SU-F-BRD-15: Quality Correction Factors in Scanned Or Broad Proton Therapy Beams Are Indistinguishable

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

Sorriaux, J; Lee, J; ICTEAM Institute, Universite catholique de Louvain, Louvain-la-Neuve

2015-06-15

Purpose: The IAEA TRS-398 code of practice details the reference conditions for reference dosimetry of proton beams using ionization chambers and the required beam quality correction factors (kQ). Pencil beam scanning (PBS) requires multiple spots to reproduce the reference conditions. The objective is to demonstrate, using Monte Carlo (MC) calculations, that kQ factors for broad beams can be used for scanned beams under the same reference conditions with no significant additional uncertainty. We consider hereafter the general Alfonso formalism (Alfonso et al, 2008) for non-standard beam. Methods: To approach the reference conditions and the associated dose distributions, PBS must combinemore » many pencil beams with range modulation and shaping techniques different than those used in passive systems (broad beams). This might lead to a different energy spectrum at the measurement point. In order to evaluate the impact of these differences on kQ factors, ion chamber responses are computed with MC (Geant4 9.6) in a dedicated scanned pencil beam (Q-pcsr) producing a 10×10cm2 composite field with a flat dose distribution from 10 to 16 cm depth. Ion chamber responses are also computed by MC in a broad beam with quality Q-ds (double scattering). The dose distribution of Q -pcsr matches the dose distribution of Q-ds. k-(Q-pcsr,Q-ds) is computed for a 2×2×0.2cm{sup 3} idealized air cavity and a realistic plane-parallel ion chamber (IC). Results: Under reference conditions, quality correction factors for a scanned composite field versus a broad beam are the same for air cavity dose response, k-(Q-pcsr,Q-ds) =1.001±0.001 and for a Roos IC, k-(Q-pcsr,Q-ds) =0.999±0.005. Conclusion: Quality correction factors for ion chamber response in scanned and broad proton therapy beams are identical under reference conditions within the calculation uncertainties. The results indicate that quality correction factors published in IAEA TRS-398 can be used for scanned beams in the SOBP of a high-energy proton beam. Jefferson Sorriaux is financed by the Walloon Region under the convention 1217662. Jefferson Sorriaux is sponsored by a public-private partnership IBA - Walloon Region.« less

Differences between the nonselective adenosine receptor antagonists caffeine and theophylline in motor and mood effects: studies using medium to high doses in animal models.

PubMed

López-Cruz, Laura; Pardo, Marta; Salamone, John D; Correa, Mercè

2014-08-15

Caffeine and theophylline are methylxanthines that are broadly consumed, sometimes at high doses, and act as minor psychostimulants. Both are nonselective adenosine antagonists for A1 and A2A receptors, which are colocalized with dopamine D1 and D2 receptors in striatal areas. Adenosine antagonists generally have opposite actions to those of dopamine antagonists. Although the effects of caffeine are widely known, theophylline has been much less well characterized, especially at high doses. Adult male CD1 mice were used to study the effect of a broad range of doses (25.0, 50.0 or 100.0mg/kg) of caffeine and theophylline on measures of spontaneous locomotion and coordination, as well as the pattern of c-Fos immunoreactivity in brain areas rich in adenosine and dopamine receptors. In addition, we evaluated possible anxiety and stress effects of these doses. Caffeine, at these doses, impaired or suppressed locomotion in several paradigms. However, theophylline was less potent than caffeine at suppressing motor parameters, and even stimulated locomotion. Both drugs induced corticosterone release, however caffeine was more efficacious at intermediate doses. While caffeine showed an anxiogenic profile at all doses, theophylline only did so at the highest dose used (50mg/kg). Only theophylline increased c-Fos immunoreactivity in cortical areas. Theophylline has fewer disruptive effects than caffeine on motor parameters and produces less stress and anxiety effects. These results are relevant for understanding the potential side effects of methylxanthines when consumed at high doses. Copyright © 2014 Elsevier B.V. All rights reserved.

Reanalysis of cancer mortality in Japanese A-bomb survivors exposed to low doses of radiation: bootstrap and simulation methods

PubMed Central

2009-01-01

Background The International Commission on Radiological Protection (ICRP) recommended annual occupational dose limit is 20 mSv. Cancer mortality in Japanese A-bomb survivors exposed to less than 20 mSv external radiation in 1945 was analysed previously, using a latency model with non-linear dose response. Questions were raised regarding statistical inference with this model. Methods Cancers with over 100 deaths in the 0 - 20 mSv subcohort of the 1950-1990 Life Span Study are analysed with Poisson regression models incorporating latency, allowing linear and non-linear dose response. Bootstrap percentile and Bias-corrected accelerated (BCa) methods and simulation of the Likelihood Ratio Test lead to Confidence Intervals for Excess Relative Risk (ERR) and tests against the linear model. Results The linear model shows significant large, positive values of ERR for liver and urinary cancers at latencies from 37 - 43 years. Dose response below 20 mSv is strongly non-linear at the optimal latencies for the stomach (11.89 years), liver (36.9), lung (13.6), leukaemia (23.66), and pancreas (11.86) and across broad latency ranges. Confidence Intervals for ERR are comparable using Bootstrap and Likelihood Ratio Test methods and BCa 95% Confidence Intervals are strictly positive across latency ranges for all 5 cancers. Similar risk estimates for 10 mSv (lagged dose) are obtained from the 0 - 20 mSv and 5 - 500 mSv data for the stomach, liver, lung and leukaemia. Dose response for the latter 3 cancers is significantly non-linear in the 5 - 500 mSv range. Conclusion Liver and urinary cancer mortality risk is significantly raised using a latency model with linear dose response. A non-linear model is strongly superior for the stomach, liver, lung, pancreas and leukaemia. Bootstrap and Likelihood-based confidence intervals are broadly comparable and ERR is strictly positive by bootstrap methods for all 5 cancers. Except for the pancreas, similar estimates of latency and risk from 10 mSv are obtained from the 0 - 20 mSv and 5 - 500 mSv subcohorts. Large and significant cancer risks for Japanese survivors exposed to less than 20 mSv external radiation from the atomic bombs in 1945 cast doubt on the ICRP recommended annual occupational dose limit. PMID:20003238

Nanogram quantities of a DNA vaccine protect rainbow trout fry against heterologous strains of infectious hematopoietic necrosis virus

USGS Publications Warehouse

Corbeil, S.; LaPatra, S.E.; Anderson, E.D.; Kurath, G.

2000-01-01

The efficacy of a DNA vaccine containing the glycoprotein gene of infectious hematopoietic necrosis virus (IHNV), a rhabdovirus affecting trout and salmon, was investigated. The minimal dose of vaccine required, the protection against heterologous strains, and the titers of neutralizing antibodies produced were used to evaluate the potential of the vaccine as a control pharmaceutical. Results indicated that a single dose of as little as 1–10 ng of vaccine protected rainbow trout fry against waterborne challenge by IHNV. An optimal dose of 100 ng per fish was selected to assure strong protection under various conditions. Neutralizing antibody titers were detected in fish vaccinated with concentrations of DNA ranging from 5 to 0.01 μg. Furthermore, the DNA vaccine protected fish against a broad range of viral strains from different geographic locations, including isolates from France and Japan, suggesting that the vaccine could be used worldwide. A single dose of this DNA vaccine induced protection in fish at a lower dose than is usually reported in mammalian DNA vaccine studies.

Digital radiography can reduce scoliosis x-ray exposure

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

Kling, T.F. Jr.; Cohen, M.J.; Lindseth, R.E.

1990-09-01

Digital radiology is a new computerized system of acquiring x-rays in a digital (electronic) format. It possesses a greatly expanded dose response curve that allows a very broad range of x-ray dose to produce a diagnostic image. Potential advantages include significantly reduced radiation exposure without loss of image quality, acquisition of images of constant density irrespective of under or over exposure, and reduced repeat rates for unsatisfactory films. The authors prospectively studied 30 adolescents with scoliosis who had both conventional (full dose) and digital (full, one-half, or one-third dose) x-rays. They found digital made AP and lateral image with allmore » anatomic areas clearly depicted at full and one-half dose. Digital laterals were better at full dose and equal to conventional at one-half dose. Cobb angles were easily measured on all one-third dose AP and on 8 of 10 one-third dose digital laterals. Digital clearly depicted the Risser sign at one-half and one-third dose and the repeat rate was nil in this study, indicating digital compensates well for exposure errors. The study indicates that digital does allow radiation dose to be reduced by at least one-half in scoliosis patients and that it does have improved image quality with good contrast over a wide range of x-ray exposure.« less

A feasibility study on the use of phantoms with statistical lung masses for determining the uncertainty in the dose absorbed by the lung from broad beams of incident photons and neutrons

PubMed Central

Khankook, Atiyeh Ebrahimi; Hakimabad, Hashem Miri

2017-01-01

Abstract Computational models of the human body have gradually become crucial in the evaluation of doses absorbed by organs. However, individuals may differ considerably in terms of organ size and shape. In this study, the authors sought to determine the energy-dependent standard deviations due to lung size of the dose absorbed by the lung during external photon and neutron beam exposures. One hundred lungs with different masses were prepared and located in an adult male International Commission on Radiological Protection (ICRP) reference phantom. Calculations were performed using the Monte Carlo N-particle code version 5 (MCNP5). Variation in the lung mass caused great uncertainty: ~90% for low-energy broad parallel photon beams. However, for high-energy photons, the lung-absorbed dose dependency on the anatomical variation was reduced to <1%. In addition, the results obtained indicated that the discrepancy in the lung-absorbed dose varied from 0.6% to 8% for neutron beam exposure. Consequently, the relationship between absorbed dose and organ volume was found to be significant for low-energy photon sources, whereas for higher energy photon sources the organ-absorbed dose was independent of the organ volume. In the case of neutron beam exposure, the maximum discrepancy (of 8%) occurred in the energy range between 0.1 and 5 MeV. PMID:28077627

Dose coefficients in pediatric and adult abdominopelvic CT based on 100 patient models.

PubMed

Tian, Xiaoyu; Li, Xiang; Segars, W Paul; Frush, Donald P; Paulson, Erik K; Samei, Ehsan

2013-12-21

Recent studies have shown the feasibility of estimating patient dose from a CT exam using CTDI(vol)-normalized-organ dose (denoted as h), DLP-normalized-effective dose (denoted as k), and DLP-normalized-risk index (denoted as q). However, previous studies were limited to a small number of phantom models. The purpose of this work was to provide dose coefficients (h, k, and q) across a large number of computational models covering a broad range of patient anatomy, age, size percentile, and gender. The study consisted of 100 patient computer models (age range, 0 to 78 y.o.; weight range, 2-180 kg) including 42 pediatric models (age range, 0 to 16 y.o.; weight range, 2-80 kg) and 58 adult models (age range, 18 to 78 y.o.; weight range, 57-180 kg). Multi-detector array CT scanners from two commercial manufacturers (LightSpeed VCT, GE Healthcare; SOMATOM Definition Flash, Siemens Healthcare) were included. A previously-validated Monte Carlo program was used to simulate organ dose for each patient model and each scanner, from which h, k, and q were derived. The relationships between h, k, and q and patient characteristics (size, age, and gender) were ascertained. The differences in conversion coefficients across the scanners were further characterized. CTDI(vol)-normalized-organ dose (h) showed an exponential decrease with increasing patient size. For organs within the image coverage, the average differences of h across scanners were less than 15%. That value increased to 29% for organs on the periphery or outside the image coverage, and to 8% for distributed organs, respectively. The DLP-normalized-effective dose (k) decreased exponentially with increasing patient size. For a given gender, the DLP-normalized-risk index (q) showed an exponential decrease with both increasing patient size and patient age. The average differences in k and q across scanners were 8% and 10%, respectively. This study demonstrated that the knowledge of patient information and CTDIvol/DLP values may be used to estimate organ dose, effective dose, and risk index in abdominopelvic CT based on the coefficients derived from a large population of pediatric and adult patients.

