(®) alone; Group 3, a booster dose of hexavalent vaccine alone. Two serum samples were collected, within 7 days prior to vaccination and Days 42-56 post-vaccination for antibody testing. Antibody response rates to measles, mumps, rubella, varicella, hepatitis B and Haemophilus influenzae type b following concomitant administration of ProQuad(®) and hexavalent vaccine were non-inferior compared with those following the individual vaccines. Antibody response rates to these antigens were all >95% in all groups. Antibody titres for the pertussis antigens following concomitant administration were also non-inferior to those following the individual vaccines. Antibody titres for the other valences were numerically comparable between groups with the exception of hepatitis B, Haemophilus influenzae type b, tetanus and poliomyelitis, which were higher in the concomitant than in the non-concomitant groups. The safety profiles of each vaccination regimen were comparable, with the exception of solicited ProQuad(®)-related injection-site reactions (Days 0-4), which occurred more frequently in the concomitant than in the non-concomitant groups. These immunogenicity data support the concomitant administration of ProQuad(®) with a hexavalent vaccine. The safety profile of concomitant ProQuad(®) and hexavalent vaccination was also in line with that of the individual Summaries of Product Characteristics. Copyright © 2015 Elsevier Ltd. All rights reserved.

MO-E-18A-01: Imaging: Best Practices In Pediatric Imaging

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

Willis, C; Strauss, K; MacDougall, R

This imaging educational program will focus on solutions to common pediatric imaging challenges. The speakers will present collective knowledge on best practices in pediatric imaging from their experience at dedicated children's hospitals. Areas of focus will include general radiography, the use of manual and automatic dose management in computed tomography, and enterprise-wide radiation dose management in the pediatric practice. The educational program will begin with a discussion of the complexities of exposure factor control in pediatric projection radiography. Following this introduction will be two lectures addressing the challenges of computed tomography (CT) protocol optimization in the pediatric population. The firstmore » will address manual CT protocol design in order to establish a managed radiation dose for any pediatric exam on any CT scanner. The second CT lecture will focus on the intricacies of automatic dose modulation in pediatric imaging with an emphasis on getting reliable results in algorithmbased technique selection. The fourth and final lecture will address the key elements needed to developing a comprehensive radiation dose management program for the pediatric environment with particular attention paid to new regulations and obligations of practicing medical physicists. Learning Objectives: To understand how general radiographic techniques can be optimized using exposure indices in order to improve pediatric radiography. To learn how to establish diagnostic dose reference levels for pediatric patients as a function of the type of examination, patient size, and individual design characteristics of the CT scanner. To learn how to predict the patient's radiation dose prior to the exam and manually adjust technique factors if necessary to match the patient's dose to the department's established dose reference levels. To learn how to utilize manufacturer-provided automatic dose modulation technology to consistently achieve patient doses within the department's established size-based diagnostic reference range. To understand the key components of an enterprise-wide pediatric dose management program that integrates the expanding responsibilities of medial physicists in the new era of dose monitoring.« less

Measures for curtailment of iatrogenic exposure. Guide to correct x-ray examinations (in Japanese)

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

Misonoo, K.

1973-08-01

Of the coposure dose for humans from various radiation sources, introgenic exposure amounts to 1/2 to twice the natural radiation source. Although the mechanism of induction of malignant tumor by radiation is not clanified, it is evident that it is induced after receiving a dose above 100 rads. However, the presence of a threshold, under which it does not develop, is unknown. Tabulated were ICRP's calculations on the degree of risk of injury and the estimated values of genetic injury due to 1 rad. In order to estimate the harmful effect of exposure in x-ray diagnosis, the dose in themore » critical tissue of the human body and the types and the frequency of radiation examinations are important. The judgment of genetic injury is expressed by the genetically significant dose, which is calculated from the dose in the genital gland received by individuals. The impcrtant criterion for the judgment of physical injury is the mean annual dose per person in the marrow (mean dose in the red marrow). The dose in the genital organ is important as the dose related to the evaluation of the degree of genetic risk. The characteristics of iatrogenic exposure are partial and acute exposure and a high dose rate. Tabulated individually were the frequency of x-ray examinations, the mean dose in the genital organ according urce. The radiation dose during x-ray pelvimetry to 51 patients was estimated, and the cytogenetic response of peripheral lymphocytes was determined in 25 of their newborn babies. The calculations resulted in an average midline fetal dose of 1,035 and 1,860 mrads for the patients receiving 2 projections and more than 2 projections, respectively. There was no evidence of radioinduced chromosomal darnage in the newborn infants following x-ray exposure in utero. (auth)« less

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

PubMed

Roberts, Steven; Martin, Michael A

2007-06-01

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

An extract of Agaricus blazei Murill administered orally promotes immune responses in murine leukemia BALB/c mice in vivo.

PubMed

Lin, Jaung-Geng; Fan, Ming-Jen; Tang, Nou-Ying; Yang, Jai-Sing; Hsia, Te-Chun; Lin, Jen-Jyh; Lai, Kuang-Chi; Wu, Rick Sai-Chuen; Ma, Chia-Yu; Wood, W Gibson; Chung, Jing-Gung

2012-03-01

The edible mushroom (fungus) Agaricus blazei Murill (ABM) is a health food in many countries. Importantly, it has been shown to have antitumor and immune effects. There is no available information on ABM-affected immune responses in leukemia mice in vivo. Experimental Design. In this study, the authors investigated the immunopotentiating activities of boiled water-soluble extracts from desiccated ABM in WEHI-3 leukemia mice. The major characteristic of WEHI-3 leukemia mice are enlarged spleens and livers after intraperitoneal injection with murine leukemia WEHI-3 cells. Isolated T cells from spleens of ABM-treated mice resulted in increased T-cell proliferation compared with the untreated control with concanavalin A stimulation. ABM decreased the spleen and liver weights when compared with WEHI-3 leukemia mice and this effect was a dose-dependent response. ABM promoted natural killer cell activity and phagocytosis by macrophage/monocytes in leukemia mice in a dose-dependent manner. ABM also enhanced cytokines such as interleukin (IL)-1β, IL-6, and interferon-γ levels but reduced the level of IL-4 in WEHI-3 leukemia mice. Moreover, ABM increased the levels of CD3 and CD19 but decreased the levels of Mac-3 and CD11b in leukemia mice. The ABM extract is likely to stimulate immunocytes and regulate immune response in leukemia mice in vivo.

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

Mechanistic simulation of normal-tissue damage in radiotherapy—implications for dose-volume analyses

NASA Astrophysics Data System (ADS)

Rutkowska, Eva; Baker, Colin; Nahum, Alan

2010-04-01

A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies.

WHERE THE INDIVIDUAL MEETS THE ECOLOGICAL: A STUDY OF PARENT DRINKING PATTERNS, ALCOHOL OUTLETS AND CHILD PHYSICAL ABUSE

PubMed Central

Freisthler, Bridget; Gruenewald, Paul J.

2012-01-01

Background Despite well-known associations between heavy drinking and child physical abuse, little is known about specific risks related to drinking different amounts of alcohol in different drinking venues. This study uses a context specific dose-response model to examine how drinking in various venues (e.g., at bars or parties) are related to physically abusive parenting practices while controlling for individual and psychosocial characteristics. Methods Data were collected via a telephone survey of parents in 50 cities in California resulting in 2,163 respondents who reported drinking in the past year. Child physical abuse and corporal punishment were measured using the Conflict Tactics Scale, Parent Child version. Drinking behaviors were measured using continued drinking measures. Data were analyzed using zero inflated Poisson models. Results Drinking at homes, parties or bars more frequently was related to greater frequencies of physically abusive parenting practices. The use of greater amounts of alcohol in association with drinking at bars appeared to increase risks for corporal punishment, a dose-response effect. Dose-response relationships were not found for drinking at homes or parties or drinking at bars for physical abuse nor for drinking at home and parties for corporal punishment. Conclusion Frequencies of using drinking venues, particularly bars and home or parties, are associated with greater use of abusive parenting practices. These findings suggest that a parent’s routine drinking activities place children at different risks for being physically abused. They also suggest that interventions that take into account parents’ alcohol use at drinking venues are an important avenue for secondary prevention efforts. PMID:23316780

Remitting seronegative symmetrical synovitis with pitting oedema: a study of 12 cases.

PubMed

Paira, S; Graf, C; Roverano, S; Rossini, J

2002-05-01

Twelve patients with remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) were analysed. Eight of them had typical RS3PE without underlying disease, and four presented associated neoplasia. The first patients experienced an excellent response to low doses of prednisone, and they all achieved complete and permanent remission. The mean treatment duration was 18 months and the mean follow-up was 4.4 years. During the follow-up, none of these patients relapsed, had fever or general health deterioration, and hand and foot radiographs did not show erosion. One of them developed a panarteritis nodosa 6 years later. Four RS3PE patients had associated neoplasia. Two were with solid malignancies, and the other two presented haematological malignancies. In one of them RS3PE preceded the diagnosis of malignancy. The diagnosis of RS3PE in the other patients was subsequent to cancer. The first patients presented clinical characteristics suggestive of paraneoplastic RS3PE, and they had a poor response to corticosteroid therapy. Two patients died, and the rest of them had a complete response to surgical resection of the tumour or to chemotherapy. In general, idiopathic RS3PE patients do not show either general health deterioration or fever and they do respond to low doses of steroids (10 mg/day). We observed strong contrasts with the results obtained when treating RS3PE patients with associated neoplasia. In patients with RS3PE the presence of systemic symptoms along with resistance to low doses of corticosteroid therapy should alert the physician to the possible presence of malignancy.

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

PubMed

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

2007-07-01

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

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.

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2018-03-01

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

Pharmacokinetic and Tolerability Assessment of a Pediatric Oral Formulation of Pentoxifylline in Kawasaki Disease☆

PubMed Central

Best, Brookie M.; Burns, Jane C.; DeVincenzo, John; Phelps, Stephanie J.; Blumer, Jeffrey L.; Wilson, John T.; Capparelli, Edmund V.; Connor, James D.

2003-01-01

Background: In infants and children, treatment of Kawasaki disease (KD) with high-dose intravenous immunoglobulin (IVIG) and acetylsalicylic acid ([ASA] aspirin) diminishes inflammatory response and reduces the risk for coronary artery abnormalities. However, patients with high serum concentrations of tumor necrosis factor (TNF)-alpha, which is associated with vascular damage, may develop coronary artery lesions even with treatment. The hemorheologic agent pentoxifylline blocks the production of TNF-alpha and may be an appropriate adjunctive therapy to IVIG and ASA. Objective: The objective of this study was to assess the pharmacokinetic characteristics and tolerability of a new oral syrup formulation of pentoxifylline as an adjunct to IVIG and ASA in the treatment of KD in children. Methods: Hospitalized boys and girls aged 6 months to 5 years and who were diagnosed with KD within the first 10 days of illness were eligible. Patients were assigned to 1 of 4 pentoxifylline treatment groups, by dose level (dose levels 1, 2, 3, and 4: 10, 15, 20, and 25 mg/kg daily, respectively, divided into 3 doses). Six plasma samples collected at the time the first dose was administered, and 4 samples collected after administration of the last dose on study day 6, were assessed by high-performance liquid chromatography using noncompartmental and 1-compartment pharmacokinetic analyses for pentoxifylline and its active metabolite (M-1). TNF-alpha levels on days 1 and 6 were assessed using electroimmunoassay. Results: Fourteen boys and 10 girls were enrolled. The mean age, body weight, and illness day at study entry were 34.5 months, 13.8 kg, and 6, respectively. Pentoxifylline exhibited nonlinear kinetic characteristics, with median area under the plasma concentration–time curve from time 0 to infinity(AUC0–∞) values of 622, 3428, 8416, and 10,347 ng/mL · h for dose levels 1 to 4, respectively, on study day 1. Pentoxifylline noncompartmental oral clearance and volume of distribution were significantly lower, and dose-normalized AUC0–∞ was significantly higher, for dose level 3 than dose level 1. M-1 parameters were not significantly different between dose levels. No accumulation of pentoxifylline or M-1 was noted. Fifteen of 24 patients (63%) reported mild to moderate adverse events that may or may not have been treatment related. Frequency and severity did not differ significantly between dose levels. Conclusions: In the children in this study, pentoxifylline was well tolerated at the doses studied. No notable differences in clinical outcomes were observed between dose levels, and dose levels 3 and 4 (20 and 25 mg/kg daily, respectively) resulted in similar exposure to both pentoxifylline and M-1. Future efficacy and tolerability studies should use a daily dose of 20 mg/kg of pentoxifylline in acute KD. PMID:24944359

SU-E-T-275: Dose Build Up and Bolusing Characteristics for Total Body Irradiation Dosimetry

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

Butson, M; Pope, D; Whitaker, M

2015-06-15

Purpose: Total Body Irradiation (TBI) treatments are mainly used in a preparative regimen for haematopoietic stem cell (or bone marrow) transplantation. Our standard regimen is a 12 Gy / 6 fraction bi-daily technique. To evaluate the delivered dose homogeneity to the patient, EBT3 Gafchromic film is positioned at the head, neck, chest, pelvis and groin for all fractions. This work investigates and quantifies the build-up dose characteristics at TBI distances and requirements for in-vivo dosimetry bolusing. Methods: Percentage dose build up characteristics of photon beams have been investigated at large extended SSD’s using parallel plate ionisations chambers (Attix) and EBT3more » Gafchromic film. Measurements were made to open fields at different field sizes as well as large 40cm × 40cm fields with differing scatter conditions such as the introduction of standard Perspex scattering plates at different distances to the measurement point. Results: Percentage surface dose measured values for open fields at 300 cm SSD were found to range from 20 % up to 65.5 % for fields of 5 cm × 5 cm to 40 cm × 40 cm. With the introduction of 1cm Perspex scattering plates used in TBI treatments the surface dose values increased up to 83% to 90%, depending on the position of the Perspex scattering plate compared to the measurement point. Our work showed that at least 3mm water equivalent bolus / scatter material should be placed over the EBT3 for accurate dose assessment for TBI treatments. Conclusion: Build up dose characteristics exist at long (300cm) SSD’s including treatments using Perspex scattering plates placed at various distances form the patient during TBI treatment. Top accurately assess the applied dose during treatment, in-vivo dosimeters such as Gafchromic EBT3 should have at least 3mm bolus / scatter material placed over them to measure actual applied doses.« less

Characteristics and verification of a car-borne survey system for dose rates in air: KURAMA-II.

PubMed

Tsuda, S; Yoshida, T; Tsutsumi, M; Saito, K

2015-01-01

The car-borne survey system KURAMA-II, developed by the Kyoto University Research Reactor Institute, has been used for air dose rate mapping after the Fukushima Dai-ichi Nuclear Power Plant accident. KURAMA-II consists of a CsI(Tl) scintillation detector, a GPS device, and a control device for data processing. The dose rates monitored by KURAMA-II are based on the G(E) function (spectrum-dose conversion operator), which can precisely calculate dose rates from measured pulse-height distribution even if the energy spectrum changes significantly. The characteristics of KURAMA-II have been investigated with particular consideration to the reliability of the calculated G(E) function, dose rate dependence, statistical fluctuation, angular dependence, and energy dependence. The results indicate that 100 units of KURAMA-II systems have acceptable quality for mass monitoring of dose rates in the environment. Copyright © 2014 Elsevier Ltd. All rights reserved.

SU-E-J-274: Responses of Medulloblastoma Cells to Radiation Dosimetric Parameters in Intensity-Modulated Radiation Therapy

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

Park, J; Molecular Imaging Program at Stanford, Stanford, CA; Bio-X Program, Stanford, CA

2015-06-15

Purpose: To evaluate radiation responses of the medulloblastoma cell line Daoy in intensity-modulated radiation therapy (IMRT), quantitative variations to variable radiation dosimetic parameters were tracked by bioluminescent images (BLIs). Methods: The luciferase and green fluorescent protein positive Daoy cells were cultured on dishes. The medulloblastoma cells irradiated to different dose rate, interval of fractionated doses, field margin and misalignment, and dose uniformity in IMRT were monitored using bioluminescent images. The cultured cells were placed into a dedicated acrylic phantom to deliver intensity-modulated fluences and calculate accurate predicted dose distribution. The radiation with dose rate from 0.5 Gy/min to 15 Gy/minmore » was irradiated by adjusting monitor unit per minute and source-to-surface distances. The intervals of fractionated dose delivery were changed considering the repair time of double strand breaks (DSB) revealed by straining of gamma-H2AX.The effect of non-uniform doses on the cells were visualized by registering dose distributions and BLIs. The viability according to dosimetric parameters was correlated with bioluminescent intensities for cross-check of radiation responses. Results: The DSB and cell responses due to the first fractionated dose delivery significantly affected final tumor control rather than other parameters. The missing tumor volumes due to the smaller field margin than the tumor periphery or field misalignment caused relapse of cell responses on BLIs. The dose rate and gradient had effect on initial responses but could not bring out the distinguishable killing effect on cancer cells. Conclusion: Visualized and quantified bioluminescent images were useful to correlate the dose distributions with spatial radiation effects on cells. This would derive the effective combination of dose delivery parameters and fractionation. Radiation responses in particular IMRT configuration could be reflected to image based-dose re-optimization.« less

Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects.