Dose coefficients in pediatric and adult abdominopelvic CT based on 100 patient models

NASA Astrophysics Data System (ADS)

Tian, Xiaoyu; Li, Xiang; Segars, W. Paul; Frush, Donald P.; Paulson, Erik K.; Samei, Ehsan

2013-12-01

Recent studies have shown the feasibility of estimating patient dose from a CT exam using CTDIvol-normalized-organ dose (denoted as h), DLP-normalized-effective dose (denoted as k), and DLP-normalized-risk index (denoted as q). However, previous studies were limited to a small number of phantom models. The purpose of this work was to provide dose coefficients (h, k, and q) across a large number of computational models covering a broad range of patient anatomy, age, size percentile, and gender. The study consisted of 100 patient computer models (age range, 0 to 78 y.o.; weight range, 2-180 kg) including 42 pediatric models (age range, 0 to 16 y.o.; weight range, 2-80 kg) and 58 adult models (age range, 18 to 78 y.o.; weight range, 57-180 kg). Multi-detector array CT scanners from two commercial manufacturers (LightSpeed VCT, GE Healthcare; SOMATOM Definition Flash, Siemens Healthcare) were included. A previously-validated Monte Carlo program was used to simulate organ dose for each patient model and each scanner, from which h, k, and q were derived. The relationships between h, k, and q and patient characteristics (size, age, and gender) were ascertained. The differences in conversion coefficients across the scanners were further characterized. CTDIvol-normalized-organ dose (h) showed an exponential decrease with increasing patient size. For organs within the image coverage, the average differences of h across scanners were less than 15%. That value increased to 29% for organs on the periphery or outside the image coverage, and to 8% for distributed organs, respectively. The DLP-normalized-effective dose (k) decreased exponentially with increasing patient size. For a given gender, the DLP-normalized-risk index (q) showed an exponential decrease with both increasing patient size and patient age. The average differences in k and q across scanners were 8% and 10%, respectively. This study demonstrated that the knowledge of patient information and CTDIvol/DLP values may be used to estimate organ dose, effective dose, and risk index in abdominopelvic CT based on the coefficients derived from a large population of pediatric and adult patients.

Nonreplicating Influenza A Virus Vaccines Confer Broad Protection against Lethal Challenge

PubMed Central

Baz, Mariana; Boonnak, Kobporn; Paskel, Myeisha; Santos, Celia; Powell, Timothy; Townsend, Alain

2015-01-01

ABSTRACT New vaccine technologies are being investigated for their ability to elicit broadly cross-protective immunity against a range of influenza viruses. We compared the efficacies of two intranasally delivered nonreplicating influenza virus vaccines (H1 and H5 S-FLU) that are based on the suppression of the hemagglutinin signal sequence, with the corresponding H1N1 and H5N1 cold-adapted (ca) live attenuated influenza virus vaccines in mice and ferrets. Administration of two doses of H1 or H5 S-FLU vaccines protected mice and ferrets from lethal challenge with homologous, heterologous, and heterosubtypic influenza viruses, and two doses of S-FLU and ca vaccines yielded comparable effects. Importantly, when ferrets immunized with one dose of H1 S-FLU or ca vaccine were challenged with the homologous H1N1 virus, the challenge virus failed to transmit to naive ferrets by the airborne route. S-FLU technology can be rapidly applied to any emerging influenza virus, and the promising preclinical data support further evaluation in humans. PMID:26489862

Magnetic properties of square Py nanowires: Irradiation dose and geometry dependence

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

Ehrmann, A., E-mail: andrea.ehrmann@fh-bielefeld.de; Blachowicz, T.; Komraus, S.

Arrays of ferromagnetic patterned nanostructures with single particle lateral dimensions between 160 nm and 400 nm were created by electron-beam lithography. The fourfold particles with rectangular-shaped walls around a square open area were produced from permalloy. Their magnetic properties were measured using the longitudinal magneto-optical Kerr effect. The article reports about the angle-dependent coercive fields and the influence of the e-beam radiation dose on sample shapes. It is shown that a broad range of radiation dose intensities enables reliable creation of nanostructures with parameters relevant for the desired magnetization reversal scenario. The experimental results are finally compared with micromagnetic simulations to explainmore » the findings.« less

Impact of Monoenergetic Photon Sources on Nonproliferation Applications Final Report

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

Geddes, Cameron; Ludewigt, Bernhard; Valentine, John

Near-monoenergetic photon sources (MPSs) have the potential to improve sensitivity at greatly reduced dose in existing applications and enable new capabilities in other applications, particularly where passive signatures do not penetrate or are insufficiently accurate. MPS advantages include the ability to select energy, energy spread, flux, and pulse structures to deliver only the photons needed for the application, while suppressing extraneous dose and background. Some MPSs also offer narrow angular divergence photon beams which can target dose and/or mitigate scattering contributions to image contrast degradation. Current bremsstrahlung photon sources (e.g., linacs and betatrons) produce photons over a broad range ofmore » energies, thus delivering unnecessary dose that in some cases also interferes with the signature to be detected and/or restricts operations. Current sources must be collimated (reducing flux) to generate narrow divergence beams. While MPSs can in principle resolve these issues, they remain at relatively low TRL status. Candidate MPS technologies for nonproliferation applications are now being developed, each of which has different properties (e.g. broad vs. narrow angular divergence). Within each technology, source parameters trade off against one another (e.g. flux vs. energy spread), representing a large operation space. This report describes a broad survey of potential applications, identification of high priority applications, and detailed simulations addressing those priority applications. Requirements were derived for each application, and analysis and simulations were conducted to define MPS parameters that deliver benefit. The results can inform targeting of MPS development to deliver strong impact relative to current systems.« less

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

PubMed Central

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

2015-01-01

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

A feasibility study on the use of phantoms with statistical lung masses for determining the uncertainty in the dose absorbed by the lung from broad beams of incident photons and neutrons.

PubMed

Khankook, Atiyeh Ebrahimi; Hakimabad, Hashem Miri; Motavalli, Laleh Rafat

2017-05-01

Computational models of the human body have gradually become crucial in the evaluation of doses absorbed by organs. However, individuals may differ considerably in terms of organ size and shape. In this study, the authors sought to determine the energy-dependent standard deviations due to lung size of the dose absorbed by the lung during external photon and neutron beam exposures. One hundred lungs with different masses were prepared and located in an adult male International Commission on Radiological Protection (ICRP) reference phantom. Calculations were performed using the Monte Carlo N-particle code version 5 (MCNP5). Variation in the lung mass caused great uncertainty: ~90% for low-energy broad parallel photon beams. However, for high-energy photons, the lung-absorbed dose dependency on the anatomical variation was reduced to <1%. In addition, the results obtained indicated that the discrepancy in the lung-absorbed dose varied from 0.6% to 8% for neutron beam exposure. Consequently, the relationship between absorbed dose and organ volume was found to be significant for low-energy photon sources, whereas for higher energy photon sources the organ-absorbed dose was independent of the organ volume. In the case of neutron beam exposure, the maximum discrepancy (of 8%) occurred in the energy range between 0.1 and 5 MeV. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Monte Carlo study of si diode response in electron beams.

PubMed

Wang, Lilie L W; Rogers, David W O

2007-05-01

Silicon semiconductor diodes measure almost the same depth-dose distributions in both photon and electron beams as those measured by ion chambers. A recent study in ion chamber dosimetry has suggested that the wall correction factor for a parallel-plate ion chamber in electron beams changes with depth by as much as 6%. To investigate diode detector response with respect to depth, a silicon diode model is constructed and the water/silicon dose ratio at various depths in electron beams is calculated using EGSnrc. The results indicate that, for this particular diode model, the diode response per unit water dose (or water/diode dose ratio) in both 6 and 18 MeV electron beams is flat within 2% versus depth, from near the phantom surface to the depth of R50 (with calculation uncertainty <0.3%). This suggests that there must be some other correction factors for ion chambers that counter-balance the large wall correction factor at depth in electron beams. In addition, the beam quality and field-size dependence of the diode model are also calculated. The results show that the water/diode dose ratio remains constant within 2% over the electron energy range from 6 to 18 MeV. The water/diode dose ratio does not depend on field size as long as the incident electron beam is broad and the electron energy is high. However, for a very small beam size (1 X 1 cm(2)) and low electron energy (6 MeV), the water/diode dose ratio may decrease by more than 2% compared to that of a broad beam.

Space System Survivability

NASA Astrophysics Data System (ADS)

Kuller, W. G.; Hanifen, D. W.

1982-07-01

Exoatmospheric detonations of nuclear weapons produce a broad spectrum of effects which can prevent operational space missions from being successfully accomplished. The spacecraft may be exposed to the prompt radiation from the detonations which can cause upset or burnout of critical mission components through Transient Radiation Effects on Electronics (TREE) or System Generated Electromagnetic Pulse (SGEMP). Continual exposure to the trapped radiation environment may cause component failure due to total dose or Electron Caused EMP (ECEMP). Satellite links to ground and airborne terminals are subject to serious degradation due to signal absorption and scintillation. The ground data stations and lines of communications are subject to failure from the broad range effects of high-altitude EMP.

A novel approach for estimating ingested dose associated with paracetamol overdose

PubMed Central

Zurlinden, Todd J.; Heard, Kennon

2015-01-01

Aim In cases of paracetamol (acetaminophen, APAP) overdose, an accurate estimate of tissue‐specific paracetamol pharmacokinetics (PK) and ingested dose can offer health care providers important information for the individualized treatment and follow‐up of affected patients. Here a novel methodology is presented to make such estimates using a standard serum paracetamol measurement and a computational framework. Methods The core component of the computational framework was a physiologically‐based pharmacokinetic (PBPK) model developed and evaluated using an extensive set of human PK data. Bayesian inference was used for parameter and dose estimation, allowing the incorporation of inter‐study variability, and facilitating the calculation of uncertainty in model outputs. Results Simulations of paracetamol time course concentrations in the blood were in close agreement with experimental data under a wide range of dosing conditions. Also, predictions of administered dose showed good agreement with a large collection of clinical and emergency setting PK data over a broad dose range. In addition to dose estimation, the platform was applied for the determination of optimal blood sampling times for dose reconstruction and quantitation of the potential role of paracetamol conjugate measurement on dose estimation. Conclusions Current therapies for paracetamol overdose rely on a generic methodology involving the use of a clinical nomogram. By using the computational framework developed in this study, serum sample data, and the individual patient's anthropometric and physiological information, personalized serum and liver pharmacokinetic profiles and dose estimate could be generated to help inform an individualized overdose treatment and follow‐up plan. PMID:26441245

A novel approach for estimating ingested dose associated with paracetamol overdose.

PubMed

Zurlinden, Todd J; Heard, Kennon; Reisfeld, Brad

2016-04-01

In cases of paracetamol (acetaminophen, APAP) overdose, an accurate estimate of tissue-specific paracetamol pharmacokinetics (PK) and ingested dose can offer health care providers important information for the individualized treatment and follow-up of affected patients. Here a novel methodology is presented to make such estimates using a standard serum paracetamol measurement and a computational framework. The core component of the computational framework was a physiologically-based pharmacokinetic (PBPK) model developed and evaluated using an extensive set of human PK data. Bayesian inference was used for parameter and dose estimation, allowing the incorporation of inter-study variability, and facilitating the calculation of uncertainty in model outputs. Simulations of paracetamol time course concentrations in the blood were in close agreement with experimental data under a wide range of dosing conditions. Also, predictions of administered dose showed good agreement with a large collection of clinical and emergency setting PK data over a broad dose range. In addition to dose estimation, the platform was applied for the determination of optimal blood sampling times for dose reconstruction and quantitation of the potential role of paracetamol conjugate measurement on dose estimation. Current therapies for paracetamol overdose rely on a generic methodology involving the use of a clinical nomogram. By using the computational framework developed in this study, serum sample data, and the individual patient's anthropometric and physiological information, personalized serum and liver pharmacokinetic profiles and dose estimate could be generated to help inform an individualized overdose treatment and follow-up plan. © 2015 The British Pharmacological Society.

Object Kinetic Monte Carlo Simulations of Radiation Damage In Bulk Tungsten

NASA Astrophysics Data System (ADS)

Nandipati, Giridhar; Setyawan, Wahyu; Heinisch, Howard; Roche, Kenneth; Kurtz, Richard; Wirth, Brian

2015-11-01

Results are presented for the evolution of radiation damage in bulk tungsten investigated using the object KMC simulation tool, KSOME, as a function of dose, dose rate and primary knock-on atom (PKA) energies in the range of 10 to 100 keV, at temperatures of 300, 1025 and 2050 K. At 300 K, the number density of vacancies changes minimally with dose rate while the number density of vacancy clusters slightly decreases with dose rate indicating that larger clusters are formed at higher dose rates. Although the average vacancy cluster size increases slightly, the vast majority exists as mono-vacancies. At 1025 K void lattice formation was observed at all dose rates for cascades below 60 keV and at lower dose rates for higher PKA energies. After the appearance of initial features of the void lattice, vacancy cluster density increased minimally while the average vacancy cluster size increases rapidly with dose. At 2050 K, no accumulation of defects was observed over a broad range of dose rates for all PKA energies studied in this work. Further comparisons of results of irradiation simulations at various dose rates and PKA spectra, representative of the High Flux Isotope Reactor and future fusion relevant irradiation facilities will be discussed. The U.S. Department of Energy, Office of Fusion Energy Sciences (FES) and Office of Advanced Scientific Computing Research (ASCR) has supported this study through the SciDAC-3 program.

Dosimetric properties of germanium doped calcium borate glass subjected to 6 MV and 10 MV X-ray irradiations

NASA Astrophysics Data System (ADS)

Tengku Kamarul Bahri, T. N. H.; Wagiran, H.; Hussin, R.; Saeed, M. A.; Hossain, I.; Ali, H.

2014-10-01

Germanium doped calcium borate glasses are investigated in term of thermoluminescence properties to seek their possibility to use as glass radiation dosimeter. The samples were exposed to 6 MV, and 10 MV photon beams in a dose range of 0.5-4.0 Gy. There is a single and broad thermoluminescence glow curve that exhibits its maximum intensity at about 300 °C. Linear dose response behavior has been found in this dose range for the both photon energies. Effective atomic number, TL sensitivity, and reproducibility have also been studied. It is found that the sensitivity of germanium doped sample at 6 MV is only 1.28% and it is superior to the sensitivity at 10 MV. The reproducibility of germanium doped sample is good with a percentage of relative error less than 10%. The results indicate that this glass has a potential to be used as a radiation dosimetry, especially for application in radiotherapy.

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.

Radiation dose effect of DNA repair-related gene expression in mouse white blood cells.

PubMed

Li, Ming-juan; Wang, Wei-wei; Chen, Shi-wei; Shen, Qian; Min, Rui

2011-10-01

The aim of this study was to screen molecular biomarkers for biodosimetry from DNA repair-related gene expression profiles. Mice were subjected to whole-body exposure with 60Co gamma rays with a dose range of 0-8 Gy at a dose rate of 0.80 Gy/min. RNA was extracted from the peripheral blood of irradiated mice at 4, 8, 12, 24 and 48hrs post-irradiation. The mRNA transcriptional changes of 11 genes related to DNA damage and repair were detected using real-time quantitative polymerase chain reaction (RT-PCR). Of the 11 genes examined, CDKN1A (cyclin-dependent kinase inhibitor 1A or p21, Cip1) and ATM (ataxia telangiectasia mutated) expression levels were found to be heavily up- and down-regulated, respectively, with exposure dose increasing at different post-irradiation times. RAD50 (RAD50 homolog), PLK3 (polo-like kinase 3), GADD45A (growth arrest and DNA damage-inducible, alpha), DDB2 (damage-specific DNA-binding protein 2), BBC3 (BCL2-binding component 3) and IER5 (immediate early response 5) gene expression levels were found to undergo significant oscillating changes over a broad dose range of 2-8 Gy at post-exposure time points observed. Three of the genes were found not to change within the observed exposure dose and post-radiation time ranges. The results of this study add to the biodosimetry with biomarker data pool and will be helpful for constructing appropriate gene expression biomarker systems to evaluate radiation exposure doses.

Acute effects of a wild green-oat (Avena sativa) extract on cognitive function in middle-aged adults: A double-blind, placebo-controlled, within-subjects trial.

PubMed

Kennedy, David O; Jackson, Philippa A; Forster, Joanne; Khan, Julie; Grothe, Torsten; Perrinjaquet-Moccetti, Tania; Haskell-Ramsay, Crystal F

2017-02-01

A wild green-oats extract (Neuravena ® ) containing a range of potentially bioactive components, including flavonoids and triterpene saponins, has previously been shown to enhance animal stress responses and memory, and improve cognitive performance in humans at a dose of 1600 mg. Methods This double-blind, placebo-controlled, counterbalanced cross-over study assessed the effects of single doses of the green-oat extract (GOE) across a broad range of cognitive domains in healthy adults aged 40-65 years who self-reported that they felt that their memory had declined with age. Participants attended on six occasions, receiving a single dose of either placebo, 800, or 1600 mg GOE on each occasion, with the counterbalanced order of treatments repeated twice for each participant. Cognitive function was assessed with a range of computerized tasks measuring attention, spatial/working/episodic memory, and executive function pre-dose and at 1, 2.5, 4, and 6 hours post-dose. Results The results showed that 800mg GOE increased the speed of performance across post-dose assessments on a global measure including data from all of the timed tasks. It also improved performance of a delayed word recall task in terms of errors and an executive function task (Peg and Ball) in terms of decreased thinking time and overall completion time. Working memory span (Corsi blocks) was also increased, but only on the second occasion that this dose was taken. Discussion These results confirm the acute cognitive effects of GOE seen in previous research, and suggest that the optimal dose lies at or below 800 mg.

Ultralow Dose MSCT Imaging in Dental Implantology

PubMed Central

Widmann, Gerlig; Al-Ekrish, Asma'a A.

2018-01-01

Introduction: The Council Directive 2013/59 Euratom has a clear commitment for keeping medical radiation exposure as low as reasonably achievable and demands a regular review and use of diagnostic reference levels. Methods: In dental implantology, the range of effective doses for cone beam computed tomography (CBCT) shows a broad overlap with multislice computed tomography (MSCT). More recently, ultralow dose imaging with new generations of MSCT scanners may impart radiation doses equal to or lower than CBCT. Dose reductions in MSCT have been further facilitated by the introduction of iterative image reconstruction technology (IRT), which provides substantial noise reduction over the current standard of filtered backward projection (FBP). Aim: The aim of this article is to review the available literature on ultralow dose CT imaging and IRTs in dental implantology imaging and to summarize their influence on spatial and contrast resolution, image noise, tissue density measurements, and validity of linear measurements of the jaws. Conclusion: Application of ultralow dose MSCT with IRT technology in dental implantology offers the potential for very large dose reductions compared with standard dose imaging. Yet, evaluation of various diagnostic tasks related to dental implantology is still needed to confirm the results obtained with various IRTs and ultra-low doses so far. PMID:29492174

The small-animal radiation research platform (SARRP): dosimetry of a focused lens system.

PubMed

Deng, Hua; Kennedy, Christopher W; Armour, Elwood; Tryggestad, Erik; Ford, Eric; McNutt, Todd; Jiang, Licai; Wong, John

2007-05-21

A small animal radiation platform equipped with on-board cone-beam CT and conformal irradiation capabilities is being constructed for translational research. To achieve highly localized dose delivery, an x-ray lens is used to focus the broad beam from a 225 kVp x-ray tube down to a beam with a full width half maximum (FWHM) of approximately 1.5 mm in the energy range 40-80 keV. Here, we report on the dosimetric characteristics of the focused beam from the x-ray lens subsystem for high-resolution dose delivery. Using the metric of the average dose within a 1.5 mm diameter area, the dose rates at a source-to-surface distance (SSD) of 34 cm are 259 and 172 cGy min(-1) at 6 mm and 2 cm depths, respectively, with an estimated uncertainty of +/-5%. The per cent depth dose is approximately 56% at 2 cm depth for a beam at 34 cm SSD.

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

PubMed Central

Upton, A C

1983-01-01

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

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.

PubMed

Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. Published by Elsevier Inc.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

PubMed Central

Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

2014-01-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; Mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA- activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32%–87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. PMID:24971906

Neon transport in selected organic composites. [stopping power of Kapton and polyethylene

NASA Technical Reports Server (NTRS)

Townsend, L. W.; Wilson, J. W.; Bidasaria, H. B.

1984-01-01

An energy-dependent, perturbation expansion solution for heavy-ion transport in one dimension was used to calculate the dose from Ne-20 beams at incident kinetic energies of 350, 670, and 2000 MeV/amu onto selected organic composites. Transport coefficients, applicable to arbitrary ion beams over a broad range of energies, are presented. Polyethylene and Kapton were tested as constituents of multilayered shielding for spacecraft and astronauts.

Noninvasive Biomonitoring Approaches to Determine Dosimetry and Risk Following Acute Chemical Exposure: Analysis of Lead or Organophosphate Insecticide in Saliva

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

Timchalk, Chuck; Poet, Torka S.; Kousba, Ahmed A.

2004-04-01

There is a need to develop approaches for assessing risk associated with acute exposures to a broad-range of chemical agents and to rapidly determine the potential implications to human health. Non-invasive biomonitoring approaches are being developed using reliable portable analytical systems to quantitate dosimetry utilizing readily obtainable body fluids, such as saliva. Saliva has been used to evaluate a broad range of biomarkers, drugs, and environmental contaminants including heavy metals and pesticides. To advance the application of non-invasive biomonitoring a microfluidic/ electrochemical device has also been developed for the analysis of lead (Pb), using square wave anodic stripping voltammetry. Themore » system demonstrates a linear response over a broad concentration range (1 2000 ppb) and is capable of quantitating saliva Pb in rats orally administered acute doses of Pb-acetate. Appropriate pharmacokinetic analyses have been used to quantitate systemic dosimetry based on determination of saliva Pb concentrations. In addition, saliva has recently been used to quantitate dosimetry following exposure to the organophosphate insecticide chlorpyrifos in a rodent model system by measuring the major metabolite, trichloropyridinol, and saliva cholinesterase inhibition following acute exposures. These results suggest that technology developed for non-invasive biomonitoring can provide a sensitive, and portable analytical tool capable of assessing exposure and risk in real-time. By coupling these non-invasive technologies with pharmacokinetic modeling it is feasible to rapidly quantitate acute exposure to a broad range of chemical agents. In summary, it is envisioned that once fully developed, these monitoring and modeling approaches will be useful for accessing acute exposure and health risk.« less

Comprehensive evaluation of broad-beam transmission of patient supports from three fluoroscopy-guided interventional systems.

PubMed

DeLorenzo, Matthew C; Yang, Kai; Li, Xinhua; Liu, Bob

2018-04-01

The purpose of the study was to measure, evaluate, and model the broad-beam x-ray transmission of the patient supports from representative modern fluoroscopy-guided interventional systems, for patient skin dose calculation. Broad-beam transmission was evaluated by varying incident angle, kVp, added copper (Cu) filter, and x-ray field size for three fluoroscopy systems: General Electric (GE) Innova 4100 with Omega V table and pad, Siemens Axiom Artis with Siemens tabletop "narrow" (CARD) table and pad, and Siemens Zeego with Trumpf TruSystem 7500 table and pad. Field size was measured on the table using a lead ruler for all setups in this study. Exposure rates were measured in service mode using a calibrated Radcal 10 × 6-60 ion chamber above the patient support at the assumed skin location. Broad-beam transmission factors were calculated by the ratio of air kerma rates measured with and without a patient support in the beam path. First, angle dependency was investigated on the GE system, with the chamber at isocenter, for angles of 0°, 15°, 30°, and 40°, for a variety of kVp, added Cu filters, and for two field sizes (small and large). Second, the broad-beam transmission factor at normal incidence was evaluated for all three fluoroscopes by varying kVp, added Cu filter, and field size (small, medium, and large). An analytical equation was created to fit the data as to maximize R 2 and minimize maximum percentage difference across all measurements for each system. For all patient supports, broad-beam transmission factor increased with field size, kVp, and added Cu filtration and decreased with incident angle. Oblique incidence measurements show that the transmission decreased by about 1%, 3%, and 6% for incident angles of 15°, 30°, and 40°, respectively. The broad-beam transmission factors at 0° for the table and table plus pad ranged from 0.73 to 0.96 and from 0.59 to 0.89, respectively. The GE and Siemens transmission factors were comparable, while the Trumpf transmission factors were the lowest. The data were successfully fitted to a function of angle, field size, kVp, and added Cu filtration using nine parameters, with an average R 2 value of 0.977 and maximum percentage difference of 4.08%. This study evaluated the broad-beam transmission for three representative fluoroscopy systems and their dependency on angle, kVp, added Cu filter, and field size. The comprehensive data provided for patient support transmission will facilitate accurate calculation of peak skin dose (PSD) and may potentially be integrated into real-time and retrospective dose monitoring with access to Radiation Dose Structured Reports (RDSR) and radiation event data. © 2018 American Association of Physicists in Medicine.

Investigation of time-resolved proton radiography using x-ray flat-panel imaging system

NASA Astrophysics Data System (ADS)

Jee, K.-W.; Zhang, R.; Bentefour, E. H.; Doolan, P. J.; Cascio, E.; Sharp, G.; Flanz, J.; Lu, H.-M.