PubMed

Togawa, Michinori; Yamaya, Hidetoshi; Rodríguez, Mónica; Nagashima, Hirotaka

2016-12-01

Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). After single oral doses, maximum plasma concentrations (C max ) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

Monitoring exposure to atomic bomb radiation by somatic mutation

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

Akiyama, Mitoshi; Kyoizumi, Seishi; Kusunoki, Yoichiro

Atomic bomb survivors are a population suitable for studying the relationship between somatic mutation and cancer risk because their exposure doses are relatively well known and their dose responses in terms of cancer risk have also been thoroughly studied. An analysis has been made of erythrocyte glycophorin A (GPA) gene mutations in 1,226 atomic bomb survivors in Hiroshima and Nagasaki. The GPA mutation frequency (Mf) increased slightly but significantly with age at the time of measurement and with the number of cigarettes smoked. After adjustment for the effect of smoking, the Mf was significantly higher in males than in femalesmore » and higher in Hiroshima than in Nagasaki. All of these characteristics of the background GPA Mf were in accord with those of solid tumor incidence obtained from an earlier epidemiological study of A-bomb survivors. Analysis of the dose effect on Mf revealed the doubling dose to be about 1.20 Sv and the minimum dose for detection of a significant increase to be about 0.24 Sv. No significant dose effect for difference in sex, city, or age at the time of bombing was observed. Interestingly, the doubling dose for the GPA Mf approximated that for solid cancer incidence (1.59 Sv). And the minimum dose for detection was not inconsistent with the data for solid cancer incidence. The dose effect was significantly higher in those diagnosed with cancer before or after measurement than in those without a history of cancer. These findings are consistent with the hypothesis that somatic mutations are the main cause of excess cancer risk from radiation exposure. 27 refs., 2 figs.« less

Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations.

PubMed

Gan, Gin Gin; Phipps, Maude E; Lee, Michael M T; Lu, Liang S; Subramaniam, Rajallectchumy Y; Bee, Ping C; Chang, Sean H

2011-06-01

Within the Asian populations, Indian patients had been reported to require higher warfarin dose compared with the Chinese and Malay patients, and this could not entirely be explained by cytochrome P450 (CYP)2C9 gene variants. Genetic variants of vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1) has been well established as one of key determinants in the different responses of warfarin amongst patients. Adult patients who attended an anticoagulation clinic with stable INR were recruited. VKORC1 and CYP2C9 genotype were sequenced, and clinical characteristics were assessed. A total of 91 Malays, 96 Chinese, and 46 Indian patients were recruited. The mean age was 55 years and 51.5% were males. The mean dose of warfarin for all patients was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians compared with the Chinese and Malay patients, 4.9 versus 3.5 and 3.3 mg, respectively (p < 0.001). VKORC1 GG genotype was more commonly seen in Indian patients. The mean warfarin dose in patients with GG genotype required a significant higher warfarin dose compared with those with AG and AA genotype (4.9 vs. 3.7 vs. 3.1 mg, respectively; p < 0.001). CYP2C9*2 and *3 is associated with a lower maintenance dose, 2.9 versus 3.7 mg in CYP2C9*1; p < 0.01. In multivariate analysis, age, ethnic groups, and genotypes had a significant influence on the required warfarin dose. In conclusion, VKORC1 and CYP2C9 polymorphism contribute to the difference dose requirement amongst the patients but other additional possible factors may play a role in the Indian race.

Characteristic of interactions between intrathecal gabapentin and either clonidine or neostigmine in the formalin test.

PubMed

Yoon, Myung Ha; Choi, Jeong Il; Kwak, Sang Hyun

2004-05-01

Intrathecal gabapentin is effective for phase 2 of the formalin response but not for acute pain. Unlike gabapentin, intrathecal clonidine and neostigmine attenuate both acute pain and phase 2 of the formalin response. We evaluated gabapentin's interactions with either clonidine or neostigmine in the formalin test. Male Sprague-Dawley rats were used. For the formalin test, 50 microL of 5% formalin solution was injected into the hindpaw. The interaction of drugs was investigated by a fixed-dose analysis or an isobolographic analysis. Intrathecal gabapentin produced a suppression of the phase 2 flinching response, but not the phase 1 response, in the formalin test. Intrathecal clonidine and neostigmine resulted in a reduction of the pain behavior in both phases. A fixed-dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of clonidine and neostigmine. An isobolographic analysis in phase 2 revealed a synergistic interaction after intrathecal administration of gabapentin-clonidine or gabapentin-neostigmine mixture. We conclude that the combination of gabapentin with either clonidine or neostigmine at the level of the spinal cord could play a major role not only in acute pain, but also in phase 2 of the formalin response. We determined the pharmacological properties of gabapentin combined with either clonidine or neostigmine in the formalin test. Spinal gabapentin reinforced the effects of clonidine and neostigmine in the formalin test. The hitherto unreported action of gabapentin on acute nociceptive stimulus could be of considerable significance.

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

PubMed

Aldelaijan, Saad; Devic, Slobodan

2018-05-01

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

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

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

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

Dose response and repair kinetics of gamma-H2AX foci induced by in vitro irradiation of whole blood and T-lymphocytes with X- and gamma-radiation.

PubMed

Beels, Laurence; Werbrouck, Joke; Thierens, Hubert

2010-09-01

Dose response and repair kinetics of phosphorylated histone H2A isoform X (gamma-H2AX) foci in T-lymphocytes were investigated in the low-dose range after in vitro irradiation of whole blood and T-lymphocytes with 100 kVp X-rays and (60)Co gamma-rays. Whole blood or isolated T-lymphocytes were irradiated in vitro and gamma-H2AX foci were scored. Dose response was determined in the 0-500 mGy dose range. Foci kinetics were studied at doses of 5 and 200 mGy up to 24 h post-irradiation. After X-irradiation, the dose response for whole blood shows a biphasic behaviour with a low-dose hypersensitivity, which is less pronounced for isolated T-lymphocytes. In contrast, gamma-radiation shows a linear dose response for both irradiation conditions. Concerning repair kinetics, delayed repair was found after X-ray whole blood irradiation (5 and 200 mGy) with 40% of the foci persisting 24 h post-irradiation. This number of foci is reduced to 10% after irradiation of isolated T-lymphocytes with 200 mGy X-rays. On the contrary, gamma-H2AX foci are reduced to background levels 24 h post-irradiation with 200 mGy (60)Co gamma-rays. gamma-H2AX foci response and repair kinetics depend on irradiation conditions and radiation quality, possibly linked to Bystander response.

Thermoluminescence dosimetry features of DY and Cu doped SrF2 nanoparticles under gamma irradiation.

PubMed

Zahedifar, M; Sadeghi, E; Kashefi Biroon, M; Harooni, S; Almasifard, F

2015-11-01

Dy and Cu-doped SrF2 nanoparticles (NPs) were synthesized by using co-precipitation method and their possible application to solid state dosimetry were studied and compared to that of pure SrF2 NPs. X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive spectrometer (EDS) were used for sample characterization. The highest thermoluminescence (TL) response of SrF2:Dy and SrF2:Cu NPs were found respectively at 0.5 and 0.7mol% of Dy and Cu impurities. Seven overlapping glow peaks at 384, 406, 421, 449, 569, 495, 508K and three component glow peaks at 381, 421 and 467K were identified respectively for SrF2:Dy and SrF2:Cu NPs employing Tm-Tstop and computerized glow curve deconvolution (CGCD) methods. The TL sensitivity of SrF2:Dy is approximately the same as that of LiF:Mg,Ti (TLD-100) cheeps. Linear dose response were observed for the SrF2:Dy and SrF2:Cu NPs up to the absorbed doses of 1kGy and 10kGy correspondingly. Regarding other dosimetry characteristics of the produced NPs such as fading, reproducibility and thermal treatment, Dy and Cu doped SrF2 NPs recommend for high dose TL dosimetry applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

EVALUATING QUANTITATIVE FORMULAS FOR DOSE-RESPONSE ASSESSMENT OF CHEMICAL MIXTURES

EPA Science Inventory

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

Analysis of Transcriptomic Dose Response Data in the ...

EPA Pesticide Factsheets

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

Therapy operating characteristic curves: tools for precision chemotherapy

PubMed Central

Barrett, Harrison H.; Alberts, David S.; Woolfenden, James M.; Caucci, Luca; Hoppin, John W.

2016-01-01

Abstract. The therapy operating characteristic (TOC) curve, developed in the context of radiation therapy, is a plot of the probability of tumor control versus the probability of normal-tissue complications as the overall radiation dose level is varied, e.g., by varying the beam current in external-beam radiotherapy or the total injected activity in radionuclide therapy. This paper shows how TOC can be applied to chemotherapy with the administered drug dosage as the variable. The area under a TOC curve (AUTOC) can be used as a figure of merit for therapeutic efficacy, analogous to the area under an ROC curve (AUROC), which is a figure of merit for diagnostic efficacy. In radiation therapy, AUTOC can be computed for a single patient by using image data along with radiobiological models for tumor response and adverse side effects. The mathematical analogy between response of observers to images and the response of tumors to distributions of a chemotherapy drug is exploited to obtain linear discriminant functions from which AUTOC can be calculated. Methods for using mathematical models of drug delivery and tumor response with imaging data to estimate patient-specific parameters that are needed for calculation of AUTOC are outlined. The implications of this viewpoint for clinical trials are discussed. PMID:27175376

Waterborne gastroenteritis outbreak at a scouting camp caused by two norovirus genogroups: GI and GII.

PubMed

ter Waarbeek, Henriëtte L G; Dukers-Muijrers, Nicole H T M; Vennema, Harry; Hoebe, Christian J P A

2010-03-01

A cross-border gastroenteritis outbreak at a scouting camp was associated with drinking water from a farmer's well. A retrospective cohort study was performed to identify size and source of the outbreak, as well as other characteristics. Epidemiological investigation included standardized questionnaires about sex, age, risk exposures, illness and family members. Stool and water (100mL) samples were analyzed for bacteria, viruses and parasites. Questionnaires were returned by 84 scouts (response rate 82%), mean age of 13 years. The primary attack rate was 85% (diarrhoea and/or vomiting). Drinking water was the strongest independent risk factor showing a dose-response effect with 50%, 75%, 75%, 93% and 96% case prevalence for 0, 1, 2-3, 4-5 and >5 glasses consumed, respectively. Norovirus (GI.2 Southampton and GII.7 Leeds) was detected in 51 stool specimens (75%) from ill scouts. Water analysis showed fecal contamination, but no norovirus. The secondary attack rate was 20%. This remarkable outbreak was caused by a point-source infection with two genogroups of noroviruses most likely transmitted by drinking water from a well. Finding a dose-response relationship was striking. Specific measures to reduce the risk of waterborne diseases, outbreak investigation and a good international public health network are important.

Comparison of extracellular striatal acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs.

PubMed

O'Donnell, John C; Acon-Chen, Cindy; McDonough, John H; Shih, Tsung-Ming

2010-11-01

Organophosphorus nerve agents like cyclosarin and tabun are potent cholinesterase inhibitors. The inhibition of acetylcholinesterase, which is responsible for breaking down acetylcholine (ACh) at the synapse and neuromuscular junction, leads to a build-up of extracellular ACh and a series of toxic consequences including hypersecretion, tremor, convulsion/seizure, respiratory distress, coma, and death. This study employed simultaneous and continuous electroencephalographic recording and striatal microdialysis collection for quantification of ACh changes (via subsequent HPLC analysis) during acute exposure to a 1.0 × LD(50) subcutaneous dose of either cyclosarin or tabun to investigate differences in cholinergic and behavioral effects. Information about the unique mechanisms and consequences of different nerve agents is intended to aid in the development of broad-spectrum medical countermeasures for nerve agents. At the dose administered, non-seizure and sustained seizure responses were observed in both agent groups and in the tabun-exposed group some subjects experienced an unsustained seizure response. Significant extracellular ACh increases were only observed in seizure groups. Cyclosarin and tabun were found to exhibit some unique cholinergic and ictogenic characteristics. Lethality only occurred in subjects experiencing sustained seizure, and there was no difference in lethality between agent groups that progressed to sustained seizure.

The development of a 6 to 7 MeV photon field for instrument calibration

NASA Astrophysics Data System (ADS)

Duvall, K. C.; Soares, C. G.; Heaton, H. T.; Seltzer, S. M.

1985-05-01

A photon source has been developed at the National Bureau of Standards to measure the response of radiological survey instruments to high-energy photons. The 19F(p, αγ) 16 O reaction has been used to produce a 6 to 7 MeV photon field with a fairly uniform photon flux density of approximately 3 × 10 3 cm -2 s -1 at one meter from the source. The photon flux density is obtained from measurements with a 3 × 3 inch 2 Nal detector whose absolute response has been determined by a Monte Carlo calculation. The spectral characteristics of the high-energy photons have been determined from measurements with a large volume high purity germanium detector. The absorbed dose rate to water was measured with LiF thermoluminescent dosimeters (TLDs) at several depths in a 30 × 30 × 30 cm 3 Lucite phantom. It is planned to compare absorbed dose determinations from the TLD measurements with those computed from spectral measurements. The response of six commercial radiological survey instruments has been measured behind various thicknesses of plastic absorber. The results indicate that approximately 2.5 cm of plastic in front of these instruments is sufficient to discriminate against the associated high-energy electron contamination.

A Study of Gamma-Ray Exposure of Cu-SiO2 Programmable Metallization Cells

NASA Astrophysics Data System (ADS)

Chen, W.; Barnaby, H. J.; Kozicki, M. N.; Edwards, A. H.; Gonzalez-Velo, Y.; Fang, R.; Holbert, K. E.; Yu, S.; Yu, W.

2015-12-01

The Cu-SiO2 based programmable metallization cell (PMC) is a promising alternative to the Ag-chalcogenide glass PMC because of its low power consumption and CMOS-compatibility. Understanding its total ionizing dose (TID) response helps in assessing the reliability of this technology in ionizing radiation environments and benefits its expansion in the space electronics market. In this paper, the impacts of TID on the switching characteristics of Cu-SiO2 PMC are investigated for the first time. The devices were step irradiated with 60Co gamma-rays to a maximum dose of 7.1 Mrad ( SiO2). The results show that gamma-ray irradiation has a negligible impact on the virgin-state and on-state resistance of Cu-SiO2 PMCs. The off-state resistance slightly decreases after the first 1.5 Mrad( SiO2) of exposure, but this reduction saturates after higher levels of TID. Other switching characteristics such as the set voltage, multilevel switching capability and endurance were also studied, all of which did not show observable changes after gamma-ray radiation. The immunity to ionizing radiation is attributed to the suppression of the photo-doping process.

Using LiF:Mg,Cu,P TLDs to estimate the absorbed dose to water in liquid water around an 192Ir brachytherapy source.

PubMed

Lucas, P Avilés; Aubineau-Lanièce, I; Lourenço, V; Vermesse, D; Cutarella, D

2014-01-01

The absorbed dose to water is the fundamental reference quantity for brachytherapy treatment planning systems and thermoluminescence dosimeters (TLDs) have been recognized as the most validated detectors for measurement of such a dosimetric descriptor. The detector response in a wide energy spectrum as that of an (192)Ir brachytherapy source as well as the specific measurement medium which surrounds the TLD need to be accounted for when estimating the absorbed dose. This paper develops a methodology based on highly sensitive LiF:Mg,Cu,P TLDs to directly estimate the absorbed dose to water in liquid water around a high dose rate (192)Ir brachytherapy source. Different experimental designs in liquid water and air were constructed to study the response of LiF:Mg,Cu,P TLDs when irradiated in several standard photon beams of the LNE-LNHB (French national metrology laboratory for ionizing radiation). Measurement strategies and Monte Carlo techniques were developed to calibrate the LiF:Mg,Cu,P detectors in the energy interval characteristic of that found when TLDs are immersed in water around an (192)Ir source. Finally, an experimental system was designed to irradiate TLDs at different angles between 1 and 11 cm away from an (192)Ir source in liquid water. Monte Carlo simulations were performed to correct measured results to provide estimates of the absorbed dose to water in water around the (192)Ir source. The dose response dependence of LiF:Mg,Cu,P TLDs with the linear energy transfer of secondary electrons followed the same variations as those of published results. The calibration strategy which used TLDs in air exposed to a standard N-250 ISO x-ray beam and TLDs in water irradiated with a standard (137)Cs beam provided an estimated mean uncertainty of 2.8% (k = 1) in the TLD calibration coefficient for irradiations by the (192)Ir source in water. The 3D TLD measurements performed in liquid water were obtained with a maximum uncertainty of 11% (k = 1) found at 1 cm from the source. Radial dose values in water were compared against published results of the American Association of Physicists in Medicine and the European Society for Radiotherapy and Oncology and no significant differences (maximum value of 3.1%) were found within uncertainties except for one position at 9 cm (5.8%). At this location the background contribution relative to the TLD signal is relatively small and an unexpected experimental fluctuation in the background estimate may have caused such a large discrepancy. This paper shows that reliable measurements with TLDs in complex energy spectra require a study of the detector dose response with the radiation quality and specific calibration methodologies which model accurately the experimental conditions where the detectors will be used. The authors have developed and studied a method with highly sensitive TLDs and contributed to its validation by comparison with results from the literature. This methodology can be used to provide direct estimates of the absorbed dose rate in water for irradiations with HDR (192)Ir brachytherapy sources.

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

PubMed

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

2013-07-01

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

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.

Efficacy and tolerability of a fixed-dose combination of metoprolol extended release/amlodipine in patients with mild-to-moderate hypertension: a randomized, parallel-group, multicentre comparison with losartan plus amlodipine.

PubMed

Pareek, Anil; Chandurkar, Nitin B; Sharma, Ravishankar; Tiwari, Dharmendra; Gupta, Bhagwan S

2010-01-01

Epidemiological studies and clinical trials have shown that prevention of cardiovascular disease, the ultimate goal of hypertension treatment, requires a sufficient reduction in blood pressure. The primary objective of this study was to compare the mean decrease in systolic (SBP) and diastolic (DBP) blood pressure between metoprolol extended release (XL)/amlodipine fixed-dose combination and losartan plus amlodipine combination in patients with mild-to-moderate essential hypertension. The secondary objectives of this study were to compare the proportion of responders in the two treatment groups and to evaluate the tolerability of the study medications. This was a randomized, parallel-group, multicentre comparative study conducted at the outpatient departments of three teaching hospitals in India. Patients with mild-to-moderate hypertension (defined as DBP 90-109 mmHg) aged between 18 and 75 years were enrolled in this study and followed up for 12 weeks. Response to study treatments was evaluated in terms of mean decrease in SBP and DBP and the response rate (reduction to SBP <140 mmHg and DBP <90 mmHg). Out of 152 patients who underwent a 1-week placebo washout, 148 eligible patients were randomized to receive either metoprolol XL 25 mg/amlodipine 2.5 mg fixed-dose combination (76 patients) or losartan 25 mg plus amlodipine 2.5 mg (72 patients). The two treatment groups were similar with respect to demographic and baseline characteristics. Non-responders after 4 weeks of therapy were escalated to metoprolol XL 50 mg/amlodipine 5 mg fixed-dose combination or losartan 50 mg plus amlodipine 5 mg, respectively. The study was completed by 66 patients in each group, of whom 43 patients in each group responded to the starting doses. After 4 weeks' therapy, both treatments were associated with significant decreases in SBP and DBP from baseline (p < 0.001) and were comparable with respect to mean decrease in SBP (p = 0.304), mean decrease in DBP (p = 0.630) and response rate (p = 1.0). Also, both the step-up therapies were comparable with respect to mean decrease in SBP (p = 0.484), mean decrease in DBP (p = 0.650) and response rate (p = 0.134) at week 12. Both treatments were well tolerated in the studied population. Metoprolol XL/amlodipine fixed-dose combination was found to be as effective and well tolerated as losartan plus amlodipine in the treatment of essential hypertension.

Gafchromic EBT‐XD film: Dosimetry characterization in high‐dose, volumetric‐modulated arc therapy

PubMed Central

Ozawa, Shuichi; Hosono, Fumika; Sumida, Naoki; Okazue, Toshiya; Yamada, Kiyoshi; Nagata, Yasushi

2016-01-01

Radiochromic films are important tools for assessing complex dose distributions. Gafchromic EBT‐XD films have been designed for optimal performance in the 40–4,000 cGy dose range. We investigated the dosimetric characteristics of these films, including their dose‐response, postexposure density growth, and dependence on scanner orientation, beam energy, and dose rate with applications to high‐dose volumetric‐modulated arc therapy (VMAT) verification. A 10 MV beam from a TrueBeam STx linear accelerator was used to irradiate the films with doses in the 0–4,000 cGy range. Postexposure coloration was analyzed at postirradiation times ranging from several minutes to 48 h. The films were also irradiated with 6 MV (dose rate (DR): 600 MU/min), 6 MV flattening filter‐free (FFF) (DR: 1,400 MU/ min), and 10 MV FFF (DR: 2,400 MU/min) beams to determine the energy and dose‐rate dependence. For clinical examinations, we compared the dose distribution measured with EBT‐XD films and calculated by the planning system for four VMAT cases. The red channel of the EBT‐XD film exhibited a wider dynamic range than the green and blue channels. Scanner orientation yielded a variation of ∼3% in the net optical density (OD). The difference between the film front and back scan orientations was negligible, with variation of ∼1.3% in the net OD. The net OD increased sharply within the first 6 hrs after irradiation and gradually afterwards. No significant difference was observed for the beam energy and dose rate, with a variation of ∼1.5% in the net OD. The gamma passing rates (at 3%, 3 mm) between the film‐ measured and treatment planning system (TPS)‐calculated dose distributions under a high dose VMAT plan in the absolute dose mode were more than 98.9%. PACS number(s): 87.56 Fc PMID:27929504

Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer: a phase II study of the German Testicular Cancer Study Group.

PubMed

Kollmannsberger, C; Rick, O; Klaproth, H; Kubin, T; Sayer, H G; Hentrich, M; Welslau, M; Mayer, F; Kuczyk, M; Spott, C; Kanz, L; Bokemeyer, C

2002-09-23

Despite generally high cure rates in patients with metastatic germ cell cancer, patients with progressive disease on first-line cisplatin-based chemotherapy or with relapsed disease following high-dose salvage therapy exhibit a very poor prognosis. Irinotecan has shown antitumour activity in human testicular tumour xenografts in nude mice. We have performed a phase II study examining the single agent activity of irinotecan in patients with metastatic relapsed or cisplatin-refractory germ cell cancer. Refractory disease was defined as progression or relapse within 4 weeks after cisplatin-based chemotherapy or relapse after salvage high-dose chemotherapy with autologous stem cell support. Irinotecan was administered at a dose of 300 (-350) mg m(-2) every 3 weeks. Response was evaluated every 4 weeks. Fifteen patients have been enrolled. Median age was 35 (19-53) years. Primary tumour localisation was gonadal/mediastinal in 12/3 patients. Patients had been pretreated with a median of six (4-12) cisplatin-containing cycles and 13 out of 15 patients had previously failed high-dose chemotherapy with blood stem cell support. Median number of irinotecan applications was two (1-3). Fourteen patients are assessable for response and all for toxicity. In one patient, no adequate response evaluation was performed. Toxicity was generally acceptable and consisted mainly of haematological side effects with common toxicity criteria 3 degrees anaemia (two patients), common toxicity criteria 3 degrees leukocytopenia (one patient) and common toxicity criteria 3 degrees thrombocytopenia (three patients). Common toxicity criteria 3/4 degrees non-haematological toxicity occurred in five patients (33%): 1 x diarrhoea, 2 x alopecia, 1 x fever and in one patient worsening of pre-existing peripheral polyneuropathy from 1 degrees to 4 degrees. No response was observed to irinotecan therapy. Currently, 13 patients have died of the disease and two patients are alive with the disease. The patients included in our study exhibit similar prognostic characteristics as patients treated in previous trials evaluating new drugs in this setting. Irinotecan at a dose of 300-350 mg m(-2) every 3 weeks appears to have no antitumour activity in patients with cisplatin-refractory germ cell cancer and, thus, further investigation in this disease is not justified.

Using machine learning to model dose-response relationships.

PubMed

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

2016-12-01

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

Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens.

PubMed Central

Tinwell, Helen; Ashby, John

2004-01-01

We have evaluated whether mixtures of estrogens, present in the mix at doses that are individually inactive in the immature rat uterotrophic assay, can give a uterotrophic response. Seven chemicals were evaluated: nonylphenol, bisphenol A (BPA), methoxychlor, genistein (GEN), estradiol, diethylstilbestrol, and ethinyl estradiol. Dose responses in the uterotrophic assay were constructed for each chemical. The first series of experiments involved evaluating binary mixtures of BPA and GEN at dose levels that gave moderate uterotrophic responses when tested individually. The mixtures generally showed an intermediate or reduced uterotrophic effect compared with when the components of the mixture were tested alone at the dose used in the mixture. The next series of experiments used a multicomponent (complex) mixture of all seven chemicals evaluated at doses that gave either weakly positive or inactive uterotrophic responses when tested individually in the assay. Doses that were nominally equi-uterotrophic ranged over approximately six orders of magnitude for the seven chemicals. Doses of agents that gave a weak uterotrophic response when tested individually gave a marginally enhanced positive response in the assay when tested combined as a mixture. Doses of agents that gave a negative uterotrophic response when tested individually gave a positive response when tested as a mixture. These data indicate that a variety of different estrogen receptor (ER) agonists, present individually at subeffective doses, can act simultaneously to evoke an ER-regulated response. However, translating these findings into the process of environmental hazard assessment will be difficult. The simple addition of the observed, or predicted, activities for the components of a mixture is confirmed here to be inappropriate and to overestimate the actual effect induced by the mixture. Equally, isobole analysis is only suitable for two- or three-component mixtures, and concentration addition requires access to dose-response data and EC50 values (concentration giving 50% of the maximum response) for the individual components of the mixture--requirements that will rarely be fulfilled for complex environmental samples. Given these uncertainties, we conclude that it may be most expedient to select and bioassay whole environmental mixtures of potential concern. PMID:15064164

Dynamics of the h-LH and h-FSH response after the stimulation test with Gn-RH-LH/FSH in man.

PubMed

Klepsch, I; Grigorescu, A; Eşanu, C

1976-01-01

A study was carried out on a number of 17 subjects concerning the dynamics of LH and FSH response after stimulation with Gn-RH-LH/FSH. The results show a stimulation 10 minutes after quick i.v. injection of synthetic RH, with a peak at 20-30 minutes and a persistence of the response of up to 180 min. The variation of the response is proportional with the dose, the response to stimulation being higher for LH than for FSH. The response in the normal adult male is of 82-858% for LH and of 157-250% for FSH. In aged subjects there is an increased response capacity showing that the hypophysis still reacts at an advanced age, with variations depending on the individual characteristics. In Sheehan's syndrome the basal values of FSH and LH are low, with a slight response after stimulation with RH, suggesting the possibility of a partial regeneration of the hypophysis if any intact areas were left after the initial necrotic process.

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

Wyrobek, A. J.; Manohar, C. F.; Nelson, D. O.

We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues. Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of {approx}80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, moleculemore » transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.« less

Maternal characteristics and hospital policies as risk factors for nonreceipt of hepatitis B vaccine in the newborn nursery.

PubMed

O'Leary, Sean T; Nelson, Christina; Duran, Julie

2012-01-01

A birth dose of hepatitis B vaccine (HBV) is a primary focus of the Advisory Committee on Immunization Practices' strategy to eliminate transmission of hepatitis B virus in the United States. We sought to assess the impact of maternal characteristics and hospital policy on the receipt of a birth dose of HBV. A retrospective cohort study was performed using data from the 2008 Colorado birth registry. Hospital policy was assessed by state health department personnel. Univariate and multivariate logistic regression analyses were used to examine the association of maternal characteristics and hospital policy with nonreceipt of HBV. A total of 64,425 infants were identified in the birth cohort, of whom 61.6% received a birth dose of HBV. Higher maternal education and income were associated with nonreceipt of HBV (master's degree vs. eighth grade or less: adjusted odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.49-1.85; >$75,000 vs. <$15,000: adjusted OR = 1.21, 95% CI = 1.13-1.30). Lack of a hospital policy stipulating a universal birth dose strongly predicted nonreceipt of a birth dose of HBV (policy with no birth dose vs. policy with a birth dose: adjusted OR = 2.21, 95% CI = 2.13-2.30). Maternal characteristics such as higher education and income are associated with nonreceipt of the HBV during the perinatal period. To effectively reduce risk of perinatal hepatitis B transmission, hospitals should stipulate that all infants are offered HBV and ensure that these policies are implemented and followed.

Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis.

PubMed

Ding, Kuan-Fu; Petricoin, Emanuel F; Finlay, Darren; Yin, Hongwei; Hendricks, William P D; Sereduk, Chris; Kiefer, Jeffrey; Sekulic, Aleksandar; LoRusso, Patricia M; Vuori, Kristiina; Trent, Jeffrey M; Schork, Nicholas J

2018-01-12

Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC 50 ). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC 50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC 50 -based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.

Enhancement of phototropic response to a range of light doses in Triticum aestivum coleoptiles in clinostat-simulated microgravity

NASA Technical Reports Server (NTRS)

Heathcote, D. G.; Bircher, B. W.; Brown, A. H. (Principal Investigator)

1987-01-01

The phototropic dose-response relationship has been determined for Triticum aestivum cv. Broom coleoptiles growing on a purpose-built clinostat apparatus providing gravity compensation by rotation about a horizontal axis at 2 rev min-1. These data are compared with data sets obtained with the clinostat axis vertical and stationary, as a 1 g control, and rotating vertically to examine clinostat effects other than gravity compensation. Triticum at 1 g follows the well-established pattern of other cereal coleoptiles with a first positive curvature at low doses, followed by an indifferent response region, and a second positive response at progressively increasing doses. However, these response regions lie at higher dose levels than reported for Avena. There is no significant difference between the responses observed with the clinostat axis vertical in the rotating and stationary modes, but gravity compensation by horizontal rotation increases the magnitude of first and second positive curvatures some threefold at 100 min after stimulation. The indifferent response is replaced by a significant curvature towards the light source, but remains apparent as a reduced curvature response at these dose levels.

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

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

PubMed Central

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

2017-01-01

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

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

PubMed Central

Leonard, Bobby E.

2008-01-01

Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type 125I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite primary unresolved questions regarding adaptive response behavior and bystander behavior. The five features of major significance provided by the Microdose Model so far are 1.) Single Specific Energy Hits initiate Adaptive Response, 2.) Mammogram and diagnostic X-rays induce a protective Bystander Effect as well as Adaptive Response radio-protection. 3.) For mammogram X-rays the Adaptive Response protection is retained at high primer dose levels. 4.) The dose range of the AR protection depends on the value of the Specific Energy per Hit, . 5.) Alpha particle induced deleterious Bystander damage is modulated by low LET radiation. PMID:18648579

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

Regional radiation dose-response modeling of functional liver in hepatocellular carcinoma patients with longitudinal sulfur colloid SPECT/CT: a proof of concept.

PubMed

Price, Ryan G; Apisarnthanarax, Smith; Schaub, Stephanie K; Nyflot, Matthew J; Chapman, Tobias R; Matesan, Manuela; Vesselle, Hubert J; Bowen, Stephen R

2018-06-19

We report on patient-specific quantitative changes in longitudinal sulfur colloid SPECT/CT as a function of regional radiation dose distributions to normal liver in a cohort of hepatocellular carcinoma patients. Dose-response thresholds and slopes varied with baseline liver function metrics, and extreme values were found in patients with fatal hepatotoxicity. Dose-response modeling of normal liver in individual HCC patients has potential to characterize in vivo radiosensitivity, identify high risk subgroups, and personalize treatment planning dose constraints. Hepatotoxicity risk in hepatocellular carcinoma (HCC) patients is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [ 99m Tc]sulfur colloid (SC) SPECT/CT liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity. SC SPECT/CT images of 15 HCC patients with variable Child-Pugh status (8 CP-A, 7 CP-B/C) were acquired in treatment position prior to and 1 month (nominal) after SBRT (n=6) or proton therapy (n=9). Localized rigid registrations between pre/post-treatment CT to planning CT scans were performed, and transformations were applied to pre/post-treatment SC SPECT images. Radiotherapy doses were converted to EQD2 α/β=3 and Gy (RBE), and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and post-treatment SPECT uptake, normalized to regions receiving < 5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSC max ), dose midpoint (D mid ), and dose-response slope (α mid ) parameters. Individual patient sigmoid dose-response curves had high goodness-of-fit (median R 2 = 0.96, range 0.76-0.99). Large inter-patient variability was observed, with median (range) in %ΔSC max of 44% (20-75%), D mid of 13 Gy (4-27 GyEQD2), and α mid of 0.11 GyEQD2 -1 (0.04-0.29 GyEQD2 -1 ), respectively. Eight of 15 patients had %ΔSC max = 20-45%, while 7/15 had %ΔSC max = 60-75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2/15) with low TLF (< 0.12) and low D mid (< 7 GyEQD2). Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response, and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints. Copyright © 2018 Elsevier Inc. All rights reserved.

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

EPA Science Inventory

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

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

EPA Science Inventory

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

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

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

USDA-ARS?s Scientific Manuscript database

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

USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

EPA Science Inventory

Use of Mechanistic Data to Help Define Dose-Response Curves

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

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

DOT National Transportation Integrated Search

1998-07-01

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

Characterization of the a-Si EPID in the unity MR-linac for dosimetric applications.