2017-03-01

Proton beam therapy benefits from the Bragg peak and delivers highly conformal dose distributions. However, the location of the end-of-range is subject to uncertainties related to the accuracy of the relative proton stopping power estimates and thereby the water-equivalent path length (WEPL) along the beam. To remedy the range uncertainty, an in vivo measurement of the WEPL through the patient, i.e. a proton-range radiograph, is highly desirable. Towards that goal, we have explored a novel method of proton radiography based on the time-resolved dose measured by a flat panel imager (FPI). A 226 MeV pencil beam and a custom-designed range modulator wheel (MW) were used to create a time-varying broad beam. The proton imaging technique used exploits this time dependency by looking at the dose rate at the imager as a function of time. This dose rate function (DRF) has a unique time-varying dose pattern at each depth of penetration. A relatively slow rotation of the MW (0.2 revolutions per second) and a fast image acquisition (30 frames per second, ~33 ms sampling) provided a sufficient temporal resolution for each DRF. Along with the high output of the CsI:Tl scintillator, imaging with pixel binning (2  ×  2) generated high signal-to-noise data at a very low radiation dose (~0.1 cGy). Proton radiographs of a head phantom and a Gammex CT calibration phantom were taken with various configurations. The results of the phantom measurements show that the FPI can generate low noise and high spatial resolution proton radiographs. The WEPL values of the CT tissue surrogate inserts show that the measured relative stopping powers are accurate to ~2%. The panel did not show any noticeable radiation damage after the accumulative dose of approximately 3831 cGy. In summary, we have successfully demonstrated a highly practical method of generating proton radiography using an x-ray flat panel imager.

Investigation of time-resolved proton radiography using x-ray flat-panel imaging system.

PubMed

Jee, K-W; Zhang, R; Bentefour, E H; Doolan, P J; Cascio, E; Sharp, G; Flanz, J; Lu, H-M

2017-03-07

Proton beam therapy benefits from the Bragg peak and delivers highly conformal dose distributions. However, the location of the end-of-range is subject to uncertainties related to the accuracy of the relative proton stopping power estimates and thereby the water-equivalent path length (WEPL) along the beam. To remedy the range uncertainty, an in vivo measurement of the WEPL through the patient, i.e. a proton-range radiograph, is highly desirable. Towards that goal, we have explored a novel method of proton radiography based on the time-resolved dose measured by a flat panel imager (FPI). A 226 MeV pencil beam and a custom-designed range modulator wheel (MW) were used to create a time-varying broad beam. The proton imaging technique used exploits this time dependency by looking at the dose rate at the imager as a function of time. This dose rate function (DRF) has a unique time-varying dose pattern at each depth of penetration. A relatively slow rotation of the MW (0.2 revolutions per second) and a fast image acquisition (30 frames per second, ~33 ms sampling) provided a sufficient temporal resolution for each DRF. Along with the high output of the CsI:Tl scintillator, imaging with pixel binning (2  ×  2) generated high signal-to-noise data at a very low radiation dose (~0.1 cGy). Proton radiographs of a head phantom and a Gammex CT calibration phantom were taken with various configurations. The results of the phantom measurements show that the FPI can generate low noise and high spatial resolution proton radiographs. The WEPL values of the CT tissue surrogate inserts show that the measured relative stopping powers are accurate to ~2%. The panel did not show any noticeable radiation damage after the accumulative dose of approximately 3831 cGy. In summary, we have successfully demonstrated a highly practical method of generating proton radiography using an x-ray flat panel imager.

Tutorial: Radiation Effects in Electronic Systems

NASA Technical Reports Server (NTRS)

Pellish, Jonathan A.

2017-01-01

This tutorial presentation will give an overview of radiation effects in electrical, electronic, and electromechanical (EEE) components as it applies to civilian space systems of varying size and complexity. The natural space environment presents many unique threats to electronic systems regardless of where the systems operate from low-Earth orbit to interplanetary space. The presentation will cover several topics, including: an overview and introduction to the applicable space radiation environments common to a broad range of mission designs; definitions and impacts of effects due to impinging particles in the space environment e.g., total ionizing dose (TID), total non-ionizing dose (TNID), and single-event effects (SEE); and, testing for and evaluation of TID, TNID, and SEE in EEE components.

Vaccine hypersensitivity--update and overview.

PubMed

Fritsche, Philipp J; Helbling, Arthur; Ballmer-Weber, Barbara K

2010-05-01

Concerns about possible reactions to vaccines or vaccinations are frequently raised. However, the rate of reported vaccine-induced adverse events is low and ranges between 4.8-83.0 per 100,000 doses of the most frequently used vaccines. The number of true allergic reactions to routine vaccines is not known; estimations range from 1 per 500,000 to 1 per 1,000,000 doses for most vaccines. When allergens such as gelatine or egg proteins are components of the formulation, the rate for serious allergic reactions may be higher. Nevertheless, anaphylactic, potentially life-threatening reactions to vaccines are still a rare event (approximately 1 per 1,500,000 doses). The variety of reported vaccine-related adverse events is broad. Most frequently, reactions to vaccines are limited to the injection site and result from a non specific activation of the inflammatory system by, for example, aluminium salts or the active microbial components. If allergy is suspected, an accurate examination followed by algorithms is the key for correct diagnosis, treatment and the decision regarding revaccination in patients with immediate-type reactions to vaccines.

Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range.

PubMed

Bachmann, Julie; Raue, Andreas; Schilling, Marcel; Böhm, Martin E; Kreutz, Clemens; Kaschek, Daniel; Busch, Hauke; Gretz, Norbert; Lehmann, Wolf D; Timmer, Jens; Klingmüller, Ursula

2011-07-19

Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. The specific contributions of individual feedback regulators, however, remain unclear. Based on extensive time-resolved data sets in primary erythroid progenitor cells, we established a dynamic pathway model to dissect the roles of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK2/STAT5 signaling. Facilitated by the model, we calculated the STAT5 response for experimentally unobservable Epo concentrations and provide a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. Model predictions show that the two feedbacks CIS and SOCS3 are most effective at different ligand concentration ranges due to their distinct inhibitory mechanisms. This divided function of dual feedback regulation enables control of STAT5 responses for Epo concentrations that can vary 1000-fold in vivo. Our modeling approach reveals dose-dependent feedback control as key property to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.

LiF TLD-100 as a Dosimeter in High Energy Proton Beam Therapy-Can It Yield Accurate Results?

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

Zullo, John R.; Kudchadker, Rajat J.; Zhu, X. Ronald

In the region of high-dose gradients at the end of the proton range, the stopping power ratio of the protons undergoes significant changes, allowing for a broad spectrum of proton energies to be deposited within a relatively small volume. Because of the potential linear energy transfer dependence of LiF TLD-100 (thermolumescent dosimeter), dose measurements made in the distal fall-off region of a proton beam may be less accurate than those made in regions of low-dose gradients. The purpose of this study is to determine the accuracy and precision of dose measured using TLD-100 for a pristine Bragg peak, particularly inmore » the distal fall-off region. All measurements were made along the central axis of an unmodulated 200-MeV proton beam from a Probeat passive beam-scattering proton accelerator (Hitachi, Ltd., Tokyo, Japan) at varying depths along the Bragg peak. Measurements were made using TLD-100 powder flat packs, placed in a virtual water slab phantom. The measurements were repeated using a parallel plate ionization chamber. The dose measurements using TLD-100 in a proton beam were accurate to within {+-}5.0% of the expected dose, previously seen in our past photon and electron measurements. The ionization chamber and the TLD relative dose measurements agreed well with each other. Absolute dose measurements using TLD agreed with ionization chamber measurements to within {+-} 3.0 cGy, for an exposure of 100 cGy. In our study, the differences in the dose measured by the ionization chamber and those measured by TLD-100 were minimal, indicating that the accuracy and precision of measurements made in the distal fall-off region of a pristine Bragg peak is within the expected range. Thus, the rapid change in stopping power ratios at the end of the range should not affect such measurements, and TLD-100 may be used with confidence as an in vivo dosimeter for proton beam therapy.« less

Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

PubMed Central

Larsen, R A; Bauer, M; Weiner, J M; Diamond, D M; Leal, M E; Ding, J C; Rinaldi, M G; Graybill, J R

1996-01-01

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily). PMID:8878602

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.

Computational Transport Modeling of High-Energy Neutrons Found in the Space Environment

NASA Technical Reports Server (NTRS)

Cox, Brad; Theriot, Corey A.; Rohde, Larry H.; Wu, Honglu

2012-01-01

The high charge and high energy (HZE) particle radiation environment in space interacts with spacecraft materials and the human body to create a population of neutrons encompassing a broad kinetic energy spectrum. As an HZE ion penetrates matter, there is an increasing chance of fragmentation as penetration depth increases. When an ion fragments, secondary neutrons are released with velocities up to that of the primary ion, giving some neutrons very long penetration ranges. These secondary neutrons have a high relative biological effectiveness, are difficult to effectively shield, and can cause more biological damage than the primary ions in some scenarios. Ground-based irradiation experiments that simulate the space radiation environment must account for this spectrum of neutrons. Using the Particle and Heavy Ion Transport Code System (PHITS), it is possible to simulate a neutron environment that is characteristic of that found in spaceflight. Considering neutron dosimetry, the focus lies on the broad spectrum of recoil protons that are produced in biological targets. In a biological target, dose at a certain penetration depth is primarily dependent upon recoil proton tracks. The PHITS code can be used to simulate a broad-energy neutron spectrum traversing biological targets, and it account for the recoil particle population. This project focuses on modeling a neutron beamline irradiation scenario for determining dose at increasing depth in water targets. Energy-deposition events and particle fluence can be simulated by establishing cross-sectional scoring routines at different depths in a target. This type of model is useful for correlating theoretical data with actual beamline radiobiology experiments. Other work exposed human fibroblast cells to a high-energy neutron source to study micronuclei induction in cells at increasing depth behind water shielding. Those findings provide supporting data describing dose vs. depth across a water-equivalent medium. This poster presents PHITS data suggesting an increase in dose, up to roughly 10 cm depth, followed by a continual decrease as neutrons come to a stop in the target.

Assessment of the Technologies for Molecular Biodosimetry for Human Low-Dose Radiation Exposure Symposium: Agenda and Abstracts

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

Coleman, Matthew A.; Ramakrishnan, Narayani

In the event of a radiological accident, the rapid evaluation of the individual absorbed dose is paramount to discriminate those individuals who must receive medical attention. New research with genomic- and proteomic-wide tools is showing that within minutes to hours after exposure to ionizing radiation the cellular machinery is modified. For example: large-scale changes occur in the gene expression profiles involving a broad variety of cellular pathways after a wide range of both low dose (<10 cGy) and high dose (>10 cGy) ionizing radiation exposures. Symposium 12 was organized to address a wide range of biological effects using the latestmore » technologies. To address current models following ionizing radiation exposure, methods in biodosimetry and dose effects the symposia featured a general overview titled “Model Systems and Current Approaches in Biodosimetry” by Matthew A. Coleman, from Lawrence Livermore National Laboratory and a talk entitled “Brief Overview of Biodosimetry Projects in the NIH Rad/Nuc Program” by Dr. Narayani Ramakrishnan, National Institute of Allergy and Infectious Diseases. These two talk set the tone for issues in data and model integration as well as addressing the national need for robust technologies for biological dosimetry. The report continues with more description of the presentations, along with the agenda and abstracts of the papers presented.« less

Calorimetry of electron beams and the calibration of dosimeters at high doses

NASA Astrophysics Data System (ADS)

Humphreys, J. C.; McLaughlin, W. L.

Graphite or metal calorimeters are used to make absolute dosimetric measurements of high-energy electron beams. These calibrated beams are then used to calibrate several types of dosimeters for high-dose applications such as medical-product sterilization, polymer modification, food processing, or electronic-device hardness testing. The electron beams are produced either as continuous high-power beams at approximately 4.5 MeV by d.c. type accelerators or in the energy range of approximately 8 to 50 MeV using pulsed microwave linear accelerators (linacs). The continuous beams are generally magnetically scanned to produce a broad, uniform radiation environment for the processing of materials of extended lateral dimensions. The higher-energy pulsed beams may also be scanned for processing applications or may be used in an unscanned, tightly-focused mode to produce maximum absorbed dose rates such as may be required for electronic-device radiation hardness testing. The calorimeters are used over an absorbed dose range of 10 2 to 10 4 Gy. Intercomparison studies are reported between National Institute of Standards and Technology (NIST) and UK National Physical Laboratory (NPL) graphite disk calorimeters at high doses, using the NPL 10-MeV linac, and agreement was found within 1.5%. It was also shown that the electron-beam responses of radiochromic film dosimeters and alanine pellet dosimeters can be accurately calibrated by comparison with calorimeter readings.