PubMed

Torres-Xirau, I; Olaciregui-Ruiz, I; Baldvinsson, G; Mijnheer, B J; van der Heide, U A; Mans, A

2018-01-09

Electronic portal imaging devices (EPIDs) are frequently used in external beam radiation therapy for dose verification purposes. The aim of this study was to investigate the dose-response characteristics of the EPID in the Unity MR-linac (Elekta AB, Stockholm, Sweden) relevant for dosimetric applications under clinical conditions. EPID images and ionization chamber (IC) measurements were used to study the effects of the magnetic field, the scatter generated in the MR housing reaching the EPID, and inhomogeneous attenuation from the MR housing. Dose linearity and dose rate dependencies were also determined. The magnetic field strength at EPID level did not exceed 10 mT, and dose linearity and dose rate dependencies proved to be comparable to that on a conventional linac. Profiles of fields, delivered with and without the magnetic field, were indistinguishable. The EPID center had an offset of 5.6 cm in the longitudinal direction, compared to the beam central axis, meaning that large fields in this direction will partially fall outside the detector area and not be suitable for verification. Beam attenuation by the MRI scanner and the table is gantry angle dependent, presenting a minimum attenuation of 67% relative to the 90° measurement. Repeatability, observed over two months, was within 0.5% (1 SD). In order to use the EPID for dosimetric applications in the MR-linac, challenges related to the EPID position, scatter from the MR housing, and the inhomogeneous, gantry angle-dependent attenuation of the beam will need to be solved.

Characterization of the a-Si EPID in the unity MR-linac for dosimetric applications

NASA Astrophysics Data System (ADS)

Torres-Xirau, I.; Olaciregui-Ruiz, I.; Baldvinsson, G.; Mijnheer, B. J.; van der Heide, U. A.; Mans, A.

2018-01-01

Electronic portal imaging devices (EPIDs) are frequently used in external beam radiation therapy for dose verification purposes. The aim of this study was to investigate the dose-response characteristics of the EPID in the Unity MR-linac (Elekta AB, Stockholm, Sweden) relevant for dosimetric applications under clinical conditions. EPID images and ionization chamber (IC) measurements were used to study the effects of the magnetic field, the scatter generated in the MR housing reaching the EPID, and inhomogeneous attenuation from the MR housing. Dose linearity and dose rate dependencies were also determined. The magnetic field strength at EPID level did not exceed 10 mT, and dose linearity and dose rate dependencies proved to be comparable to that on a conventional linac. Profiles of fields, delivered with and without the magnetic field, were indistinguishable. The EPID center had an offset of 5.6 cm in the longitudinal direction, compared to the beam central axis, meaning that large fields in this direction will partially fall outside the detector area and not be suitable for verification. Beam attenuation by the MRI scanner and the table is gantry angle dependent, presenting a minimum attenuation of 67% relative to the 90° measurement. Repeatability, observed over two months, was within 0.5% (1 SD). In order to use the EPID for dosimetric applications in the MR-linac, challenges related to the EPID position, scatter from the MR housing, and the inhomogeneous, gantry angle-dependent attenuation of the beam will need to be solved.

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.

A comparison of community response to aircraft noise at Toronto International and Oshawa Municipal airports†

NASA Astrophysics Data System (ADS)

Taylor, S. M.; Hall, F. L.; Birnie, S. E.

1981-07-01

Debate continues over the validity of a single dose-response relationship to describe annoyance due to transportation noise. Doubts about the appropriateness of a single relationship have centred primarily on the issue of differential response to the same noise level for different sources (e.g., aircraft, road traffic and trains). However, recent work suggests that response may vary for different types of the same source, namely aircraft, dependent upon the character, and specifically the number, of operations. Recent data collected around Toronto International and Oshawa Municipal airports permit a test of differences in four aggregate response variables. For the same NEF level, the percent at all annoyed at the two airports is not statistically different. The percent highly annoyed and the percent reporting speech interference are both significantly greater at Toronto but the percent reporting sleep interruption is greater at Oshawa. These differences can be explained in terms of the operational characteristics of the two airports.

Biphasic responses in multi-site phosphorylation systems.

PubMed

Suwanmajo, Thapanar; Krishnan, J

2013-12-06

Multi-site phosphorylation systems are repeatedly encountered in cellular biology and multi-site modification is a basic building block of post-translational modification. In this paper, we demonstrate how distributive multi-site modification mechanisms by a single kinase/phosphatase pair can lead to biphasic/partial biphasic dose-response characteristics for the maximally phosphorylated substrate at steady state. We use simulations and analysis to uncover a hidden competing effect which is responsible for this and analyse how it may be accentuated. We build on this to analyse different variants of multi-site phosphorylation mechanisms showing that some mechanisms are intrinsically not capable of displaying this behaviour. This provides both a consolidated understanding of how and under what conditions biphasic responses are obtained in multi-site phosphorylation and a basis for discriminating between different mechanisms based on this. We also demonstrate how this behaviour may be combined with other behaviour such as threshold and bistable responses, demonstrating the capacity of multi-site phosphorylation systems to act as complex molecular signal processors.

Dynamics of Cellular Responses to Radiation

PubMed Central

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

2014-01-01

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

SU-E-T-607: Performance Quantification of the Nine Detectors Used for Dosimetry Measurements in Advanced Radiation Therapy Treatments

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

Markovic, M; Stathakis, S; Jurkovic, I

2015-06-15

Purpose: The purpose of this study was to quantify performance of the nine detectors used for dosimetry measurements in advanced radiation therapy treatments. Methods: The 6 MV beam was utilized for measurements of the field sizes with the lack of lateral charge particle equilibrium. For dose fidelity aspect, energy dependence was studied by measuring PDD and profiles at different depths. The volume effect and its influence on the measured dose profiles have been observed by measuring detector’s response function. Output factor measurements with respect to change in energy spectrum have been performed and collected data has been analyzed. The linearitymore » of the measurements with the dose delivered has been evaluated and relevant comparisons were done. Results: The measured values of the output factors with respect to change in energy spectrum indicated presence of the energy dependence. The detectors with active volume size ≤ 0.3 mm3 maximum deviation from the mean is 5.6% for the field size 0.5 x 0.5 cm2 while detectors with active volume size > 0.3 mm3 have maximum deviation from the mean 7.1%. Linearity with dose at highest dose rate examined for diode detectors showed maximum deviation of 4% while ion chambers showed maximum deviation of 2.2%. Dose profiles showed energy dependence at shallow depths (surface to dmax) influenced by low energy particles with 12 % maximum deviation from the mean for 5 mm2 field size. In relation to Monte Carlo calculation, the detector’s response function σ values were between (0.42±0.25) mm and (1.2±0.25) mm. Conclusion: All the detectors are appropriate for the dosimetry measurements in advanced radiation therapy treatments. The choice of the detectors has to be determined by the application and the scope of the measurements in respect to energy dependence and ability to accurately resolve dose profiles as well as to it’s intrinsic characteristics.« less

Salicylate-induced cochlear impairments, cortical hyperactivity and re-tuning, and tinnitus.

PubMed

Chen, Guang-Di; Stolzberg, Daniel; Lobarinas, Edward; Sun, Wei; Ding, Dalian; Salvi, Richard

2013-01-01

High doses of sodium salicylate (SS) have long been known to induce temporary hearing loss and tinnitus, effects attributed to cochlear dysfunction. However, our recent publications reviewed here show that SS can induce profound, permanent, and unexpected changes in the cochlea and central nervous system. Prolonged treatment with SS permanently decreased the cochlear compound action potential (CAP) amplitude in vivo. In vitro, high dose SS resulted in a permanent loss of spiral ganglion neurons and nerve fibers, but did not damage hair cells. Acute treatment with high-dose SS produced a frequency-dependent decrease in the amplitude of distortion product otoacoustic emissions and CAP. Losses were greatest at low and high frequencies, but least at the mid-frequencies (10-20 kHz), the mid-frequency band that corresponds to the tinnitus pitch measured behaviorally. In the auditory cortex, medial geniculate body and amygdala, high-dose SS enhanced sound-evoked neural responses at high stimulus levels, but it suppressed activity at low intensities and elevated response threshold. When SS was applied directly to the auditory cortex or amygdala, it only enhanced sound evoked activity, but did not elevate response threshold. Current source density analysis revealed enhanced current flow into the supragranular layer of auditory cortex following systemic SS treatment. Systemic SS treatment also altered tuning in auditory cortex and amygdala; low frequency and high frequency multiunit clusters up-shifted or down-shifted their characteristic frequency into the 10-20 kHz range thereby altering auditory cortex tonotopy and enhancing neural activity at mid-frequencies corresponding to the tinnitus pitch. These results suggest that SS-induced hyperactivity in auditory cortex originates in the central nervous system, that the amygdala potentiates these effects and that the SS-induced tonotopic shifts in auditory cortex, the putative neural correlate of tinnitus, arises from the interaction between the frequency-dependent losses in the cochlea and hyperactivity in the central nervous system. Copyright © 2012 Elsevier B.V. All rights reserved.

Next generation microbiological risk assessment-Potential of omics data for hazard characterisation.

PubMed

Haddad, Nabila; Johnson, Nick; Kathariou, Sophia; Métris, Aline; Phister, Trevor; Pielaat, Annemarie; Tassou, Chrysoula; Wells-Bennik, Marjon H J; Zwietering, Marcel H

2018-04-12

According to the World Health Organization estimates in 2015, 600 million people fall ill every year from contaminated food and 420,000 die. Microbial risk assessment (MRA) was developed as a tool to reduce and prevent risks presented by pathogens and/or their toxins. MRA is organized in four steps to analyse information and assist in both designing appropriate control options and implementation of regulatory decisions and programs. Among the four steps, hazard characterisation is performed to establish the probability and severity of a disease outcome, which is determined as function of the dose of toxin and/or pathogen ingested. This dose-response relationship is subject to both variability and uncertainty. The purpose of this review/opinion article is to discuss how Next Generation Omics can impact hazard characterisation and, more precisely, how it can improve our understanding of variability and limit the uncertainty in the dose-response relation. The expansion of omics tools (e.g. genomics, transcriptomics, proteomics and metabolomics) allows for a better understanding of pathogenicity mechanisms and virulence levels of bacterial strains. Detection and identification of virulence genes, comparative genomics, analyses of mRNA and protein levels and the development of biomarkers can help in building a mechanistic dose-response model to predict disease severity. In this respect, systems biology can help to identify critical system characteristics that confer virulence and explain variability between strains. Despite challenges in the integration of omics into risk assessment, some omics methods have already been used by regulatory agencies for hazard identification. Standardized methods, reproducibility and datasets obtained from realistic conditions remain a challenge, and are needed to improve accuracy of hazard characterisation. When these improvements are realized, they will allow the health authorities and government policy makers to prioritize hazards more accurately and thus refine surveillance programs with the collaboration of all stakeholders of the food chain. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS.

PubMed

Tack, J; Schumacher, K; Tonini, G; Scartoni, S; Capriati, A; Maggi, C A

2017-08-01

Tachykinins have been implicated in the pathophysiology of IBS with diarrhoea (IBS-D). Our aim was to study the efficacy and safety of ibodutant, a selective neurokinin-2 (NK2) receptor antagonist, in patients with IBS-D. This multinational double-blind, placebo-controlled study recruited 559 patients with IBS-D according to Rome III criteria. After a 2-week treatment-free run-in, patients were randomised to ibodutant 1 mg, 3 mg, 10 mg or placebo once daily for eight consecutive weeks. Responders were those with a combined response of satisfactory relief (weekly binary question yes/no) of overall IBS symptoms and abdominal pain/discomfort on ≥75% weeks (primary end point). Secondary end points included abdominal pain and stool pattern. Data were also analysed according to US Food and Drug Administration (FDA)-approved interim end points (improvement of pain and stool consistency). Safety was assessed by monitoring adverse events and laboratory tests. Prespecified statistical analysis involved the whole group as well as gender subgroups. Demographics and baseline characteristics were comparable for all treatment arms. In the overall population, responsiveness tended to increase with escalating ibodutant doses. In the prespecified analysis by gender, ibodutant 10 mg demonstrated significant superiority over placebo in females (p=0.003), while no significant effect occurred in males. This was confirmed for secondary end points and for the responder analysis according to FDA-approved end points. The tolerability and safety of ibodutant was excellent at all doses. Ibodutant showed dose-dependent efficacy response in IBS-D, reaching statistical significance at the 10 mg dose in female patients. The safety and tolerability profile of ibodutant was similar to placebo. NCT01303224. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PSA Response to Neoadjuvant Androgen Deprivation Therapy Is a Strong Independent Predictor of Survival in High-Risk Prostate Cancer in the Dose-Escalated Radiation Therapy Era

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

McGuire, Sean E., E-mail: semcguir@mdanderson.org; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; Lee, Andrew K.

2013-01-01

Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specificmore » mortality (PCSM) and overall survival (OS) were examined. Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs {>=}0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level {>=}0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level {>=}0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation.« less

Dose characteristics of in-house-built collimators for stereotactic radiotherapy with a linear accelerator.

PubMed

Norrgård, F S; Sipilä, P M; Kulmala, J A; Minn, H R

1998-06-01

Dose characteristics of a stereotactic radiotherapy unit based on a standard Varian Clinac 4/100 4 MV linear accelerator, in-house-built Lipowitz collimators and the SMART stereotactic radiotherapy treatment planning software have been determined. Beam collimation is constituted from the standard collimators of the linear accelerator and a tertiary collimation consisting of a replaceable divergent Lipowitz collimator. Four collimators with isocentre diameters of 15, 25, 35 and 45 mm, respectively, were constructed. Beam characteristics were measured in air, acrylic or water with ionization chamber, photon diode, electron diode, diamond detector and film. Monte Carlo simulation was also applied. The radiation leakage under the collimators was less than 1% at 50 mm depth in water. Specific beam characteristics for each collimator were imported to SMART and dose planning with five non-coplanar converging 140 degrees arcs separated by 36 degrees angles was performed for treatment of a RANDO phantom. Dose verification was made with TLD and radiochromic film. The in-house-built collimators were found to be suitable for stereotactic radiotherapy and patient treatments with this system are in progress.

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.

Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose

PubMed Central

Carlson, Nicole S.; Corwin, Elizabeth J.; Lowe, Nancy K.

2017-01-01

Background Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. Objectives This study had two main objectives: 1) Examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and 2) Examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. Study design Longitudinal study of a cohort (N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI ≥ 30 kg/m2) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. Results Maternal BMI explained 16.56% (95% CI [13.7-20.04], p < 0.001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women (p < 0.001). Conclusions Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation. PMID:28347147

Radiobiology of hypofractionated stereotactic radiotherapy: what are the optimal fractionation schedules?

PubMed Central

Shibamoto, Yuta; Miyakawa, Akifumi; Otsuka, Shinya; Iwata, Hiromitsu

2016-01-01

In hypofractionated stereotactic radiotherapy (SRT), high doses per fraction are usually used and the dose delivery pattern is different from that of conventional radiation. The daily dose is usually given intermittently over a longer time compared with conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. In in vivo tumors, however, this decrease in effect may be counterbalanced by rapid reoxygenation. Another issue related to hypofractionated SRT is the mathematical model for dose evaluation and conversion. The linear–quadratic (LQ) model and biologically effective dose (BED) have been suggested to be incorrect when used for hypofractionation. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when used for tumor responses in vivo, since it does not take reoxygenation into account. Correction of the errors, estimated at 5–20%, associated with the use of BED is necessary when it is used for SRT. High fractional doses have been reported to exhibit effects against tumor vasculature and enhance host immunity, leading to increased antitumor effects. This may be an interesting topic that should be further investigated. Radioresistance of hypoxic tumor cells is more problematic in hypofractionated SRT, so trials of hypoxia-targeted agents are encouraged in the future. In this review, the radiobiological characteristics of hypofractionated SRT are summarized, and based on the considerations, we would like to recommend 60 Gy in eight fractions delivered three times a week for lung tumors larger than 2 cm in diameter. PMID:27006380

Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose.

PubMed

Carlson, Nicole S; Corwin, Elizabeth J; Lowe, Nancy K

2017-07-01

Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. This study had two main objectives: (1) examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and (2) examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. Longitudinal study of a cohort ( N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI ≥ 30 kg/m 2 ) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. Maternal BMI explained 16.56% (95% confidence interval [CI] = [13.7, 20.04], p < .001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women ( p < .001). Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation.

The c-Abl signaling network in the radioadaptive response

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

Chi-Min, Yuan

2014-01-28

The radioadaptive response, or radiation hormesis, i.e. a low dose of radiation can protect cells and organisms from the effects of a subsequent higher dose, is a widely recognized phenomenon. Mechanisms underlying such radiation hormesis, however, remain largely unclear. Preliminary studies indicate an important role of c-Abl signaling in mediating the radioadaptive response. We propose to investigate how c-Abl regulates the crosstalk between p53 and NFκB in response to low doses irradiation. We found in our recent study that low dose IR induces a reciprocal p53 suppression and NFκB activation, which induces HIF-a and subsequently a metabolic reprogramming resulting inmore » a transition from oxidative phosphorylation to glycolysis. Of importance is that this glycolytic switch is essential for the radioadaptive response. This low-dose radiationinduced HIF1α activation was in sharp contrast with the high-dose IR-induced p53 activation and HIF1α inhibition. HIF1α and p53 seem to play distinct roles in mediating the radiation dose-dependent metabolic response. The induction of HIF1α-mediated glycolysis is restricted to a low dose range of radiation, which may have important implications in assessing the level of radiation exposure and its potential health risk. Our results support a dose-dependent metabolic response to IR. When IR doses are below the threshold of causing detectable DNA damage (<0.2Gy) and thus little p53 activation, HIF1α is induced resulting in induction of glycolysis and increased radiation resistance. When the radiation dose reaches levels eliciting DNA damage, p53 is activated and diminishes the activity of HIF1α and glycolysis, leading to the induction of cell death. Our work challenges the LNT model of radiation exposure risk and provides a metabolic mechanism of radioadaptive response. The study supports a need for determining the p53 and HIF1α activity as a potential reliable biological readout of radiation exposure in humans. The exquisite sensitivity of cellular metabolism to low doses of radiation could also serve as a valuable biomarker for estimating the health effects of low-level radiation exposure.« less

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

PubMed

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

2014-10-01

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

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.

Effects and Dose-Response Relationships of Motor Imagery Practice on Strength Development in Healthy Adult Populations: a Systematic Review and Meta-analysis.

PubMed

Paravlic, Armin H; Slimani, Maamer; Tod, David; Marusic, Uros; Milanovic, Zoran; Pisot, Rado

2018-05-01

Motor imagery (MI), a mental simulation of a movement without overt muscle contraction, has been largely used to improve general motor tasks. However, the effects of MI practice on maximal voluntary strength (MVS) remain equivocal. The aims of this meta-analysis were to (1) estimate whether MI practice intervention can meaningfully improve MVS in healthy adults; (2) compare the effects of MI practice on MVS with its combination with physical practice (MI-C), and with physical practice (PP) training alone; and (3) investigate the dose-response relationships of MI practice. Seven electronic databases were searched up to April 2017. Initially 717 studies were identified; however, after evaluation of the study characteristics, data from 13 articles involving 370 participants were extracted. The meta-analysis was completed on MVS as the primary parameter. In addition, parameters associated with training volume, training intensity, and time spent training were used to investigate dose-response relationships. MI practice moderately improved MVS. When compared to conventional PP, effects were of small benefit in favour of PP. MI-C when compared to PP showed unclear effects. MI practice produced moderate effects in both upper and lower extremities on MVS. The cortical representation area of the involved muscles did not modify the effects. Meta-regression analysis revealed that (a) a training period of 4 weeks, (b) a frequency of three times per week, (c) two to three sets per single session, (d) 25 repetitions per single set, and (e) single session duration of 15 min were associated with enhanced improvements in muscle strength following MI practice. Similar dose-response relationships were observed following MI and PP. The present meta-analysis demonstrates that compared to a no-exercise control group of healthy adults, MI practice increases MVS, but less than PP. These findings suggest that MI practice could be considered as a substitute or additional training tool to preserve muscle function when athletes are not exposed to maximal training intensities.

Rates and Durability of Response to Salvage Radiation Therapy Among Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma

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

Tseng, Yolanda D., E-mail: ydt2@uw.edu; Chen, Yu-Hui; Catalano, Paul J.

Purpose: To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics. Methods and Materials: A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treatedmore » with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model. Results: Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P=.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P=.007) but not dose (P=.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy. Conclusions: Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a shorter TTLR, suggesting that radiation dose escalation, addition of radiosensitizers, or a combination of both may be indicated in these patients.« less

The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex.

PubMed

Sánchez-Porras, Renán; Santos, Edgar; Schöll, Michael; Stock, Christian; Zheng, Zelong; Schiebel, Patrick; Orakcioglu, Berk; Unterberg, Andreas W; Sakowitz, Oliver W

2014-09-01

Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization that propagates across the cerebral cortex and has been implicated in the pathophysiology of brain injury states and migraine with aura. Analgesics and sedatives seem to have a significant effect on SD modulation. Studies have shown that ketamine, an NMDA receptor blocker, has the capacity to influence SD occurrence. The aim of this study was to analyze the dose-dependent effect of ketamine on SD susceptibility through electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging in a gyrencephalic brain. Ketamine in a low-dose infusion (2 mg/kg/h) decreases SD spread and had an effect on the amplitude of SD deflections, as well as on duration, and speed. Moreover, during ketamine infusion at this dose, there was a sustained decrease in the hyperemic response following SD. However, a high-dose infusion (4 mg/kg/h) of ketamine inhibited SD induction and expansion. Furthermore, a high-dose bolus (4 mg/kg), 1 min after stimulation, blocked SD propagation abruptly within 1-2 min, and hindered SD induction and expansion for the following 15-30 min. The results suggest that ketamine may be therapeutically beneficial in preventing SDs. Nonetheless, an adequate dosage and way of administration should be considered and established for human use. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed Central

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

2018-01-01

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

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

PubMed

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

2018-01-01

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

Characterisation and novel applications of glass beads as dosimeters in radiotherapy

NASA Astrophysics Data System (ADS)

Jafari, Shakardokht

The intent of external beam radiotherapy is to deliver as high a radiation dose as possible to tumour volume whilst minimizing the dose to surrounding normal tissues. Recent development of techniques such as intensity modulated radiation therapy (IMRT) and stereotactic ablative body radiotherapy (SABR) aim to extend this capability. The main feature of these techniques is to use beams which often contain small fields and very steep dose gradients. These present several dosimetric challenges including loss of charge particle equilibrium (CPE), partial occlusion of the direct-beam source and steep fall-off in dose in the penumbra. Dosimeters which are small in size relative to the radiation field dimensions are recommended for such conditions. The particular glass beads studied herein have several potentially favourable physical characteristics; they are small in size (1 to 3 mm diameter), chemically inert, inexpensive, readily available and reusable. The dosimetric characterisation of glass beads has been obtained by irradiating them in various radiotherapy beams of kilo-voltage and mega-voltage photons, megavoltage electrons, protons and carbon ions. They exhibit minimal fading compared with commercial LiF thermo-luminescent (TL) dosimeters, have high TL light transparency, high sensitivity and a large dynamic dose range that remains linear from 1 cGy to 100 Gy They have also been shown to be independent of dose rate and beam incidence angle, as well as having a low variation in response with energy over a range of megavoltage photon and electron beams. The latter characteristic is of importance, where spectral changes may occur as a function of field size and off axis location and for the use of dosimeters in postal audit situations where each institution may have slightly different quality index (QI) for their respective photon energies thus ensuring that the calibration is still valid. These properties suggest their practical use as TL dosimeters for radiotherapy dosimetry. Investigations have been performed to evaluate the feasibility of using glass beads in treatment plan verification, small field radiation dosimetry and postal dosimetry audit.

A Four-Step and Four-Criteria Approach for Evaluating Evidence of Dose Addition in Chemical Mixture Toxicity

EPA Science Inventory

Dose addition is the most frequently-used component-based approach for predicting dose response for a mixture of toxicologically-similar chemicals and for statistical evaluation of whether the mixture response is consistent with dose additivity and therefore predictable from the ...

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

PubMed

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

2013-07-01

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

High brachytherapy doses can counteract hypoxia in cervical cancer—a modelling study

NASA Astrophysics Data System (ADS)

Lindblom, Emely; Dasu, Alexandru; Beskow, Catharina; Toma-Dasu, Iuliana

2017-01-01

Tumour hypoxia is a well-known adverse factor for the outcome of radiotherapy. For cervical tumours in particular, several studies indicate large variability in tumour oxygenation. However, clinical evidence shows that the management of cervical cancer including brachytherapy leads to high rate of success. It was the purpose of this study to investigate whether the success of brachytherapy for cervical cancer, seemingly regardless of oxygenation status, could be explained by the characteristics of the brachytherapy dose distributions. To this end, a previously used in silico model of tumour oxygenation and radiation response was further developed to simulate the treatment of cervical cancer employing a combination of external beam radiotherapy and intracavitary brachytherapy. Using a clinically-derived brachytherapy dose distribution and assuming a homogeneous dose delivered by external radiotherapy, cell survival was assessed on voxel level by taking into account the variation of sensitivity with oxygenation as well as the effects of repair, repopulation and reoxygenation during treatment. Various scenarios were considered for the conformity of the brachytherapy dose distribution to the hypoxic region in the target. By using the clinically-prescribed brachytherapy dose distribution and varying the total dose delivered with external beam radiotherapy in 25 fractions, the resulting values of the dose for 50% tumour control, D 50, were in agreement with clinically-observed values for high cure rates if fast reoxygenation was assumed. The D 50 was furthermore similar for the different degrees of conformity of the brachytherapy dose distribution to the tumour, regardless of whether the hypoxic fraction was 10%, 25%, or 40%. To achieve 50% control with external RT only, a total dose of more than 70 Gy in 25 fractions would be required for all cases considered. It can thus be concluded that the high doses delivered in brachytherapy can counteract the increased radioresistance caused by hypoxia if fast reoxygenation is assumed.

Extracting the normal lung dose-response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

NASA Astrophysics Data System (ADS)

Gordon, J. J.; Snyder, K.; Zhong, H.; Barton, K.; Sun, Z.; Chetty, I. J.; Matuszak, M.; Ten Haken, R. K.

2015-09-01

In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence. Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP. Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ~20-40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model. A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk.

Characterization of a MOSkin detector for in vivo skin dose measurements during interventional radiology procedures

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

Safari, M. J.; Wong, J. H. D.; Ng, K. H., E-mail: ngkh@um.edu.my

2015-05-15

Purpose: The MOSkin is a MOSFET detector designed especially for skin dose measurements. This detector has been characterized for various factors affecting its response for megavoltage photon beams and has been used for patient dose measurements during radiotherapy procedures. However, the characteristics of this detector in kilovoltage photon beams and low dose ranges have not been studied. The purpose of this study was to characterize the MOSkin detector to determine its suitability for in vivo entrance skin dose measurements during interventional radiology procedures. Methods: The calibration and reproducibility of the MOSkin detector and its dependency on different radiation beam qualitiesmore » were carried out using RQR standard radiation qualities in free-in-air geometry. Studies of the other characterization parameters, such as the dose linearity and dependency on exposure angle, field size, frame rate, depth-dose, and source-to-surface distance (SSD), were carried out using a solid water phantom under a clinical x-ray unit. Results: The MOSkin detector showed good reproducibility (94%) and dose linearity (99%) for the dose range of 2 to 213 cGy. The sensitivity did not significantly change with the variation of SSD (±1%), field size (±1%), frame rate (±3%), or beam energy (±5%). The detector angular dependence was within ±5% over 360° and the dose recorded by the MOSkin detector in different depths of a solid water phantom was in good agreement with the Markus parallel plate ionization chamber to within ±3%. Conclusions: The MOSkin detector proved to be reliable when exposed to different field sizes, SSDs, depths in solid water, dose rates, frame rates, and radiation incident angles within a clinical x-ray beam. The MOSkin detector with water equivalent depth equal to 0.07 mm is a suitable detector for in vivo skin dosimetry during interventional radiology procedures.« less

Characterization of a MOSkin detector for in vivo skin dose measurements during interventional radiology procedures.

PubMed

Safari, M J; Wong, J H D; Ng, K H; Jong, W L; Cutajar, D L; Rosenfeld, A B

2015-05-01

The MOSkin is a MOSFET detector designed especially for skin dose measurements. This detector has been characterized for various factors affecting its response for megavoltage photon beams and has been used for patient dose measurements during radiotherapy procedures. However, the characteristics of this detector in kilovoltage photon beams and low dose ranges have not been studied. The purpose of this study was to characterize the MOSkin detector to determine its suitability for in vivo entrance skin dose measurements during interventional radiology procedures. The calibration and reproducibility of the MOSkin detector and its dependency on different radiation beam qualities were carried out using RQR standard radiation qualities in free-in-air geometry. Studies of the other characterization parameters, such as the dose linearity and dependency on exposure angle, field size, frame rate, depth-dose, and source-to-surface distance (SSD), were carried out using a solid water phantom under a clinical x-ray unit. The MOSkin detector showed good reproducibility (94%) and dose linearity (99%) for the dose range of 2 to 213 cGy. The sensitivity did not significantly change with the variation of SSD (± 1%), field size (± 1%), frame rate (± 3%), or beam energy (± 5%). The detector angular dependence was within ± 5% over 360° and the dose recorded by the MOSkin detector in different depths of a solid water phantom was in good agreement with the Markus parallel plate ionization chamber to within ± 3%. The MOSkin detector proved to be reliable when exposed to different field sizes, SSDs, depths in solid water, dose rates, frame rates, and radiation incident angles within a clinical x-ray beam. The MOSkin detector with water equivalent depth equal to 0.07 mm is a suitable detector for in vivo skin dosimetry during interventional radiology procedures.

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

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

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

PubMed

Nilsen, Vegard; Wyller, John

2016-01-01

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

Instillation versus Inhalation of Multiwalled Carbon Nanotubes: Exposure-Related Health Effects, Clearance, and the Role of Particle Characteristics

PubMed Central

2015-01-01

Inhaled multiwalled carbon nanotubes (MWCNTs) may cause adverse pulmonary responses due to their nanoscale, fibrous morphology and/or biopersistance. This study tested multiple factors (dose, time, physicochemical characteristics, and administration method) shown to affect MWCNT toxicity with the hypothesis that these factors will influence significantly different responses upon MWCNT exposure. The study is unique in that (1) multiple administration methods were tested using particles from the same stock; (2) bulk MWCNT formulations had few differences (metal content, surface area/functionalization); and (3) MWCNT retention was quantified using a specialized approach for measuring unlabeled MWCNTs in rodent lungs. Male Sprague–Dawley rats were exposed to original (O), purified (P), and carboxylic acid functionalized (F) MWCNTs via intratracheal instillation and inhalation. Blood, bronchoalveolar lavage fluid (BALF), and lung tissues were collected at postexposure days 1 and 21 for quantifying biological responses and MWCNTs in lung tissues by programmed thermal analysis. At day 1, MWCNT instillation produced significant BALF neutrophilia and MWCNT-positive macrophages. Instilled O- and P-MWCNTs produced significant inflammation in lung tissues, which resolved by day 21 despite MWCNT retention. MWCNT inhalation produced no BALF neutrophilia and no significant histopathology past day 1. However, on days 1 and 21 postinhalation of nebulized MWCNTs, significantly increased numbers of MWCNT-positive macrophages were observed in BALF. Results suggest (1) MWCNTs produce transient inflammation if any despite persistence in the lungs; (2) instilled O-MWCNTs cause more inflammation than P- or F-MWCNTs; and (3) MWCNT suspension media produce strikingly different effects on physicochemical particle characteristics and pulmonary responses. PMID:25144856

Peficitinib, an Oral Janus Kinase Inhibitor, in Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2 Study.

PubMed

Sands, Bruce E; Sandborn, William J; Feagan, Brian G; Lichtenstein, Gary R; Zhang, Hongyan; Strauss, Richard; Szapary, Philippe; Johanns, Jewel; Panes, Julian; Vermeire, Severine; O'Brien, Christopher D; Yang, Zijiang; Bertelsen, Kirk; Marano, Colleen

2018-06-15

Janus kinase (JAK) inhibitors have shown efficacy in ulcerative colitis (UC). We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25mg once daily (qd), 75mg qd, 150mg qd, and 75mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8 with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ), and normalization of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose. A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75mg qd achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalization. Treatment-emergent adverse event (TEAE) rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than placebo; patients receiving doses of ≥75mg qd peficitinib reported TEAEs more frequently. While no dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, evidence of efficacy was suggested at doses ≥75mg qd. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282.

Antibody Secreting Cell Responses following Vaccination with Bivalent Oral Cholera Vaccine among Haitian Adults.

PubMed

Matias, Wilfredo R; Falkard, Brie; Charles, Richelle C; Mayo-Smith, Leslie M; Teng, Jessica E; Xu, Peng; Kováč, Pavol; Ryan, Edward T; Qadri, Firdausi; Franke, Molly F; Ivers, Louise C; Harris, Jason B

2016-06-01

The bivalent whole-cell (BivWC) oral cholera vaccine (Shanchol) is effective in preventing cholera. However, evaluations of immune responses following vaccination with BivWC have been limited. To determine whether BivWC induces significant mucosal immune responses, we measured V. cholerae O1 antigen-specific antibody secreting cell (ASC) responses following vaccination. We enrolled 24 Haitian adults in this study, and administered doses of oral BivWC vaccine 14 days apart (day 0 and day 14). We drew blood at baseline, and 7 days following each vaccine dose (day 7 and 21). Peripheral blood mononuclear cells (PBMCs) were isolated, and ASCs were enumerated using an ELISPOT assay. Significant increases in Ogawa (6.9 cells per million PBMCs) and Inaba (9.5 cells per million PBMCs) OSP-specific IgA ASCs were detected 7 days following the first dose (P < 0.001), but not the second dose. The magnitude of V. cholerae-specific ASC responses did not appear to be associated with recent exposure to cholera. ASC responses measured against the whole lipolysaccharide (LPS) antigen and the OSP moiety of LPS were equivalent, suggesting that all or nearly all of the LPS response targets the OSP moiety. Immunization with the BivWC oral cholera vaccine induced ASC responses among a cohort of healthy adults in Haiti after a single dose. The second dose of vaccine resulted in minimal ASC responses over baseline, suggesting that the current dosing schedule may not be optimal for boosting mucosal immune responses to V. cholerae antigens for adults in a cholera-endemic area.

Fundamental study on the characteristics of a radiophotoluminescence glass dosemeter with no energy compensation filter for measuring patient entrance doses in cardiac interventional procedures.