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

Markovic, M; Stathakis, S; Jurkovic, I

Purpose The aim for the study was to compare intrinsic characteristics of the nine detectors and evaluate their performance in non-equilibrium radiation dosimetry. Methods The intrinsic characteristics of the nine detectors that were evaluated are based on the composition and size of the active volume, operating voltage, initial recombination of the collected charge, temperature, the effective cross section of the detectors. The shortterm stability and collection efficiency has been investigated. The minimum radiation detection sensitivity and detectors leakage current has been measured. The sensitivity to changes in energy spectrum as well as change in incident beam angles were measured anmore » analyzed. Results The short-term stability of the measurements within every detector showed consistency in the measured values with the highest value of the standard deviation of the mean not exceeding 0.5%. Air ion chamber detectors showed minimum sensitivity to change in incident beam angles while diode detectors underestimated measurements up to 16%. Comparing the slope of the tangents for detector’s sensitivity curve, diode detectors illustrate more sensitivity to change in photon spectrum than ion chamber detectors. The change in radiation detection sensitivity with increase in dose delivered has been observed for semiconductor detectors with maximum deviation 0.01% for doses between 1 Gy and 10 Gy. Leakage current has been mainly influenced by bias voltage (ion chamber detectors) and room light intensity (diode detectors). With dose per pulse varying from 1.47E−4 to 5.1E−4 Gy/pulse the maximum change in collection efficiency was 1.4% for the air ion chambers up to 8% for liquid filled ion chamber. Conclusion Broad range of measurements performed showed all the detectors susceptible to some limitations and while they are suitable for use in broad scope of applications, careful selection has to be made for particular range of measurements.« less

Methods for implementing microbeam radiation therapy

DOEpatents

Dilmanian, F. Avraham; Morris, Gerard M.; Hainfeld, James F.

2007-03-20

A method of performing radiation therapy includes delivering a therapeutic dose such as X-ray only to a target (e.g., tumor) with continuous broad beam (or in-effect continuous) using arrays of parallel planes of radiation (microbeams/microplanar beams). Microbeams spare normal tissues, and when interlaced at a tumor, form a broad-beam for tumor ablation. Bidirectional interlaced microbeam radiation therapy (BIMRT) uses two orthogonal arrays with inter-beam spacing equal to beam thickness. Multidirectional interlaced MRT (MIMRT) includes irradiations of arrays from several angles, which interleave at the target. Contrast agents, such as tungsten and gold, are administered to preferentially increase the target dose relative to the dose in normal tissue. Lighter elements, such as iodine and gadolinium, are used as scattering agents in conjunction with non-interleaving geometries of array(s) (e.g., unidirectional or cross-fired (intersecting) to generate a broad beam effect only within the target by preferentially increasing the valley dose within the tumor.

Biological and dosimetric characterisation of spatially fractionated proton minibeams

NASA Astrophysics Data System (ADS)

Meyer, Juergen; Stewart, Robert D.; Smith, Daniel; Eagle, James; Lee, Eunsin; Cao, Ning; Ford, Eric; Hashemian, Reza; Schuemann, Jan; Saini, Jatinder; Marsh, Steve; Emery, Robert; Dorman, Eric; Schwartz, Jeff; Sandison, George

2017-12-01

The biological effectiveness of proton beams varies with depth, spot size and lateral distance from the beam central axis. The aim of this work is to incorporate proton relative biological effectiveness (RBE) and equivalent uniform dose (EUD) considerations into comparisons of broad beam and highly modulated proton minibeams. A Monte Carlo model of a small animal proton beamline is presented. Dose and variable RBE is calculated on a per-voxel basis for a range of energies (30-109 MeV). For an open beam, the RBE values at the beam entrance ranged from 1.02-1.04, at the Bragg peak (BP) from 1.3 to 1.6, and at the distal end of the BP from 1.4 to 2.0. For a 50 MeV proton beam, a minibeam collimator designed to produce uniform dose at the depth of the BP peak, had minimal impact on the open beam RBE values at depth. RBE changes were observed near the surface when the collimator was placed flush with the irradiated object, due to a higher neutron contribution derived from proton interactions with the collimator. For proton minibeams, the relative mean RBE weighted entrance dose (RWD) was ~25% lower than the physical mean dose. A strong dependency of the EUD with fraction size was observed. For 20 Gy fractions, the EUD varied widely depending on the radiosensitivity of the cells. For radiosensitive cells, the difference was up to ~50% in mean dose and ~40% in mean RWD and the EUD trended towards the valley dose rather than the mean dose. For comparative studies of uniform dose with spatially fractionated proton minibeams, EUD derived from a per-voxel RWD distribution is recommended for biological assessments of reproductive cell survival and related endpoints.

Biological and dosimetric characterisation of spatially fractionated proton minibeams.

PubMed

Meyer, Juergen; Stewart, Robert D; Smith, Daniel; Eagle, James; Lee, Eunsin; Cao, Ning; Ford, Eric; Hashemian, Reza; Schuemann, Jan; Saini, Jatinder; Marsh, Steve; Emery, Robert; Dorman, Eric; Schwartz, Jeff; Sandison, George

2017-11-21

The biological effectiveness of proton beams varies with depth, spot size and lateral distance from the beam central axis. The aim of this work is to incorporate proton relative biological effectiveness (RBE) and equivalent uniform dose (EUD) considerations into comparisons of broad beam and highly modulated proton minibeams. A Monte Carlo model of a small animal proton beamline is presented. Dose and variable RBE is calculated on a per-voxel basis for a range of energies (30-109 MeV). For an open beam, the RBE values at the beam entrance ranged from 1.02-1.04, at the Bragg peak (BP) from 1.3 to 1.6, and at the distal end of the BP from 1.4 to 2.0. For a 50 MeV proton beam, a minibeam collimator designed to produce uniform dose at the depth of the BP peak, had minimal impact on the open beam RBE values at depth. RBE changes were observed near the surface when the collimator was placed flush with the irradiated object, due to a higher neutron contribution derived from proton interactions with the collimator. For proton minibeams, the relative mean RBE weighted entrance dose (RWD) was ~25% lower than the physical mean dose. A strong dependency of the EUD with fraction size was observed. For 20 Gy fractions, the EUD varied widely depending on the radiosensitivity of the cells. For radiosensitive cells, the difference was up to ~50% in mean dose and ~40% in mean RWD and the EUD trended towards the valley dose rather than the mean dose. For comparative studies of uniform dose with spatially fractionated proton minibeams, EUD derived from a per-voxel RWD distribution is recommended for biological assessments of reproductive cell survival and related endpoints.

3DHZETRN: Inhomogeneous Geometry Issues

NASA Technical Reports Server (NTRS)

Wilson, John W.; Slaba, Tony C.; Badavi, Francis F.

2017-01-01

Historical methods for assessing radiation exposure inside complicated geometries for space applications were limited by computational constraints and lack of knowledge associated with nuclear processes occurring over a broad range of particles and energies. Various methods were developed and utilized to simplify geometric representations and enable coupling with simplified but efficient particle transport codes. Recent transport code development efforts, leading to 3DHZETRN, now enable such approximate methods to be carefully assessed to determine if past exposure analyses and validation efforts based on those approximate methods need to be revisited. In this work, historical methods of representing inhomogeneous spacecraft geometry for radiation protection analysis are first reviewed. Two inhomogeneous geometry cases, previously studied with 3DHZETRN and Monte Carlo codes, are considered with various levels of geometric approximation. Fluence, dose, and dose equivalent values are computed in all cases and compared. It is found that although these historical geometry approximations can induce large errors in neutron fluences up to 100 MeV, errors on dose and dose equivalent are modest (<10%) for the cases studied here.

Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS)

PubMed Central

Diamond, David M.

2004-01-01

Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people. PMID:19330152

Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults.

PubMed

Ledgerwood, J E; Coates, E E; Yamshchikov, G; Saunders, J G; Holman, L; Enama, M E; DeZure, A; Lynch, R M; Gordon, I; Plummer, S; Hendel, C S; Pegu, A; Conan-Cibotti, M; Sitar, S; Bailer, R T; Narpala, S; McDermott, A; Louder, M; O'Dell, S; Mohan, S; Pandey, J P; Schwartz, R M; Hu, Z; Koup, R A; Capparelli, E; Mascola, J R; Graham, B S

2015-12-01

VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n = 18), the clearance was 0.016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies. © 2015 British Society for Immunology.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

PubMed

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

PubMed Central

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

Overview of the AFRL’s Demonstration and Science Experiments (DSX) Program

DTIC Science & Technology

2006-09-01

most of the space weather data to-date has been accumulated in the LEO and GEO regimes, as illustrated in Figure 11 with data from dosimeters aboard...Composed of two dosimeters , two particle telescopes and a Single Event Effect detector, CEASE has the capability to monitor a broad range of space...panel of the payload module. One change for DSX is that CEASE will capture and downlink the full dose spectra from each dosimeter , whereas prior

Intravenous sub-anesthetic ketamine for perioperative analgesia

PubMed Central

Gorlin, Andrew W; Rosenfeld, David M; Ramakrishna, Harish

2016-01-01

Ketamine, an N-methyl-d-aspartate antagonist, blunts central pain sensitization at sub-anesthetic doses (0.3 mg/kg or less) and has been studied extensively as an adjunct for perioperative analgesia. At sub-anesthetic doses, ketamine has a minimal physiologic impact though it is associated with a low incidence of mild psychomimetic symptoms as well as nystagmus and double vision. Contraindications to its use do exist and due to ketamine's metabolism, caution should be exercised in patients with renal or hepatic dysfunction. Sub-anesthetic ketamine improves pain scores and reduces perioperative opioid consumption in a broad range of surgical procedures. In addition, there is evidence that ketamine may be useful in patients with opioid tolerance and for preventing chronic postsurgical pain. PMID:27275042

Role of Curcumin in Disease Prevention and Treatment.

PubMed

Rahmani, Arshad Husain; Alsahli, Mohammed A; Aly, Salah M; Khan, Masood A; Aldebasi, Yousef H

2018-01-01

Treatment based on traditional medicine is very popular in developing world due to inexpensive properties. Nowadays, several types of preparations based on medicinal plants at different dose have been extensively recognized in the diseases prevention and treatment. In this vista, latest findings support the effect of Curcuma longa and its chief constituents curcumin in a broad range of diseases cure via modulation of physiological and biochemical process. In addition, various studies based on animal mode and clinical trials showed that curcumin does not cause any adverse complications on liver and kidney function and it is safe at high dose. This review article aims at gathering information predominantly on pharmacological activities such as anti-diabetic, anti-microbial, hepato-protective activity, anti-inflammatory, and neurodegenerative diseases.

Role of Curcumin in Disease Prevention and Treatment

PubMed Central

Rahmani, Arshad Husain; Alsahli, Mohammed A.; Aly, Salah M.; Khan, Masood A.; Aldebasi, Yousef H.

2018-01-01

Treatment based on traditional medicine is very popular in developing world due to inexpensive properties. Nowadays, several types of preparations based on medicinal plants at different dose have been extensively recognized in the diseases prevention and treatment. In this vista, latest findings support the effect of Curcuma longa and its chief constituents curcumin in a broad range of diseases cure via modulation of physiological and biochemical process. In addition, various studies based on animal mode and clinical trials showed that curcumin does not cause any adverse complications on liver and kidney function and it is safe at high dose. This review article aims at gathering information predominantly on pharmacological activities such as anti-diabetic, anti-microbial, hepato-protective activity, anti-inflammatory, and neurodegenerative diseases. PMID:29629341

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

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

NASA Astrophysics Data System (ADS)

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

2015-04-01

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

Modeling to optimize operational practices to limit shallow dose and dose to the lens at the Weldon Spring Site Remedial Action Project.

PubMed

Hillman, D J; Green, S W

1994-10-01

The Weldon Spring Site Remedial Action Project (WSSRAP) began remediation of its chemical plant buildings in June 1992. The chemical plant was used by the Atomic Energy Commission in the 1950's and 1960's to process uranium ore and natural thorium. Many remaining equipment surfaces were highly contaminated with uranium and thorium product residues, which are relatively weak gamma emitters, but are strong beta emitters that deposit the majority of their energy within the first centimeter of tissue. An essential part of the remediation, therefore, is to control the dose to the skin, extremities, and the lens of the eye from the broad range of betas emitted by uranium and thorium decay series radionuclides. The WSSRAP planned to quantitatively record the dose to the skin, extremities, and the lens of the eye, when warranted, through selection and use of appropriate passive dosimeters. That would not, however, constitute control. A direct-reading instrument was needed that could be used by field technicians to anticipate and prevent work methods and situations that would otherwise result in the unnecessary commitment of dose. However, the interpretation of real-time instrument readings produced by a broad spectrum of beta energies is typically challenging at best, particularly when the shallow dose rate and the lens dose rate are both of interest. The purpose of this effort was, therefore, to (1) select a direct-reading instrument for use in the buildings that could be used to provide rule-of-thumb action levels for field technicians, which, if exceeded, would warrant worker protective measures; (2) determine the approximate conversions between the instrument readings and the shallow (including extremity) dose rate and lens of the eye dose rate; and (3) specify protective measures and dosimetry for the lens of the eye, if warranted. Methods described in the literature are used to estimate action levels for direct instrument readings and to demonstrate that lens dosimetry and special protective measures for the lens of the eye are not necessary at the WSSRAP.