PubMed

Kato, Mamoru; Chida, Koichi; Moritake, Takashi; Koguchi, Yasuhiro; Sato, Tadaya; Oosaka, Hajime; Tosa, Tetsuo; Kadowaki, Ken

2014-12-01

Cardiac interventional procedures have been increasing year by year. However, radiation skin injuries have been still reported. There is a necessity to measure the patient entrance skin dose (ESD), but an accurate dose measurement method has not been established. To measure the ESD, a lot of radiophotoluminescence dosemeters (RPLDs) provide an accurate measurement of the direct actual ESD at the points they are arrayed. The purpose of this study was to examine the characteristics of RPLD to measure the ESD. As a result, X-ray permeable RPLD (with no tin filter) did not interfere with the percutaneous coronary intervention procedure. The RPLD also had good fundamental performance characteristics. Although the RPLD had a little energy dependence, it showed excellent dose and dose-rate linearity, and good angular dependence. In conclusion, by calibrating the energy dependence, RPLDs are useful dosemeter to measure the ESD in cardiac intervention. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Comprehensive evaluation of poly(I:C) induced inflammatory response in an airway epithelial model

PubMed Central

Lever, Amanda R; Park, Hyoungshin; Mulhern, Thomas J; Jackson, George R; Comolli, James C; Borenstein, Jeffrey T; Hayden, Patrick J; Prantil-Baun, Rachelle

2015-01-01

Respiratory viruses invade the upper airway of the lung, triggering a potent immune response that often exacerbates preexisting conditions such as asthma and COPD. Poly(I:C) is a synthetic analog of viral dsRNA that induces the characteristic inflammatory response associated with viral infection, such as loss of epithelial integrity, and increased production of mucus and inflammatory cytokines. Here, we explore the mechanistic responses to poly(I:C) in a well-defined primary normal human bronchial epithelial (NHBE) model that recapitulates in vivo functions and responses. We developed functional and quantifiable methods to evaluate the physiology of our model in both healthy and inflamed states. Through gene and protein expression, we validated the differentiation state and population of essential cell subtypes (i.e., ciliated, goblet, club, and basal cells) as compared to the human lung. Assays for total mucus production, cytokine secretion, and barrier function were used to evaluate in vitro physiology and response to viral insult. Cells were treated apically with poly(I:C) and evaluated 48 h after induction. Results revealed a dose-dependent increase in goblet cell differentiation, as well as, an increase in mucus production relative to controls. There was also a dose-dependent increase in secretion of IL-6, IL-8, TNF-α, and RANTES. Epithelial barrier function, as measured by TEER, was maintained at 1501 ± 355 Ω*cm² postdifferentiation, but dropped significantly when challenged with poly(I:C). This study provides first steps toward a well-characterized model with defined functional methods for understanding dsRNA stimulated inflammatory responses in a physiologically relevant manner. PMID:25847914

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

EPA Science Inventory

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

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

PubMed

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

2008-06-01

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

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

NASA Technical Reports Server (NTRS)

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

1999-01-01

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

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

NASA Technical Reports Server (NTRS)

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

2014-01-01

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

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.

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

PubMed

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

2016-04-01

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

Comparative dosimetric characterization for different types of detectors in high-energy electron beams

NASA Astrophysics Data System (ADS)

Lee, Chang Yeol; Kim, Woo Chul; Kim, Hun Jeong; Huh, Hyun Do; Park, Seungwoo; Choi, Sang Hyoun; Kim, Kum Bae; Min, Chul Kee; Kim, Seong Hoon; Shin, Dong Oh

2017-02-01

The purpose of this study is to perform a comparison and on analysis of measured dose factor values by using various commercially available high-energy electron beam detectors to measure dose profiles and energy property data. By analyzing the high-energy electron beam data from each detector, we determined the optimal detector for measuring electron beams in clinical applications. The dose linearity, dose-rate dependence, percentage depth dose, and dose profile of each detector were measured to evaluate the dosimetry characteristics of high-energy electron beams. The dose profile and the energy characteristics of high-energy electron beams were found to be different when measured by different detectors. Through comparison with other detectors based on the analyzed data, the microdiamond detector was found to have outstanding dose linearity, a low dose-rate dependency, and a small effective volume. Thus, this detector has outstanding spatial resolution and is the optimal detector for measuring electron beams. Radiation therapy results can be improved and related medical accidents can be prevented by using the procedure developed in this research in clinical practice for all beam detectors when measuring the electron beam dose.

Ceruletide intravenous dose-response study by a simplified scintigraphic technique

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

Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.

1985-04-01

The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less

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

PubMed

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

2006-12-01

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

[Customizing dosage drugs what contribution in therapeutic drug monitoring?].

PubMed

Abdessadek, Mohammed; Magoul, Rabia; Amarti, Afaf; El Ouezzani, Seloua; Khabbal, Youssef

2014-01-01

Drug response is often variable from an individual to another: the same dose of drug administered to different patients could cause variable pharmacological effects in nature and intensity. Those effects are often the result of variability in drugs pharmacokinetics (absorption, distribution, metabolism and elimination) which alter their bioavailability. In fact, two factors should be taken into account: the disease(s) from which the patient suffers, and the associated drugs, because many drug interactions may alter their pharmacokinetics causing consequently quite enough of different therapeutic effects. The choice of the assay of the drug subject in monitoring is crucial, it allows quantifying the in vivo dose of the drug and the quality of compliance thereof, the pharmacokinetic characteristics allows the clinician to adjust the dosage by different approaches so that plasma concentrations are included in the therapeutic range. Therapeutic monitoring aims to increase clinical efficacy and to minimize toxicity.

DOSIMETRIC CHARACTERISTICS OF GAMMA-TRON-2 (in Russian)

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

Krongauz, A.N.; Pavlova, T.G.; Frolova, A.V.

1963-01-01

Dosimetric characteristics of the Gammatron-2 during operation in a static regimen are presented. The air dose and the distribution of doses along the central ray of the beam and on the sides were determined. The protective properties of Gammatron-2 were studied. On the basis of the measurements, charts of isodoses were elaborated. (P.C.H.)

Method to determine the position-dependant metal correction factor for dose-rate equivalent laser testing of semiconductor devices

DOEpatents

Horn, Kevin M.

2013-07-09

A method reconstructs the charge collection from regions beneath opaque metallization of a semiconductor device, as determined from focused laser charge collection response images, and thereby derives a dose-rate dependent correction factor for subsequent broad-area, dose-rate equivalent, laser measurements. The position- and dose-rate dependencies of the charge-collection magnitude of the device are determined empirically and can be combined with a digital reconstruction methodology to derive an accurate metal-correction factor that permits subsequent absolute dose-rate response measurements to be derived from laser measurements alone. Broad-area laser dose-rate testing can thereby be used to accurately determine the peak transient current, dose-rate response of semiconductor devices to penetrating electron, gamma- and x-ray irradiation.

The effect of pre-dose on thermally and optically stimulated luminescence from α-Al2O3:C,Mg and α-Al2O3:C.

PubMed

Kalita, J M; Chithambo, M L

2018-06-15

We report the effect of pre-dose on the thermoluminescence (TL) and optically stimulated luminescence (OSL) dose response of α-Al 2 O 3 :C,Mg and α-Al 2 O 3 :C. Before any luminescence measurement, the samples were irradiated with different doses, namely 100, 500 and 1000 Gy to populate the deep electron traps. This is the pre-dose. The results from TL and OSL studies are compared with results from samples used without any pre-measurement dose. The TL glow curves and OSL decay curves of α-Al 2 O 3 :C,Mg recorded after pre-doses of 100, 500 and 1000 Gy are identical to those from a sample used without any pre-dose. Further, the TL and OSL dose response of all α-Al 2 O 3 :C,Mg samples are similar regardless of pre-dose. In comparison, the TL glow curves and OSL decay curves of α-Al 2 O 3 :C are influenced by pre-dose. We conclude that the differences in the TL and OSL dose response of various pre-dosed samples of α-Al 2 O 3 :C are due to the concentration of charge in the deep traps. On the other hand, owing to the lower concentration of such deep traps in α-Al 2 O 3 :C,Mg, the TL or OSL dose responses are not affected by pre-dose in this material. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

No adaptive response is induced by chronic low-dose radiation from Ra-226 in the CHSE/F fish embryonic cell line and the HaCaT human epithelial cell line

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

Shi, Xiaopei, E-mail: shix22@mcmaster.ca; Mothersi

Purpose: To determine whether chronic low-dose α-particle radiation from Ra-226 over multiple cell generations can lead to an adaptive response in CHSE/F fish embryonic cells or HaCaT human epithelial cells receiving subsequent acute high-dose γ-ray radiation. Methods: CHSE/F and HaCaT cells were exposed to very low doses of Ra-226 in medium for multiple generations prior to being challenged by a higher dose γ-ray radiation. The clonogenic assay was used to test the clonogenic survival of cells with or without being pretreated by radiation from Ra-226. Results: In general, pretreatment with chronic radiation has no significant influence on the reaction ofmore » cells to the subsequent challenge radiation. Compared to unprimed cells, the change in clonogenic survival of primed cells after receiving challenge radiation is mainly due to the influence of the chronic exposure, and there's little adaptive response induced. However at several dose points, pretreatment of CHSE/F fish cells with chronic radiation resulted in a radiosensitive response to a challenge dose of γ-ray radiation, and pretreatment of HaCaT cells resulted in no effect except for a slightly radioresistant response to the challenge radiation which was not significant. Conclusion: The results suggest that chronic low-dose radiation is not effective enough to induce adaptive response. There was a difference between human and fish cells and it may be important to consider results from multiple species before making conclusions about effects of chronic or low doses of radiation in the environment. The term “radiosensitive” or “adaptive” make no judgment about whether such responses are ultimately beneficial or harmful. - Highlights: • No obvious adaptive response is induced by chronic low-dose radiation from Ra-226. • Priming radiation from Ra-226 sensitized CHSE/F cells to the challenge radiation. • Linear model is inconsistent with current work using chronic low-dose radiation.« less

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

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

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

Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particlemore » spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.« less

"Coffee, tea and me": moderate doses of caffeine affect sexual behavior in female rats.

PubMed

Guarraci, Fay A; Benson, Anastasia

2005-11-01

The present study evaluated the effects of acute caffeine administration on paced mating behavior and partner preference in ovariectomized rats primed with estrogen and progesterone. In Experiment 1, female rats were tested for paced mating behavior following acute administration of caffeine (15 mg/kg). Caffeine shortened the latency to return to a male following an ejaculation. Although this dose of caffeine did not alter the likelihood of leaving a male after receiving sexual stimulation, locomotor activity did increase significantly. Experiment 2 evaluated the dose response characteristics of caffeine (7.5, 15, 30 mg/kg) administration on paced mating behavior. Replicating Experiment 1, caffeine at the lower doses shortened the latency to return to a male following an ejaculation. Finally, to determine whether the effects of caffeine (15 mg/kg) on contact-return latency reflect a change in sexual motivation or merely an inability to inhibit locomotion, rats were tested for partner preference (intact male vs. estrous female) following caffeine administration (Experiment 3). Although caffeine did not disrupt preference for a sexual partner, caffeine selectively increased visits to the male when physical contact was possible. Collectively, these results suggest that the effects of caffeine on female mating behavior may reflect an increase in both sexual motivation and locomotor activity.

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.

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.

Standard-, Reduced-, and No-Dose Thin-Section Radiologic Examinations: Comparison of Capability for Nodule Detection and Nodule Type Assessment in Patients Suspected of Having Pulmonary Nodules.

PubMed

Ohno, Yoshiharu; Koyama, Hisanobu; Yoshikawa, Takeshi; Kishida, Yuji; Seki, Shinichiro; Takenaka, Daisuke; Yui, Masao; Miyazaki, Mitsue; Sugimura, Kazuro

2017-08-01

Purpose To compare the capability of pulmonary thin-section magnetic resonance (MR) imaging with ultrashort echo time (UTE) with that of standard- and reduced-dose thin-section computed tomography (CT) in nodule detection and evaluation of nodule type. Materials and Methods The institutional review board approved this study, and written informed consent was obtained from each patient. Standard- and reduced-dose chest CT (60 and 250 mA) and MR imaging with UTE were used to examine 52 patients; 29 were men (mean age, 66.4 years ± 7.3 [standard deviation]; age range, 48-79 years) and 23 were women (mean age, 64.8 years ± 10.1; age range, 42-83 years). Probability of nodule presence was assessed for all methods with a five-point visual scoring system. All nodules were then classified as missed, ground-glass, part-solid, or solid nodules. To compare nodule detection capability of the three methods, consensus for performances was rated by using jackknife free-response receiver operating characteristic analysis, and κ analysis was used to compare intermethod agreement for nodule type classification. Results There was no significant difference (F = 0.70, P = .59) in figure of merit between methods (standard-dose CT, 0.86; reduced-dose CT, 0.84; MR imaging with UTE, 0.86). There was no significant difference in sensitivity between methods (standard-dose CT vs reduced-dose CT, P = .50; standard-dose CT vs MR imaging with UTE, P = .50; reduced-dose CT vs MR imaging with UTE, P >.99). Intermethod agreement was excellent (standard-dose CT vs reduced-dose CT, κ = 0.98, P < .001; standard-dose CT vs MR imaging with UTE, κ = 0.98, P < .001; reduced-dose CT vs MR imaging with UTE, κ = 0.99, P < .001). Conclusion Pulmonary thin-section MR imaging with UTE was useful in nodule detection and evaluation of nodule type, and it is considered at least as efficacious as standard- or reduced-dose thin-section CT. © RSNA, 2017 Online supplemental material is available for this article.

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

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study.

PubMed

Popov, I P; Jelić, S B; Krivokapić, Z V; Jezdić, S D; Pesko, P M; Micev, M T; Babić, D R

2008-01-01

To investigate the activity and toxicity of high dose (HD) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer. Histologically confirmed measurable advanced gastric cancer, age < 72 yr, ECOG performance status 0-2, no prior chemo- and radiotherapy, adequate organ functions. EAP arm: doxorubicin (40 mg/m(2)), etoposide (360 mg/m(2)), and cisplatin (80 mg/m(2)) every 28 d; HD 5-FU arm: 5-FU 2.6 g/m(2) 24 h infusion, biweekly. Sixty patients were randomized. Patient characteristics (arms EAP/HD 5-FU): Median age 57/55 yr, median PS 1/1, LAD (patients) 3/8, M1 (patients) 27/22. Median number of cycles (range): EAP arm 4 (2-8), HD 5-FU arm 2 (1-8). Worst toxicity per cycle (grade 3 and 4 in%): Neutropenia 20/3, thrombocytopenia 9/0, anemia 9/13, diarrhea 3/10, nausea 17/7, vomiting 10/0 for EAP and HD 5-FU arms, respectively. All patients were eligible for response in both arms. Confirmed response rate (95%CI): EAP arm 34% [16-50%]/HD 5-FU arm 10% (0-21%), no change: 46/40%, progression of disease: 20/50, respectively. Overall survival (range): EAP arm A 7 mo [3-27], HD 5-FU arm 6 mo (4-25). Infusional HD 5-FU showed a low incidence of severe toxicity. But given the low efficacy of 5-FU in the dosage we applied in the study, it cannot be recommended as a single treatment for further studies. Assessment of higher dose intensity and/or dose density of 5-FU, with introduction of other active drugs in combination, could be an option for further studies.

A stable fixed-dose combination tablet of pseudoephedrine and KOB extracts for the extended release.

PubMed

Hwang, C-J; Park, M-H; Jung, H-W; Park, Y-K; Kim, Y-H; Kang, J-S; Cho, C-W

2013-11-01

Allergic rhinitis (AR) is characterized by inflammation of the nasal mucosa with hypersensitivity resulting from seasonal or perennial responses to specific environmental allergens and by symptoms like nasal rubbing, sneezing, rhinorrhea, lacrimation, nasal congestion and obstruction, and less frequently cough. KOB extracts, which is a polyherbal medicine consisting of 5 different herbs (Atractylodes macrocephala, Astragalus membranaceus, Saposhnikovia divaricata, Ostericum koreanum and Scutellaria baicalensis) had commonly been used for the treatment of various allergic diseases showed an anti-allergic effect by modulating mast cell-mediated allergic responses in allergic rhinitis, recently. On the other hand, pseudoephedrine is a sympathomimetic amine commonly used to relieve congestion in patients with allergic rhinitis and common colds. Considering the KOB's therapeutic mechanism, the combination with pseudoephedrine would be suitable for allergic rhinitis. This study is to obtain an effective extended release formulation using pseudoephedrine and KOB extracts to reduce side effects of drug due to repeated dosing and improve the compliance of patients for treatment of rhinitis and nasal decongestion. So, the fixed-dose combination tablet of pseudoephedrine and KOB extracts was prepared by direct compression and characterized by drug content, flowing characteristics and dissolution test. The drug content of baicalin of KOB extracts was within the range of 95-105% except for T1 formulation. The hardness and friability values of all formulations ranged from 9 to 13 kp and less than 1%, respectively. Taken together, T4 or T8 could be a stable fixed-dose combination tablet for extended release of pseudoephedrine and KOB extracts for nasal rhinitis. © Georg Thieme Verlag KG Stuttgart · New York.

Patent ductus arteriosus in infants <29 weeks gestation--outcomes and factors affecting closure.

PubMed

Popat, H; Kapoor, V; Travadi, J

2012-08-01

To determine Patent ductus arteriosus (PDA) closure rates for extremely preterm infants in a tertiary care centre, factors affecting response to indomethacin and outcomes of these infants relative to their PDA status. Neonatal intensive care unit in tertiary-care children's hospital. Retrospective medical record review. A retrospective chart review of all infants <29 weeks gestation between 1st Jan 2003 and 30th June 2006 was carried out. Multiple courses of standard intravenous indomethacin (dose: 0.2 mg/kg 12 hourly; 3 doses) followed by a tail course (0.1 mg/kg/day; 3 doses) were used to treat PDA depending on clinical and hemodynamic status. Data on demographic characteristics, PDA status, use of indomethacin, and outcome factors such as chronic lung disease and mortality were collected. A total of 166 infants were identified in the study period, of which 15 were excluded. The median gestation was 27 weeks [IQR (25, 28)] and the mean (SD) birthweight was 950 (244) grams. The remaining infants (n=151) were divided into three groups. Group1 (n=47): no or non-significant PDA, Group 2 (n=91): significant PDA closed after indomethacin treatment (= 1 course) and Group 3 (n=13): significant PDA not responding to indomethacin. The closure rate of PDA with indomethacin treatment (group 2) was 87%. A low gestational age < 26 weeks (OR 5.6, 95% CI 1.6-19.9) and female sex (OR 5.8, 95% CI 1.5-22.8) was associated with poor response to indomethacin in our study population. Multiple indomethacin courses using the standard dosing approach result in high PDA closure rates for infants < 29 weeks gestation.

Low doses of a neonicotinoid insecticide modify pheromone response thresholds of central but not peripheral olfactory neurons in a pest insect

PubMed Central

Rabhi, Kaouther K.; Deisig, Nina; Demondion, Elodie; Le Corre, Julie; Robert, Guillaume; Tricoire-Leignel, Hélène; Lucas, Philippe; Gadenne, Christophe; Anton, Sylvia

2016-01-01

Insect pest management relies mainly on neurotoxic insecticides, including neonicotinoids, leaving residues in the environment. There is now evidence that low doses of insecticides can have positive effects on pest insects by enhancing various life traits. Because pest insects often rely on sex pheromones for reproduction, and olfactory synaptic transmission is cholinergic, neonicotinoid residues could modify chemical communication. We recently showed that treatments with different sublethal doses of clothianidin could either enhance or decrease behavioural sex pheromone responses in the male moth, Agrotis ipsilon. We investigated now effects of the behaviourally active clothianidin doses on the sensitivity of the peripheral and central olfactory system. We show with extracellular recordings that both tested clothianidin doses do not influence pheromone responses in olfactory receptor neurons. Similarly, in vivo optical imaging does not reveal any changes in glomerular response intensities to the sex pheromone after clothianidin treatments. The sensitivity of intracellularly recorded antennal lobe output neurons, however, is upregulated by a lethal dose 20 times and downregulated by a dose 10 times lower than the lethal dose 0. This correlates with the changes of behavioural responses after clothianidin treatment and suggests the antennal lobe as neural substrate involved in clothianidin-induced behavioural changes. PMID:26842577

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

DTIC Science & Technology

1994-09-01

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

Comparison of immune responses to a killed bivalent whole cell oral cholera vaccine between endemic and less endemic settings.

PubMed

Desai, Sachin N; Akalu, Zenebe; Teferi, Mekonnen; Manna, Byomkesh; Teshome, Samuel; Park, Ju Yeon; Yang, Jae Seung; Kim, Deok Ryun; Kanungo, Suman; Digilio, Laura

2016-02-01

Studies on safety, immunogenicity and efficacy of the killed, bivalent whole cell oral cholera vaccine (Shanchol) have been conducted in historically endemic settings of Asia. Recent cholera vaccination campaigns in Haiti and Guinea have also demonstrated favourable immunogenicity and effectiveness in nonendemic outbreak settings. We performed a secondary analysis, comparing immune responses of Shanchol from two randomised controlled trials performed in an endemic and a less endemic area (Addis Ababa) during a nonoutbreak setting. While Shanchol may offer some degree of immediate protection in primed populations living in cholera endemic areas, as well as being highly immunogenic in less endemic settings, understanding the characteristics of immune responses in each of these areas is vital in determining ideal dosing strategies that offer the greatest public health impact to populations from areas with varying degrees of cholera endemicity. © 2015 John Wiley & Sons Ltd.

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

Development of an enzyme-linked immunosorbent assay for the serological detection of exposure of poultry in New Zealand to Erysipelothrix rhusiopathiae and their serological response to vaccination.

PubMed

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

2012-03-01

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

Efficacy of tandospirone in patients with irritable bowel syndrome-diarrhea and anxiety

PubMed Central

Lan, Ling; Chen, Yu-Long; Zhang, Hao; Jia, Bai-Ling; Chu, Yan-Jun; Wang, Jin; Tang, Shi-Xiao; Xia, Guo-Dong

2014-01-01

AIM: To investigate the efficacy of tandospirone in patients with irritable bowel syndrome-diarrhea (IBS-D) and anxiety in a prospective, randomized, controlled study. METHODS: Two hundred patients with IBS-D and moderate anxiety were randomized to receive pinaverium and tandospirone (arm A) or pinaverium and placebo (arm B). Tandospirone or placebo was given thrice daily at a fixed dose of 10 mg and pinaverium was given thrice daily at a fixed dose of 50 mg. The duration of treatment was 8 wk. Patients were assessed for abdominal pain and diarrhea. Anxiety was evaluated using the Hamilton Rating Scale for Anxiety (HAM-A). The primary study endpoints were response rates for abdominal pain and diarrhea. The secondary study endpoints were response rates for anxiety. Adverse events were also evaluated. RESULTS: One hundred and seventy of 200 patients (82 patients in arm A and 88 patients in arm B) completed the study. Demographic and baseline characteristics of the 200 participants were comparable in the two arms. At week 8, the overall response rate for abdominal pain and diarrhea was 52.0% for arm A and 37.0% for arm B (P < 0.05). The HAM-A score showed that the response rate was 61.0% for arm A and 21.0% for arm B (P < 0.01). The treatments were well tolerated and no significant adverse events were reported. CONCLUSION: Tandospirone is effective and can be combined with pinaverium in IBS-D patients with anxiety. PMID:25170231

Linear response theory for annealing of radiation damage in semiconductor devices

NASA Technical Reports Server (NTRS)

Litovchenko, Vitaly

1988-01-01

A theoretical study of the radiation/annealing response of MOS ICs is described. Although many experiments have been performed in this field, no comprehensive theory dealing with radiation/annealing response has been proposed. Many attempts have been made to apply linear response theory, but no theoretical foundation has been presented. The linear response theory outlined here is capable of describing a broad area of radiation/annealing response phenomena in MOS ICs, in particular, both simultaneous irradiation and annealing, as well as short- and long-term annealing, including the case when annealing is nearing completion. For the first time, a simple procedure is devised to determine the response function from experimental radiation/annealing data. In addition, this procedure enables us to study the effect of variable temperature and dose rate, effects which are of interest in spaceflight. In the past, the shift in threshold potential due to radiation/annealing has usually been assumed to depend on one variable: the time lapse between an impulse dose and the time of observation. While such a suggestion of uniformity in time is certainly true for a broad range of radiation annealing phenomena, it may not hold for some ranges of the variables of interest (temperature, dose rate, etc.). A response function is projected which is dependent on two variables: the time of observation and the time of the impulse dose. This dependence on two variables allows us to extend the theory to the treatment of a variable dose rate. Finally, the linear theory is generalized to the case in which the response is nonlinear with impulse dose, but is proportional to some impulse function of dose. A method to determine both the impulse and response functions is presented.

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB

PubMed Central

Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended. PMID:28644875

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

PubMed

Taylor, Olivia; Van Laeken, Nick; Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

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

PubMed

Ritz, Christian

2010-01-01

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

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

PubMed Central

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

2015-01-01

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

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

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

PubMed

Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

2015-01-01

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

Evaluation of ifosfamide salvage therapy for metastatic canine osteosarcoma.

PubMed

Batschinski, K; Dervisis, N G; Kitchell, B E

2014-12-01

A retrospective study was performed to assess toxicity and response rate of ifosfamide salvage treatment for dogs diagnosed with metastatic osteosarcoma (OSA). Dogs diagnosed with OSA and previously treated with standard chemotherapy were included in the study. Nineteen dogs met the inclusion criteria, and 17 dogs were evaluable for response. Ifosfamide doses ranged from 375 to 425 mg m(-2) (median dose 375 mg m(-2)), with a median of two doses administered per dog (range 1-7 doses). The overall response to ifosfamide was 11.8% [complete response (CR) = 1/17, partial response (PR) = 1/17, stable disease (SD) = 2/17, progressive disease (PD) = 13/17]. Two dogs were hospitalized due to ifosfamide toxicosis. The median survival duration from the first dose of ifosfamide to death was 95 days. Ifosfamide was well tolerated, but minor anti-tumour activity was observed. © 2012 Blackwell Publishing Ltd.

Predictors of patient responses to ovulation induction with clomiphene citrate in patients with polycystic ovary syndrome experiencing infertility.

PubMed

Ellakwa, Hamed E; Sanad, Zakaria F; Hamza, Haitham A; Emara, Mohamed A; Elsayed, Mohamed A

2016-04-01

To identify predictors of clomiphene citrate-induced ovulation in patients with polycystic ovary syndrome (PCOS). A prospective observational study of patients 18-40 years of age with PCOS experiencing infertility was conducted at Menoufia University Hospital between January 2011 and January 2013. A range of potential predictors of ovulation were recorded before patients received a 50-mg dose of clomiphene citrate. Following ovulation or no response to increasing clomiphene-citrate doses, correlations between predictors and treatment responses were analyzed. In total, 150 patients with PCOS experiencing infertility were enrolled. Following treatment, 110 (73.3%) patients ovulated. Highly significant differences were observed between treatment responders and non-responders in baseline amenorrhea, body mass index (BMI), waist circumference, total testosterone, anti-Müllerian hormone, fasting insulin, homeostatic model assessment of insulin resistance, and visceral fat area (P<0.001). Significant differences in mean ovarian volume (P<0.009) and ovarian stromal artery pulsatility index (P<0.003) were also observed. Total testosterone was the best individual predictor of clomiphene citrate treatment response. The area under the receiver operating characteristic curve in a multivariate prediction model was 0.98. A combination of patient amenorrhea, BMI, total testosterone, anti-Müllerian hormone, ovarian volume, ovarian stromal artery pulsatility index, and visceral fat area could be used to predict clomiphene-citrate treatment response in patients with PCOS experiencing infertility. ClinicalTrials.gov: NCT02269306. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.

PubMed

Lerman, Tamara; Depenbusch, Marion; Schultze-Mosgau, Askan; von Otte, Soeren; Scheinhardt, Markus; Koenig, Inke; Kamischke, Axel; Macek, Milan; Schwennicke, Arne; Segerer, Sabine; Griesinger, Georg

2017-05-01

The incidence of low (<6 oocytes) and high (>18 oocytes) ovarian response to 150 µg corifollitropin alfa in relation to anti-Müllerian hormone (AMH) and other biomarkers was studied in a multi-centre (n = 5), multi-national, prospective, investigator-initiated, observational cohort study. Infertile women (n = 212), body weight >60 kg, underwent controlled ovarian stimulation in a gonadotrophin-releasing hormone-antagonist multiple-dose protocol. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle day 2 or 3 of a spontaneous menstruation before the administration of 150 µg corifollitropin alfa. Serum AMH showed the best correlation with the number of oocytes obtained among all predictor variables. In receiver-operating characteristic analysis, AMH at a threshold of 0.91 ng/ml showed a sensitivity of 82.4%, specificity of 82.4%, positive predictive value 52.9%and negative predictive value 95.1% for predicting low response (area under the curve [AUC], 95% CI; P-value: 0.853, 0.769-0.936; <0.0001). For predicting high response, the optimal threshold for AMH was 2.58 ng/ml, relating to a sensitivity of 80.0%, specificity 82.1%, positive predictive value 42.5% and negative predictive value 96.1% (AUC, 95% CI; P-value: 0.871, 0.787-0.955; <0.0001). In conclusion, patients with serum AMH concentrations between approximately 0.9 and 2.6 ng/ml were unlikely to show extremes of response. Copyright © 2017. Published by Elsevier Ltd.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.

PubMed

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton; Dushek, Omer

2016-10-25

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

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.

Thermoluminescence characterization of the irradiated minerals extracted from nopal

NASA Astrophysics Data System (ADS)

Cruz-Zaragoza, E.; Furetta, C.; Kitis, G.; Gomez, B. T.; Polymeris, G. S.; Tsirliganis, N.; Loukou, Z.

2006-05-01

The mineral fraction from dehydrated nopal leaves (Opuntia ficus indica ) belonging to the Cactaceae family was extracted and selected by sizes of 10 and 74 mu m and exposed to 60 Co gamma radiation at different doses in the range 70 Gy-20 kGy. The glow-curves from these polyminerals show a thermoluminescence (TL) band with one very intense peak at a temperature around 150 degrees C and a second one emerging in the high temperature region, moving in a large zone of temperature values according to the preparation used and the level of irradiation. The XRD analysis shows a composition of both biominerals as whewellite and weddellite and a mineral fraction as anorthoclase and quartz. The main TL characteristics of the polymineral content of the nopal was analyzed, i.e . the TL response at different doses and fading during storage at room temperature. The activation energy of the traps responsible for the TL emission was also investigated and a possible continuous distribution of traps is discussed. A review of the scientific literature shows that this is the first time that a TL study on nopal ionized by irradiation has been carried out.

The logistics of broader pre-clinical evaluation of potential anti-cancer agents with reference to anti-tumour activity and toxicity of mitozolomide.

PubMed Central

Bibby, M. C.; Double, J. A.; Wahed, I. A.; Hirbawi, N.; Baker, T. G.

1988-01-01

Anti-tumour responses with CCRG81010, M & B 39565, NSC 353451, 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Mitozolomide) in a panel of 4 murine colon tumours of varying growth characteristics and chemosensitivity and a spontaneous murine lymphoma are similar to those seen with standard nitrosoureas. The moderately well differentiated colon adenocarcinoma MAC 16 is nonresponsive to mitozolomide and methylCCNU. Responses in the other 4 lines studied are only achieved near to maximum tolerated dose and at this level there is severe host toxicity. Haemopoietic toxicity is clearly demonstrated by analysis of peripheral blood counts and by CFU-S assays and severe testicular and ovarian toxicity was also seen at dose levels necessary to achieve anti-tumour effects. Using mitozolomide as an example, the study has demonstrated the feasibility of conducting simple but thorough toxicity evaluation for the determination of the therapeutic index. This approach would provide invaluable guidelines for the selection for clinical trial of the most appropriate members of a series of new cytotoxic compounds. Images Figure 4 PMID:3166903

The logistics of broader pre-clinical evaluation of potential anti-cancer agents with reference to anti-tumour activity and toxicity of mitozolomide.

PubMed

Bibby, M C; Double, J A; Wahed, I A; Hirbawi, N; Baker, T G

1988-08-01

Anti-tumour responses with CCRG81010, M & B 39565, NSC 353451, 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Mitozolomide) in a panel of 4 murine colon tumours of varying growth characteristics and chemosensitivity and a spontaneous murine lymphoma are similar to those seen with standard nitrosoureas. The moderately well differentiated colon adenocarcinoma MAC 16 is nonresponsive to mitozolomide and methylCCNU. Responses in the other 4 lines studied are only achieved near to maximum tolerated dose and at this level there is severe host toxicity. Haemopoietic toxicity is clearly demonstrated by analysis of peripheral blood counts and by CFU-S assays and severe testicular and ovarian toxicity was also seen at dose levels necessary to achieve anti-tumour effects. Using mitozolomide as an example, the study has demonstrated the feasibility of conducting simple but thorough toxicity evaluation for the determination of the therapeutic index. This approach would provide invaluable guidelines for the selection for clinical trial of the most appropriate members of a series of new cytotoxic compounds.

Demonstration of an adaptive response to preconditioning Frankliniella occidentalis (Pergande) to sublethal doses of spinosad: a hormetic-dose response.