SU-E-T-748: Theoretical Investigation On Using High Energy Proton Beam for Total-Body-Irradiation

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

Zhang, M; Zou, J; Chen, T

2015-06-15

Purpose: The broad-slow-rising entrance dose region proximal to the Bragg peak made by a mono-energetic proton beam could potentially be used for total body irradiation (TBI). Due to the quasi-uniform dose deposition, customized thickness compensation may not be required to deliver a uniform dose to patients with varied thickness. We investigated the possibility, efficacy, and hardware requirement to use such proton beam for TBI. Methods: A wedge shaped water phantom with thickness varying from 2 cm to 40 cm was designed to mimic a patient. Geant4 based Monte Carlo code was used to simulate broad mono-energetic proton beams with energymore » ranging from 250 MeV to 300 MeV radiating the phantom. A 6 MV photon with 1 cm water equivalent build-up used for conventional TBI was also calculated. A paired-opposing beam arrangement with no thickness compensation was used to generate TBI plans for all beam energies. Dose from all particles were scored on a grid size of 2 mm{sup 3}. Dose uniformity across the phantom was calculated to evaluate the plan. The field size limit and the dose uniformity of Mevion S250 proton system was examined by using radiochromic films placed at extended treatment distance with the open large applicator and 90° gantry angle. Results: To achieve a maximum ± 7.5% dose variation, the largest patient thickness variation allowed for 250 MeV, 275 MeV, and 300 MeV proton beams were 27.0 cm, 34.9 cm and 36.7 cm. The value for 6 MV photon beam was only 8.0 cm to achieve the same dose variation. With open gantry, Mevion S250 system allows 5 m source-to-surface distance producing an expected 70 cm{sup 2} field size. Conclusion: Energetic proton beam can potentially be used to deliver TBI. Treatment planning and delivery would be much simple since no thickness compensation is required to achieve a uniform dose distribution.« less

Response of avian embryonic brain to spatially segmented x-ray microbeams.

PubMed

Dilmanian, F A; Morris, G M; Le Duc, G; Huang, X; Ren, B; Bacarian, T; Allen, J C; Kalef-Ezra, J; Orion, I; Rosen, E M; Sandhu, T; Sathé, P; Wu, X Y; Zhong, Z; Shivaprasad, H L

2001-05-01

Duck embryo was studied as a model for assessing the effects of microbeam radiation therapy (MRT) on the human infant brain. Because of the high risk of radiation-induced disruption of the developmental process in the immature brain, conventional wide-beam radiotherapy of brain tumors is seldom carried out in infants under the age of three. Other types of treatment for pediatric brain tumors are frequently ineffective. Recent findings from studies in Grenoble on the brain of suckling rats indicate that MRT could be of benefit for the treatment of early childhood tumors. In our studies, duck embryos were irradiated at 3-4 days prior to hatching. Irradiation was carried out using a single exposure of synchrotron-generated X-rays, either in the form of parallel microplanar beams (microbeams), or as non-segmented broad beam. The individual microplanar beams had a width of 27 microm and height of 11 mm, and a center-to-center spacing of 100 microm. Doses to the exposed areas of embryo brain were 40, 80, 160 and 450 Gy (in-slice dose) for the microbeam, and 6, 12 and 18 Gy for the broad beam. The biological end point employed in the study was ataxia. This neurological symptom of radiation damage to the brain developed within 75 days of hatching. Histopathological analysis of brain tissue did not reveal any radiation induced lesions for microbeam doses of 40-160 Gy (in-slice), although some incidences of ataxia were observed in that dose group. However, severe brain lesions did occur in animals in the 450 Gy microbeam dose groups, and mild lesions in the 18 Gy broad beam dose group. These results indicate that embryonic duck brain has an appreciably higher tolerance to the microbeam modality, as compared to the broad beam modality. When the microbeam dose was normalized to the full volume of the irradiated tissue. i.e., the dose averaged over microbeams and the space between the microbeams, brain tolerance was estimated to be about three times higher to microbeam irradiation as compared with broad beam irradiation.

SU-F-T-428: An Optimization-Based Commissioning Tool for Finite Size Pencil Beam Dose Calculations

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

Li, Y; Tian, Z; Song, T

Purpose: Finite size pencil beam (FSPB) algorithms are commonly used to pre-calculate the beamlet dose distribution for IMRT treatment planning. FSPB commissioning, which usually requires fine tuning of the FSPB kernel parameters, is crucial to the dose calculation accuracy and hence the plan quality. Yet due to the large number of beamlets, FSPB commissioning could be very tedious. This abstract reports an optimization-based FSPB commissioning tool we have developed in MatLab to facilitate the commissioning. Methods: A FSPB dose kernel generally contains two types of parameters: the profile parameters determining the dose kernel shape, and a 2D scaling factors accountingmore » for the longitudinal and off-axis corrections. The former were fitted using the penumbra of a reference broad beam’s dose profile with Levenberg-Marquardt algorithm. Since the dose distribution of a broad beam is simply a linear superposition of the dose kernel of each beamlet calculated with the fitted profile parameters and scaled using the scaling factors, these factors could be determined by solving an optimization problem which minimizes the discrepancies between the calculated dose of broad beams and the reference dose. Results: We have commissioned a FSPB algorithm for three linac photon beams (6MV, 15MV and 6MVFFF). Dose of four field sizes (6*6cm2, 10*10cm2, 15*15cm2 and 20*20cm2) were calculated and compared with the reference dose exported from Eclipse TPS system. For depth dose curves, the differences are less than 1% of maximum dose after maximum dose depth for most cases. For lateral dose profiles, the differences are less than 2% of central dose at inner-beam regions. The differences of the output factors are within 1% for all the three beams. Conclusion: We have developed an optimization-based commissioning tool for FSPB algorithms to facilitate the commissioning, providing sufficient accuracy of beamlet dose calculation for IMRT optimization.« less

Morinda citrifolia Linn leaf extract possesses antioxidant activities and reduces nociceptive behavior and leukocyte migration.

PubMed

Serafini, Mairim Russo; Santos, Rodrigo Correia; Guimarães, Adriana Gibara; Dos Santos, João Paulo Almeida; da Conceicão Santos, Alan Diego; Alves, Izabel Almeida; Gelain, Daniel Pens; de Lima Nogueira, Paulo Cesar; Quintans-Júnior, Lucindo José; Bonjardim, Leonardo Rigoldi; de Souza Araújo, Adriano Antunes

2011-10-01

Herbal drugs have been used since ancient times to treat a wide range of diseases. Morinda citrifolia Linn (popularly known as "Noni") has been used in folk medicine by Polynesians for over 2,000 years. It is reported to have a broad range of therapeutic effects, including effects against headache, fever, arthritis, gingivitis, respiratory disorders, infections, tuberculosis, and diabetes. The aim of this study was to investigate the antioxidant, anti-inflammatory, antinociceptive, and antibacterial properties of the aqueous extract from M. citrifolia leaves (AEMC). Antioxidant activity was observed against lipid peroxidation, nitric oxide, and hydroxyl radicals. The antinociceptive effect of AEMC was observed in the acetic acid-induced writhing test at the higher dose. Moreover, AEMC significantly reduced the leukocyte migration in doses of 200 and 400 mg/kg and showed mild antibacterial activity. Together, the results suggest that properties of M. citrifolia leaf extract should be explored further in order to achieve newer tools for managing painful and inflammation conditions, including those related to oxidant states.

Modeling of beam customization devices in the pencil-beam splitting algorithm for heavy charged particle radiotherapy.

PubMed

Kanematsu, Nobuyuki

2011-03-07

A broad-beam-delivery system for radiotherapy with protons or ions often employs multiple collimators and a range-compensating filter, which offer complex and potentially useful beam customization. It is however difficult for conventional pencil-beam algorithms to deal with fine structures of these devices due to beam-size growth during transport. This study aims to avoid the difficulty with a novel computational model. The pencil beams are initially defined at the range-compensating filter with angular-acceptance correction for upstream collimation followed by stopping and scattering. They are individually transported with possible splitting near the aperture edge of a downstream collimator to form a sharp field edge. The dose distribution for a carbon-ion beam was calculated and compared with existing experimental data. The penumbra sizes of various collimator edges agreed between them to a submillimeter level. This beam-customization model will be used in the greater framework of the pencil-beam splitting algorithm for accurate and efficient patient dose calculation.

Performance of toxicity probability interval based designs in contrast to the continual reassessment method

PubMed Central

Horton, Bethany Jablonski; Wages, Nolan A.; Conaway, Mark R.

2016-01-01

Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for Phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both the mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. PMID:27435150

SU-C-204-02: Behavioral and Pathologic Differences in Mice Exposed to Proton Minibeam Arrays Versus Proton Broad Beams

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

Eley, J; Zhang, C; Wolfe, T

Purpose: Minibeam therapy using protons or light-ions offers a theoretical reduction of biologic damage to tissues upstream of a tumor compared to broad-beam therapy while providing equal tumor control. The purpose of this study was to investigate behavioral and pathologic differences in mice after exposure of healthy brain to proton minibeam arrays versus proton broad beams. Methods: Twenty-four C57BL/6J juvenile mice were divided into 5 study arms: sham irradiation (NoRT), broad-beam 10 Gy (BB10), minibeam 10Gy (MB10), broad-beam 30 Gy (BB30), and minibeam 30 Gy (MB30), approximate integral entrance doses. Circular beams of 100 MeV protons with 7-mm diameter weremore » delivered laterally through the brain, either as broad beams or as planar minibeam arrays having 300-micron beam width and 1-mm spacing on center. Mice were followed for 8 months using standard behavioral tests. Pathologic studies were carried out at 8 months after irradiation. Results: Peak entrance doses were 10.0, 23.8, 30.0, and 71.3 Gy for mice in BB10, MB10, BB30, and MB30, respectively. Despite the high single-fraction doses, no animals showed signs of radiation sickness or neurophysical impairment over the 8-month study duration. The Morris water maze alternate-starting-position trial showed significant evidence of better spatial learning for mice in MB10 versus BB10 (p=0.026), but other behavioral tests showed no significant differences. Glial fibrillary acidic protein stains showed gliosis in arms BB10, BB30, and MB30 but not in NoRT or MB10. A secondary finding was categorically higher epilation in broad-beam arms compared with their minibeam dose counterparts. Conclusion: Our findings indicate trends that, despite the higher peak doses, proton minibeam therapy can reduce radiation side effects in shallow tissue and brain compared to proton broadbeam therapy. As the behavioral findings were mixed, confirmation studies are needed with larger numbers of animals. AAPM Research Seed Funding Grant.« less

LiF TLD-100 as a dosimeter in high energy proton beam therapy--can it yield accurate results?

PubMed

Zullo, John R; Kudchadker, Rajat J; Zhu, X Ronald; Sahoo, Narayan; Gillin, Michael T

2010-01-01

In the region of high-dose gradients at the end of the proton range, the stopping power ratio of the protons undergoes significant changes, allowing for a broad spectrum of proton energies to be deposited within a relatively small volume. Because of the potential linear energy transfer dependence of LiF TLD-100 (thermolumescent dosimeter), dose measurements made in the distal fall-off region of a proton beam may be less accurate than those made in regions of low-dose gradients. The purpose of this study is to determine the accuracy and precision of dose measured using TLD-100 for a pristine Bragg peak, particularly in the distal fall-off region. All measurements were made along the central axis of an unmodulated 200-MeV proton beam from a Probeat passive beam-scattering proton accelerator (Hitachi, Ltd., Tokyo, Japan) at varying depths along the Bragg peak. Measurements were made using TLD-100 powder flat packs, placed in a virtual water slab phantom. The measurements were repeated using a parallel plate ionization chamber. The dose measurements using TLD-100 in a proton beam were accurate to within +/-5.0% of the expected dose, previously seen in our past photon and electron measurements. The ionization chamber and the TLD relative dose measurements agreed well with each other. Absolute dose measurements using TLD agreed with ionization chamber measurements to within +/- 3.0 cGy, for an exposure of 100 cGy. In our study, the differences in the dose measured by the ionization chamber and those measured by TLD-100 were minimal, indicating that the accuracy and precision of measurements made in the distal fall-off region of a pristine Bragg peak is within the expected range. Thus, the rapid change in stopping power ratios at the end of the range should not affect such measurements, and TLD-100 may be used with confidence as an in vivo dosimeter for proton beam therapy. Copyright 2010 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2015-01-01

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

Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design.