PubMed

Gong, Youhui; Xu, Baoyun; Zhang, Youjun; Gao, Xiwu; Wu, Qingjun

2015-07-01

Sublethal doses of some insecticides have been reported to either stimulate or reduce the survival and fecundity of insects. Many sublethal-effect studies have been conducted after exposure of only one generation to sublethal insecticides, and there is little information about the sublethal effects on insects after long-term exposure to sublethal insecticides. In this study, changes in biological characteristics were investigated in spinosad-susceptible (Spin-S) and sublethal-spinosad-treated (Spin-Sub) strains of Frankliniella occidentalis (Pergande) after exposure to their corresponding sublethal concentrations of spinosad. The results showed that for the Spin-S strain, the LC10 concentration of spinosad slightly affected the biotic fitness both in parents and offspring of F. occidentalis. The LC25 concentration of spinosad prolonged the development time, reduced the fecundity, and significantly reduced the intrinsic rate of increase, the net reproductive rate and the finite rate of increase in the Spin-S strain. However, the negative effects were not as pronounced in the offspring (F1 generation) as in the parent generation. For the Spin-Sub strain, the LC10 and LC25 concentrations of spinosad had little negative effect on the development and fecundity, and no significant difference was found between the effects of the LC10 and LC25 treatments on the Spin-Sub strain. The Spin-Sub strain exhibited a shorter developmental time, and larger intrinsic rates of increase and net reproductive rates, compared with the corresponding treatments of the Spin-S strain. These findings combined with our previous studies suggest that the biotic fitness increased in the Spin-Sub strain and the strain became more adaptable to sublethal doses of spinosad, compared with the Spin-S strain. Physiological and biochemical adaptation may contribute to these changes after long treatment times at sublethal doses.

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

PubMed

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

2014-06-01

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

A comprehensive evaluation of the PRESAGE/optical-CT 3D dosimetry system

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

Sakhalkar, H. S.; Adamovics, J.; Ibbott, G.

2009-01-15

This work presents extensive investigations to evaluate the robustness (intradosimeter consistency and temporal stability of response), reproducibility, precision, and accuracy of a relatively new 3D dosimetry system comprising a leuco-dye doped plastic 3D dosimeter (PRESAGE) and a commercial optical-CT scanner (OCTOPUS 5x scanner from MGS Research, Inc). Four identical PRESAGE 3D dosimeters were created such that they were compatible with the Radiologic Physics Center (RPC) head-and-neck (H and N) IMRT credentialing phantom. Each dosimeter was irradiated with a rotationally symmetric arrangement of nine identical small fields (1x3 cm{sup 2}) impinging on the flat circular face of the dosimeter. A repetitiousmore » sequence of three dose levels (4, 2.88, and 1.28 Gy) was delivered. The rotationally symmetric treatment resulted in a dose distribution with high spatial variation in axial planes but only gradual variation with depth along the long axis of the dosimeter. The significance of this treatment was that it facilitated accurate film dosimetry in the axial plane, for independent verification. Also, it enabled rigorous evaluation of robustness, reproducibility and accuracy of response, at the three dose levels. The OCTOPUS 5x commercial scanner was used for dose readout from the dosimeters at daily time intervals. The use of improved optics and acquisition technique yielded substantially improved noise characteristics (reduced to {approx}2%) than has been achieved previously. Intradosimeter uniformity of radiochromic response was evaluated by calculating a 3D gamma comparison between each dosimeter and axially rotated copies of the same dosimeter. This convenient technique exploits the rotational symmetry of the distribution. All points in the gamma comparison passed a 2% difference, 1 mm distance-to-agreement criteria indicating excellent intradosimeter uniformity even at low dose levels. Postirradiation, the dosimeters were all found to exhibit a slight increase in opaqueness with time. However, the relative dose distribution was found to be extremely stable up to 90 h postirradiation indicating excellent temporal stability. Excellent interdosimeter reproducibility was also observed between the four dosimeters. Gamma comparison maps between each dosimeter and the average distribution of all four dosimeters showed full agreement at the 2% difference, 2 mm distance-to-agreement level. Dose readout from the 3D dosimetry system was found to agree better with independent film measurement than with treatment planning system calculations in penumbral regions and was generally accurate to within 2% dose difference and 2 mm distance-to-agreement. In conclusion, these studies demonstrate excellent precision, accuracy, robustness, and reproducibility of the PRESAGE/optical-CT system for relative 3D dosimetry and support its potential integration with the RPC H and N credentialing phantom for IMRT verification.« less

Antiorthostatic suspension for 14 days does not diminish the oxidative response of neutrophils in mice

NASA Technical Reports Server (NTRS)

Smolen, J. E.; Fossett, M. C.; Joe, Y.; Prince, J. E.; Priest, E.; Kanwar, S.; Smith, C. W.

2000-01-01

The effects of long-term spaceflight on inflammatory responses have not been well-studied in either humans or animals. It is thus important to determine if the functions of immune and inflammatory cells are altered in models of spaceflight. One such animal model is antiorthostatic suspension (AOS), in which the experimental animal is subjected to a head-down tilt that mimics both the stress and the cephalad fluid shift experienced in spaceflight. A previous study reported that the peritoneal neutrophils from mice experiencing AOS generated less superoxide than unsuspended controls. We expanded on this study using several different stimuli and measuring the oxidative response of murine neutrophils in a variety of ways. These responses included the rate, lag period, and dose/response characteristics for superoxide generation, FACS analysis with dihydrodichlorofluorescein as a substrate, and a chemiluminescence response with luminol as a substrate. We also examined phagocytosis of three different microorganisms. While some effects of orthostatic suspension (attributable to the stress of the apparatus) were observed, no clear effects of AOS on oxidative function of the peritoneal neutrophils were seen.

[Scanning electron microscopic observations of Monochamus alternatus antennal sensilla and their electroantennographic responses].

PubMed

Wang, Sibao; Zhou, Hongchun; Miao, Xuexia; Fan, Meizhen; Li, Zengzhi; Si, Shengli; Huang, Yongping

2005-02-01

With scanning electron microscope (SEM), this paper observed the shape, category, amount and distribution of the main antenna sensilla of adult Monochamus alternatus, and tested their electroantennographic (EAG) responses to the main volatiles of Pinus spp.. There were seven types of antennal sensilla, i. e., sensilla trichoid, sensilla basiconica, sensilla digit-like, sensilla rod-like, sensilla bottle-like, sensilla bud-like and sensilla chaetica, among which, sensilla trichoid and sensilla basiconica were the most abundant on the antenna surface, and each of them could be divided into three subtypes. Two subtypes of sensilla digit-like could also be observed. The II and III subtypes of sensilla trichoid and I and II subtypes of sensilla basiconica had deep longitudinal grooves on their surface, the typical characteristics of olfactory receptor. The comparison of the EAG response of different parts of Monochamus alternatus antennae to alpha-Pinene showed that each volatile and their compounds could provoke significant EAG responses of both females and males. The dose-response test showed that there was a certain rule in the EAG responses of M. alternatus.

Postexposure bake characteristics of a chemically amplified deep-ultraviolet resist

NASA Astrophysics Data System (ADS)

Sturtevant, John L.; Holmes, Steven J.; Rabidoux, Paul A.

1992-06-01

In the processing of chemically amplified resist systems, two `dose' parameters must be considered. The exposure dose dictates the amount of photoacid generated, and the thermal dose that is administered during the post-exposure bake (PEB) governs the extent to which the resin is chemically transformed by the acid. An Arrhenius relationship exists between these two dose variables, and the magnitude of the effective activation energy determines the degree of PEB temperature control required for a particular linewidth budget. PEB characteristics are presented for a chemically amplified positive-tone DUV resist used by IBM in the manufacture of 0.5 micrometers 16 Mb DRAMs. The effect of PEB temperature and time on resist sensitivity, contrast, resolution, and process latitude is presented. The influence of exposure and thermal dose on the chemical contamination effect is also discussed.

SU-E-T-145: Beam Characteristics of Flattening Filter Free Beams Including Low Dose Rate Setting

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

Uehara, K; Ogata, T; Nakayama, M

2015-06-15

Purpose: In commissioning of volumetric modulated arc therapy (VMAT), it is necessary to evaluate the beam characteristics of various dose rate settings with potential to use. The aim of this study is to evaluate the beam characteristics of flattened and flattening filter free (FFF) including low dose rate setting. Methods: We used a Varian TrueBeam with Millennium 120 MLC. Both 6 and 10 MV beams with or without flattening filter were used for this study. To evaluate low-dose rate FFF beams, specially-designed leaf sequence files control out-of-field MLC leaf pair at constant dose rate ranging from 80 to 400 MU/min.more » For dose rate from 80 MU/min to the maximum usable value of all energies, beam output were measured using ionization chamber (CC04, IBA). The ionization chamber was inserted into water equivalent phantom (RT3000-New, R-tech), and the phantom was set with SAD of 100cm. The beam profiles were performed using the 2D diode array (Profiler2, Sun Nuclear). The SSD was set to 90cm and a combined 30cmx30cmx9cm phantom which consisted of solid water slabs was put on the device. All measurement were made using 100MU irradiation for 10cmx10cm jaw-defined field size with a gantry angle of 0°. Results: In all energies, the dose rate dependences with beam output and variation coefficient were within 0.2% and 0.07%, respectively. The flatness and symmetry exhibited small variations (flatness ≤0.1 point and symmetry≤0.3 point at absolute difference). Conclusion: We had studied the characteristics of flattened and FFF beam over the 80 MU/min. Our results indicated that the beam output and profiles of FFF of TrueBeam linac were highly stable at low dose rate setting.« less

Radiation Dose-Response Relationships and Risk Assessment

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

Strom, Daniel J.

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

Age-specific radiation dose commitment factors for a one-year chronic intake

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

Hoenes, G.R.; Soldat, J.K.

1977-11-01

During the licensing process for nuclear facilities, radiation doses and dose commitments must be calculated for people in the environs of a nuclear facility. These radiation doses are determined by examining characteristics of population groups, pathways to people, and radionuclides found in those pathways. The pertinent characteristics, which are important in the sense of contributing a significant portion of the total dose, must then be analyzed in depth. Dose factors are generally available for adults, see Reference 1 for example, however numerous improvements in data on decay schemes and half-lives have been made in recent years. In addition, it ismore » advisable to define parameters for calculation of the radiation dose for ages other than adults since the population surrounding nuclear facilities will be composed of various age groups. Further, since infants, children, and teens may have higher rates of intake per unit body mass, it is conceivable that the maximally exposed individual may not be an adult. Thus, it was necessary to develop new radiation-dose commitment factors for various age groups. Dose commitment factors presented in this report have been calculated for a 50-year time period for four age groups.« less

Harnessing the theoretical foundations of the exponential and beta-Poisson dose-response models to quantify parameter uncertainty using Markov Chain Monte Carlo.

PubMed

Schmidt, Philip J; Pintar, Katarina D M; Fazil, Aamir M; Topp, Edward

2013-09-01

Dose-response models are the essential link between exposure assessment and computed risk values in quantitative microbial risk assessment, yet the uncertainty that is inherent to computed risks because the dose-response model parameters are estimated using limited epidemiological data is rarely quantified. Second-order risk characterization approaches incorporating uncertainty in dose-response model parameters can provide more complete information to decisionmakers by separating variability and uncertainty to quantify the uncertainty in computed risks. Therefore, the objective of this work is to develop procedures to sample from posterior distributions describing uncertainty in the parameters of exponential and beta-Poisson dose-response models using Bayes's theorem and Markov Chain Monte Carlo (in OpenBUGS). The theoretical origins of the beta-Poisson dose-response model are used to identify a decomposed version of the model that enables Bayesian analysis without the need to evaluate Kummer confluent hypergeometric functions. Herein, it is also established that the beta distribution in the beta-Poisson dose-response model cannot address variation among individual pathogens, criteria to validate use of the conventional approximation to the beta-Poisson model are proposed, and simple algorithms to evaluate actual beta-Poisson probabilities of infection are investigated. The developed MCMC procedures are applied to analysis of a case study data set, and it is demonstrated that an important region of the posterior distribution of the beta-Poisson dose-response model parameters is attributable to the absence of low-dose data. This region includes beta-Poisson models for which the conventional approximation is especially invalid and in which many beta distributions have an extreme shape with questionable plausibility. © Her Majesty the Queen in Right of Canada 2013. Reproduced with the permission of the Minister of the Public Health Agency of Canada.

Laser-based irradiation apparatus and method to measure the functional dose-rate response of semiconductor devices

DOEpatents

Horn, Kevin M [Albuquerque, NM

2008-05-20

A broad-beam laser irradiation apparatus can measure the parametric or functional response of a semiconductor device to exposure to dose-rate equivalent infrared laser light. Comparisons of dose-rate response from before, during, and after accelerated aging of a device, or from periodic sampling of devices from fielded operational systems can determine if aging has affected the device's overall functionality. The dependence of these changes on equivalent dose-rate pulse intensity and/or duration can be measured with the apparatus. The synchronized introduction of external electrical transients into the device under test can be used to simulate the electrical effects of the surrounding circuitry's response to a radiation exposure while exposing the device to dose-rate equivalent infrared laser light.

Linearity and reproducibility response of Fricke dosimetry for low energy X-Ray beam

NASA Astrophysics Data System (ADS)

Mantuano, A.; de Amorim, G. J.; David, M. G.; Rosado, P. H. G.; Salata, C.; Magalhães, L. A. G.; deAlmeida, C. E.

2018-03-01

The Fricke dosimeter is the most used, liquid chemical dosimeter. It has been shown to be a feasible option for the absorbed dose standard. The present work aims to determinate a dose-response curve of Fricke solution using different doses and reproducibility test comparing the calculated dose to Fricke solution and Ionizing Chamber. Tests were performed using an X-ray irradiator for biological research at Radiological Science Laboratory (LCR/UERJ). The results showed a linear response to different doses of type A uncertainties from 0.08 to 1.2%. Reproducibility test showed type A uncertainties of 0.16% to the dosimeter.

Comparison of effect of 5 MeV proton and Co-60 gamma irradiation on silicon NPN rf power transistors and N-channel depletion MOSFETs

NASA Astrophysics Data System (ADS)

Gnana Prakash, A. P.; Pradeep, T. M.; Hegde, Vinayakprasanna N.; Pushpa, N.; Bajpai, P. K.; Patel, S. P.; Trivedi, Tarkeshwar; Bhushan, K. G.

2017-12-01

NPN transistors and N-channel depletion metal oxide semiconductor field effect transistors (MOSFETs) were irradiated with 5 MeV protons and 60Co gamma radiation in the dose ranging from 1 Mrad(Si) to 100 Mrad(Si). The different electrical characteristics of the NPN transistor such as Gummel characteristics, excess base current (ΔIB), dc current gain (hFE), transconductance (gm), displacement damage factor (K) and output characteristics were studied as a function of total dose. The different electrical characteristics of N-channel MOSFETs such as threshold voltage (Vth), density of interface trapped charges (ΔNit), density of oxide trapped charges (ΔNot), transconductance (gm), mobility (µ) and drain saturation current (IDSat) were studied systematically before and after irradiation in the same dose ranges. A considerable increase in the base current (IB) and decrease in the hFE, gm and collector saturation current (ICSat) were observed after irradiation in the case of the NPN transistor. In the N-channel MOSFETs, the ΔNit and ΔNot were found to increase and Vth, gm, µ and IDSat were found to decrease with increase in the radiation dose. The 5 MeV proton irradiation results of both the NPN transistor and N-channel MOSFETs were compared with 60Co gamma-irradiated devices in the same dose ranges. It was observed that the degradation in 5 MeV proton-irradiated devices is more when compared with the 60Co gamma-irradiated devices at higher total doses.

Dose-Dependent Pheromone Responses of Ips pini, Orthotomicus latiden (Coleoptera: Scolytidae), and associates in stands of lodgepole pine

Treesearch

Daniel R. Miller; John H. Borden; B. Staffan Lidgren

2005-01-01

We conducted four behavioral choice tests in stands of mature lodgepole pine in British Columbia, from 1988 to 1991, to determine the dose-dependent responses of Orthotomicus latidens (LeConte) and Ips pini (Say) to their respective pheromones. Dose-dependent responses were exhibited by I. pini to (±)-ipsdienol and lanierone, with...

Enhanced Medial Collateral Ligament Healing using Mesenchymal Stem Cells: Dosage Effects on Cellular Response and Cytokine Profile

PubMed Central

Saether, Erin E.; Chamberlain, Connie S.; Leiferman, Ellen M.; Kondratko-Mittnacht, Jaclyn R.; Li, Wan Ju; Brickson, Stacey L.; Vanderby, Ray

2013-01-01

Mesenchymal stem cells (MSCs) have potential therapeutic applications for musculoskeletal injuries due to their ability to differentiate into several tissue cell types and modulate immune and inflammatory responses. These immune-modulatory properties were examined in vivo during early stage rat medial collateral ligament healing. Two different cell doses (low dose 1×106 or high dose 4×106 MSCs) were administered at the time of injury and compared with normal ligament healing at days 5 and 14 post-injury. At both times, the high dose MSC group demonstrated a significant decrease in M2 macrophages compared to controls. At day 14, fewer M1 macrophages were detected in the low dose group compared to the high dose group. These results, along with significant changes in procollagen I, proliferating cells, and endothelialization suggest that MSCs can alter the cellular response during healing in a dose-dependent manner. The higher dose ligaments also had increased expression of several pro-inflammatory cytokines at day 5 (IL-1β, IFNγ, IL-2) and increased expression of IL-12 at day 14. Mechanical testing at day 14 revealed increased failure strength and stiffness in low dose ligaments compared to controls. Based on these improved mechanical properties, MSCs enhanced functional healing when applied at a lower dose. Different doses of MSCs uniquely affected the cellular response and cytokine expression in healing ligaments. Interestingly, the lower dose of cells proved to be most effective in improving functional properties. PMID:24174129

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.