PubMed

Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

2012-06-01

MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.

Development of a synthetic single crystal diamond dosimeter for dose measurement of clinical proton beams

NASA Astrophysics Data System (ADS)

Moignier, Cyril; Tromson, Dominique; de Marzi, Ludovic; Marsolat, Fanny; García Hernández, Juan Carlos; Agelou, Mathieu; Pomorski, Michal; Woo, Romuald; Bourbotte, Jean-Michel; Moignau, Fabien; Lazaro, Delphine; Mazal, Alejandro

2017-07-01

The scope of this work was to develop a synthetic single crystal diamond dosimeter (SCDD-Pro) for accurate relative dose measurements of clinical proton beams in water. Monte Carlo simulations were carried out based on the MCNPX code in order to investigate and reduce the dose curve perturbation caused by the SCDD-Pro. In particular, various diamond thicknesses were simulated to evaluate the influence of the active volume thickness (e AV) as well as the influence of the addition of a front silver resin (250 µm in thickness in front of the diamond crystal) on depth-dose curves. The simulations indicated that the diamond crystal alone, with a small e AV of just 5 µm, already affects the dose at Bragg peak position (Bragg peak dose) by more than 2% with respect to the Bragg peak dose deposited in water. The optimal design that resulted from the Monte Carlo simulations consists of a diamond crystal of 1 mm in width and 150 µm in thickness with the front silver resin, enclosed by a water-equivalent packaging. This design leads to a deviation between the Bragg peak dose from the full detector modeling and the Bragg peak dose deposited in water of less than 1.2%. Based on those optimizations, an SCDD-Pro prototype was built and evaluated in broad passive scattering proton beams. The experimental evaluation led to probed SCDD-Pro repeatability, dose rate dependence and linearity, that were better than 0.2%, 0.4% (in the 1.0-5.5 Gy min-1 range) and 0.4% (for dose higher than 0.05 Gy), respectively. The depth-dose curves in the 90-160 MeV energy range, measured with the SCDD-Pro without applying any correction, were in good agreement with those measured using a commercial IBA PPC05 plane-parallel ionization chamber, differing by less than 1.6%. The experimental results confirmed that this SCDD-Pro is suitable for measurements with standard electrometers and that the depth-dose curve perturbation is negligible, with no energy dependence and no significant dose rate dependence.

Development of a synthetic single crystal diamond dosimeter for dose measurement of clinical proton beams.

PubMed

Moignier, Cyril; Tromson, Dominique; de Marzi, Ludovic; Marsolat, Fanny; García Hernández, Juan Carlos; Agelou, Mathieu; Pomorski, Michal; Woo, Romuald; Bourbotte, Jean-Michel; Moignau, Fabien; Lazaro, Delphine; Mazal, Alejandro

2017-07-07

The scope of this work was to develop a synthetic single crystal diamond dosimeter (SCDD-Pro) for accurate relative dose measurements of clinical proton beams in water. Monte Carlo simulations were carried out based on the MCNPX code in order to investigate and reduce the dose curve perturbation caused by the SCDD-Pro. In particular, various diamond thicknesses were simulated to evaluate the influence of the active volume thickness (e AV ) as well as the influence of the addition of a front silver resin (250 µm in thickness in front of the diamond crystal) on depth-dose curves. The simulations indicated that the diamond crystal alone, with a small e AV of just 5 µm, already affects the dose at Bragg peak position (Bragg peak dose) by more than 2% with respect to the Bragg peak dose deposited in water. The optimal design that resulted from the Monte Carlo simulations consists of a diamond crystal of 1 mm in width and 150 µm in thickness with the front silver resin, enclosed by a water-equivalent packaging. This design leads to a deviation between the Bragg peak dose from the full detector modeling and the Bragg peak dose deposited in water of less than 1.2%. Based on those optimizations, an SCDD-Pro prototype was built and evaluated in broad passive scattering proton beams. The experimental evaluation led to probed SCDD-Pro repeatability, dose rate dependence and linearity, that were better than 0.2%, 0.4% (in the 1.0-5.5 Gy min -1 range) and 0.4% (for dose higher than 0.05 Gy), respectively. The depth-dose curves in the 90-160 MeV energy range, measured with the SCDD-Pro without applying any correction, were in good agreement with those measured using a commercial IBA PPC05 plane-parallel ionization chamber, differing by less than 1.6%. The experimental results confirmed that this SCDD-Pro is suitable for measurements with standard electrometers and that the depth-dose curve perturbation is negligible, with no energy dependence and no significant dose rate dependence.

Ionizing radiation as preconditioning against transient cerebral ischemia in rats.

PubMed

Kokošová, Natália; Danielisová, Viera; Smajda, Beňadik; Burda, Jozef

2014-01-01

Induction of ischemic tolerance (IT), the ability of an organism to survive an otherwise lethal ischemia, is the most effective known approach to preventing postischemic damage. IT can be induced by exposing animals to a broad range of stimuli. In this study we tried to induce IT of brain neurons using ionizing radiation (IR). A preconditioning (pre-C) dose of 10, 20, 30 or 50 Gy of gamma rays was used 2 days before an 8 min ischemia in adult male rats. Ischemia alone caused the degeneration of almost one half of neurons in CA1 region of hippocampus. However, a significant decrease of the number of degenerating neurons was observed after higher doses of radiation (30 and 50 Gy). Moreover, ischemia significantly impaired the spatial memory of rats as tested in Morris's water maze. In rats with a 50 Gy pre-C dose, the latency times were reduced to values close to the control level. Our study is the first to reveal that IR applied in sufficient doses can induce IT and thus allow pyramidal CA1 neurons to survive ischemia. In addition, we show that the beneficial effect of IR pre-C is proportional to the radiation dose.

Monte Carlo dose calculations of beta-emitting sources for intravascular brachytherapy: a comparison between EGS4, EGSnrc, and MCNP.

PubMed

Wang, R; Li, X A

2001-02-01

The dose parameters for the beta-particle emitting 90Sr/90Y source for intravascular brachytherapy (IVBT) have been calculated by different investigators. At a distant distance from the source, noticeable differences are seen in these parameters calculated using different Monte Carlo codes. The purpose of this work is to quantify as well as to understand these differences. We have compared a series of calculations using an EGS4, an EGSnrc, and the MCNP Monte Carlo codes. Data calculated and compared include the depth dose curve for a broad parallel beam of electrons, and radial dose distributions for point electron sources (monoenergetic or polyenergetic) and for a real 90Sr/90Y source. For the 90Sr/90Y source, the doses at the reference position (2 mm radial distance) calculated by the three code agree within 2%. However, the differences between the dose calculated by the three codes can be over 20% in the radial distance range interested in IVBT. The difference increases with radial distance from source, and reaches 30% at the tail of dose curve. These differences may be partially attributed to the different multiple scattering theories and Monte Carlo models for electron transport adopted in these three codes. Doses calculated by the EGSnrc code are more accurate than those by the EGS4. The two calculations agree within 5% for radial distance <6 mm.

Further Characterization of the Mitigation of Radiation Lethality by Protective Wounding

PubMed Central

Dynlacht, Joseph R.; Garrett, Joy; Joel, Rebecca; Lane, Katharina; Mendonca, Marc S.; Orschell, Christie M.

2017-01-01

There continues to be a major effort in the United States to develop mitigators for the treatment of mass casualties that received high-intensity acute ionizing radiation exposures from the detonation of an improvised nuclear device during a radiological terrorist attack. The ideal countermeasure should be effective when administered after exposure, and over a wide range of absorbed doses. We have previously shown that the administration of a subcutaneous incision of a defined length, if administered within minutes after irradiation, protected young adult female C57BL/6 mice against radiation-induced lethality, and increased survival after total-body exposure to an LD50/30 X-ray dose from 50% to over 90%. We refer to this approach as “protective wounding”. In this article, we report on our efforts to further optimize, characterize and demonstrate the validity of the protective wounding response by comparing the response of female and male mice, varying the radiation dose, the size of the wound, and the timing of wounding with respect to administration of the radiation dose. Both male and female mice that received a subcutaneous incision after irradiation were significantly protected from radiation lethality. We observed that the extent of protection against lethality after an LD50/30 X-ray dose was independent of the size of the subcutaneous cut, and that a 3 mm subcutaneous incision is effective at enhancing the survival of mice exposed to a broad range of radiation doses (LD15–LD100). Over the range of 6.2–6.7 Gy, the increase in survival observed in mice that received an incision was associated with an enhanced recovery of hematopoiesis. The enhanced rate of recovery of hematopoiesis was preceded by an increase in the production of a select group of cytokines. Thus, a thorough knowledge of the timing of the cytokine cascade after wounding could aid in the development of novel pharmacological radiation countermeasures that can be administered several days after the actual radiation exposure. PMID:28437188

TTC-Pluronic 3D radiochromic gel dosimetry of ionizing radiation

NASA Astrophysics Data System (ADS)

Kozicki, Marek; Kwiatos, Klaudia; Kadlubowski, Slawomir; Dudek, Mariusz

2017-07-01

This work reports the first results obtained using a new 3D radiochromic gel dosimeter. The dosimeter is an aqueous physical gel matrix made of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127, PEO-PPO-PEO) doped with a representative of tetrazolium salts, 2, 3, 5-triphenyltetrazolium chloride (TTC). There were several reasons for the choice of Pluronic as a gel forming substrate: (i) the high degree of transparency and colourlessness; (ii) the possibility of gel dosimeter preparation at both high and low temperatures due to the phase behaviour of Pluronic; (iii) the broad temperature range over which the TTC-Pluronic dosimeter is stable; and (iv) the non-toxicity of Pluronic. A reason for the choice of TTC was its ionising radiation-induced transformation to water-insoluble formazan, which was assumed to impact beneficially on the spatial stability of the dose distribution. If irradiated, the TTC-Pluronic gels become red but transparent in the irradiated part, while the non-irradiated part remains crystal clear. The best obtained composition is characterised by  <4 Gy dose threshold, a dose sensitivity of 0.002 31 (Gy  ×  cm)-1, a large linear dose range of  >500 Gy and a dynamic dose response much greater than 500 Gy (7.5% TTC, 25% Pluronic F-127, 50 mmol dm-3 tetrakis). Temporal and spatial stability studies revealed that the TTC-Pluronic gels (7.5% TTC, 25% Pluronic F-127) were stable for more than one week. The addition of compounds boosting the gels’ dose performance caused deterioration of the gels’ temporal stability but did not impact the stability of the 3D dose distribution. The proposed method of preparation allows for the repeatable manufacture of the gels. There were no differences observed between gels irradiated fractionally and non-fractionally. The TTC-Pluronic dose response might be affected by the radiation source dose rate—this, however, requires further examination.

DISRUPTION OF CONDITIONED REWARD ASSOCIATION BY TYPICAL AND ATYPICAL ANTIPSYCHOTICS

PubMed Central

Danna, C.L.; Elmer, G.I.

2013-01-01

Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 μg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3–30 μg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia. PMID:20416333

Inhaled Corticosteroids in Lung Diseases

PubMed Central

Raissy, Hengameh H.; Kelly, H. William; Harkins, Michelle

2013-01-01

Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD. The available ICSs vary in their therapeutic index and potency. Although ICSs are used in all age groups, younger and smaller children may be at a greater risk for adverse systemic effects because they can receive higher mg/kg doses of ICSs compared with older children. Most of the benefit from ICSs occurs in the low to medium dose range. Minimal additional improvement is seen with higher doses, although some patients may benefit from higher doses. Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial. When used appropriately, ICSs have few adverse events at low to medium doses, but risk increases with high-dose ICSs. Although several new drugs are being developed and evaluated, it is unlikely that any of these new medications will replace ICSs as the preferred initial long-term controller therapy for asthma, but more effective initial controller therapy could be developed for COPD. PMID:23370915

Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

PubMed Central

Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

2012-01-01

BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

Meningococcal Serogroup B Bivalent rLP2086 Vaccine Elicits Broad and Robust Serum Bactericidal Responses in Healthy Adolescents

PubMed Central

Vesikari, Timo; Østergaard, Lars; Diez-Domingo, Javier; Wysocki, Jacek; Flodmark, Carl-Erik; Beeslaar, Johannes; Eiden, Joseph; Jiang, Qin; Jansen, Kathrin U.; Jones, Thomas R.; Harris, Shannon L.; O'Neill, Robert E.; York, Laura J.; Crowther, Graham; Perez, John L.

2016-01-01

Background Neisseria meningitidis serogroup B (MnB) is a leading cause of invasive meningococcal disease in adolescents and young adults. A recombinant factor H binding protein (fHBP) vaccine (Trumenba®; bivalent rLP2086) was recently approved in the United States in individuals aged 10–25 years. Immunogenicity and safety of 2- or 3-dose schedules of bivalent rLP2086 were assessed in adolescents. Methods Healthy adolescents (11 to <19 years) were randomized to 1 of 5 bivalent rLP2086 dosing regimens (0,1,6-month; 0,2,6-month; 0,2-month; 0,4-month; 0,6-month). Immunogenicity was assessed by serum bactericidal antibody assay using human complement (hSBA). Safety assessments included local and systemic reactions and adverse events. Results Bivalent rLP2086 was immunogenic when administered as 2 or 3 doses; the most robust hSBA responses occurred with 3 doses. The proportion of subjects with hSBA titers ≥1:8 after 3 doses ranged from 91.7% to 95.0%, 98.9% to 99.4%, 88.4% to 89.0%, and 86.1% to 88.5% for MnB test strains expressing vaccine­-heterologous fHBP variants A22, A56, B24, and B44, respectively. After 2 doses, responses ranged from 90.8% to 93.5%, 98.4% to 100%, 69.1% to 81.1%, and 70.1% to 77.5%. Geometric mean titers (GMTs) were highest among subjects receiving 3 doses and similar between the 2- and 3-dose regimens. After 2 doses, GMTs trended numerically higher among subjects with longer intervals between the first and second dose (6 months vs 2 and 4 months). Bivalent rLP2086 was well tolerated. Conclusions Bivalent rLP2086 was immunogenic and well tolerated when administered in 2 or 3 doses. Three doses yielded the most robust hSBA response rates against MnB strains expressing vaccine-heterologous subfamily B fHBPs. PMID:26407272

Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions.

PubMed

Antonovic, L; Brahme, A; Furusawa, Y; Toma-Dasu, I

2013-01-01

Light-ion radiation therapy against hypoxic tumors is highly curative due to reduced dependence on the presence of oxygen in the tumor at elevated linear energy transfer (LET) towards the Bragg peak. Clinical ion beams using spread-out Bragg peak (SOBP) are characterized by a wide spectrum of LET values. Accurate treatment optimization requires a method that can account for influence of the variation in response for a broad range of tumor hypoxia, absorbed doses and LETs. This paper presents a parameterization of the Repairable Conditionally-Repairable (RCR) cell survival model that can describe the survival of oxic and hypoxic cells over a wide range of LET values, and investigates the relationship between hypoxic radiation resistance and LET. The biological response model was tested by fitting cell survival data under oxic and anoxic conditions for V79 cells irradiated with LETs within the range of 30-500 keV/µm. The model provides good agreement with experimental cell survival data for the range of LET investigated, confirming the robustness of the parameterization method. This new version of the RCR model is suitable for describing the biological response of mixed populations of oxic and hypoxic cells and at the same time taking into account the distribution of doses and LETs in the incident beam and its variation with depth in tissue. The model offers a versatile tool for the selection of LET and dose required in the optimization of the therapeutic effect, without severely affecting normal tissue in realistic tumors presenting highly heterogeneous oxic and hypoxic regions.

CLARITY-BPA: Effects of chronic Bisphenol A exposure on the immune system: Part 1 - Quantification of the relative number and proportion of leukocyte populations in the spleen and thymus.

PubMed

Li, Jinpeng; Bach, Anthony; Crawford, Robert B; Phadnis-Moghe, Ashwini S; Chen, Weimin; D'Ingillo, Shawna; Kovalova, Natalia; Suarez-Martinez, Jose E; Zhou, Jiajun; Kaplan, Barbara L F; Kaminski, Norbert E

2018-03-01

Bisphenol A (BPA) is extensively used in manufacturing of a broad range of consumer products worldwide. Due to its widespread use, human exposure to BPA is virtually ubiquitous. Broad human exposure coupled with a large scientific literature describing estrogenic activity of BPA in animals has raised public health concerns. To comprehensively evaluate the health effects of BPA exposure, a chronic toxicity study using a wide-range of BPA doses (2.5-25000 μg/kg bw/day) was conducted jointly by the NTP, thirteen NIEHS-supported grantees, and the FDA, which is called the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA). As a participant in the CLARITY-BPA project, the objective of the current study was to evaluate the effects of chronic BPA exposure in Sprague-Dawley rats on the relative number and proportion of defined leukocyte populations in the spleen and the thymus. Toward this end, lymphoid tissues from a total of 641 rats were assayed after being continuously dosed with BPA or controls for up to one year. To comprehensively evaluate the effects of BPA on leukocyte compositions, extensive endpoints that cover major populations of leukocytes were assessed, including B cells, T cells, NK cells, granulocytes, monocytes, macrophages and dendritic cells. In total, of the 530 measurements in BPA-treated rats, 10 measurements were statistically different from vehicle controls and were mainly associated with either the macrophage or dendritic cell populations. Most, if not all, of these alterations were found to be transient with no persistent trend over the one-year time period. In addition, the observed BPA-associated alterations were mostly moderate in magnitude and not dose-dependent. Due to the aforementioned, it is unlikely that the observed BPA-mediated changes alone would adversely affect immune competence. Copyright © 2018 Elsevier B.V. All rights reserved.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

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

Peters, Diane E.; Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA; Hoover, Benjamin

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6more » syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor activity of protease-activated anthrax toxins were evaluated. • All anthrax toxin variants exhibited potent systemic anti-tumor activity in mice. • A dual MMP/uPA-activated anthrax toxin displayed a superior safety profile. • Clinical development of a dual MMP/uPA-activated anthrax toxin is feasible.« less

A broad scope knowledge based model for optimization of VMAT in esophageal cancer: validation and assessment of plan quality among different treatment centers.

PubMed

Fogliata, Antonella; Nicolini, Giorgia; Clivio, Alessandro; Vanetti, Eugenio; Laksar, Sarbani; Tozzi, Angelo; Scorsetti, Marta; Cozzi, Luca

2015-10-31

To evaluate the performance of a broad scope model-based optimisation process for volumetric modulated arc therapy applied to esophageal cancer. A set of 70 previously treated patients in two different institutions, were selected to train a model for the prediction of dose-volume constraints. The model was built with a broad-scope purpose, aiming to be effective for different dose prescriptions and tumour localisations. It was validated on three groups of patients from the same institution and from another clinic not providing patients for the training phase. Comparison of the automated plans was done against reference cases given by the clinically accepted plans. Quantitative improvements (statistically significant for the majority of the analysed dose-volume parameters) were observed between the benchmark and the test plans. Of 624 dose-volume objectives assessed for plan evaluation, in 21 cases (3.3 %) the reference plans failed to respect the constraints while the model-based plans succeeded. Only in 3 cases (<0.5 %) the reference plans passed the criteria while the model-based failed. In 5.3 % of the cases both groups of plans failed and in the remaining cases both passed the tests. Plans were optimised using a broad scope knowledge-based model to determine the dose-volume constraints. The results showed dosimetric improvements when compared to the benchmark data. Particularly the plans optimised for patients from the third centre, not participating to the training, resulted in superior quality. The data suggests that the new engine is reliable and could encourage its application to clinical practice.

Clinical development of BLZ-100 for real-time optical imaging of tumors during resection

NASA Astrophysics Data System (ADS)

Franklin, Heather L.; Miller, Dennis M.; Hedges, Teresa; Perry, Jeff; Parrish-Novak, Julia

2016-03-01

Complete initial resection can give cancer patients the best opportunity for long-term survival. There is unmet need in surgical oncology for optical imaging that enables simple and precise visualization of tumors and consistent contrast with surrounding normal tissues. Near-infrared (NIR) contrast agents and camera systems that can detect them represent an area of active research and development. The investigational Tumor Paint agent BLZ-100 is a conjugate of a chlorotoxin peptide and the NIR dye indocyanine green (ICG) that has been shown to specifically bind to a broad range of solid tumors. Clinical efficacy studies with BLZ-100 are in progress, a necessary step in bringing the product into clinical practice. To ensure a product that will be useful for and accepted by surgeons, the early clinical development of BLZ- 100 incorporates multiple tumor types and imaging devices so that surgeon feedback covers the range of anticipated clinical uses. Key contrast agent characteristics include safety, specificity, flexibility in timing between dose and surgery, and breadth of tumor types recognized. Imaging devices should use wavelengths that are optimal for the contrast agent, be sensitive enough that contrast agent dosing can be adjusted for optimal contrast, include real-time video display of fluorescence and white light image, and be simple for surgeons to use with minimal disruption of surgical flow. Rapid entry into clinical studies provides the best opportunity for early surgeon feedback, enabling development of agents and devices that will gain broad acceptance and provide information that helps surgeons achieve more complete and precise resections.

SU-E-T-308: Systematic Characterization of the Energy Response of Different LiF TLD Crystals for Dosimetry Applications

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

Pena, E; Caprile, P; Sanchez-Nieto, B

Purpose: The thermoluminiscense dosimeters (TLDs) are widely used in personal and clinical dosimetry due to its small size, good sensitivity and tissue equivalence, among other advantages. This study presents the characterization of Lithium Fluoride based TLDs, in terms of their absorbed dose response to successive irradiation cycles in a broad range of beam energies, measured under reference conditions. Methods: Four types of Harshaw TLD chips were used: TLD-100, TLD-600 TLD-700 and 100-H. They were irradiated with 10 photon beams of different energy spectrums, from 28 kVp to 18MV (in 30 consecutive cycles for 6 and 18 MV). Results: It wasmore » found that the response of the dosimetric system was stabilized (less than ±3%) after 10 cycles for TLD-600 and TLD-700. In the case of TLD-100 and TLD-100H this dependence was not observed. A decreased response to increasing beam energy in terms of absorbed dose to water was observed, as expected, except for TLD-100H which showed the opposite behavior. The less energy dependent detector was the TLD-100H exhibiting a maximum deviation of 12%. The highest variation observed was 33% for TLD-100. The study allowed the determination of calibration factors in absorbed dose for a wide range of energies and materials for different dosimetric applications, such as in-vivo dosimetry during imaging and radiotherapy. Conclusion: The study allowed the determination of calibration factors in absorbed dose for a wide range of energies and materials for different dosimetric applications, such as in-vivo dosimetry during imaging and radiotherapy.« less

Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

PubMed Central

Zhou, Jian; Ledesma, Kimberly R.; Chang, Kai-Tai; Abodakpi, Henrietta; Gao, Song

2017-01-01

ABSTRACT Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0–24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0–24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r2 = 0.81). The required AUCELF,0–24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted. PMID:28264853

Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model.

PubMed

Zhou, Jian; Ledesma, Kimberly R; Chang, Kai-Tai; Abodakpi, Henrietta; Gao, Song; Tam, Vincent H

2017-05-01

Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUC ELF,0-24 ]/area under the concentration time curve in serum from 0 to 24 h [AUC serum,0-24 ]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden ( r 2 = 0.81). The required AUC ELF,0-24 /MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted. Copyright © 2017 American Society for Microbiology.

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

PubMed Central

Phillips, Margaret A.; Lotharius, Julie; Marsh, Kennan; White, John; Dayan, Anthony; White, Karen L.; Njoroge, Jacqueline W.; El Mazouni, Farah; Lao, Yanbin; Kokkonda, Sreekanth; Tomchick, Diana R.; Deng, Xiaoyi; Laird, Trevor; Bhatia, Sangeeta N.; March, Sandra; Ng, Caroline L.; Fidock, David A.; Wittlin, Sergio; Lafuente-Monasterio, Maria; Benito, Francisco Javier Gamo; Alonso, Laura Maria Sanz; Martinez, Maria Santos; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Haselden, John N.; Louttit, James; Cui, Yi; Sridhar, Arun; Zeeman, Anna-Marie; Kocken, Clemens; Sauerwein, Robert; Dechering, Koen; Avery, Vicky M.; Duffy, Sandra; Delves, Michael; Sinden, Robert; Ruecker, Andrea; Wickham, Kristina S.; Rochford, Rosemary; Gahagen, Janet; Iyer, Lalitha; Riccio, Ed; Mirsalis, Jon; Bathhurst, Ian; Rueckle, Thomas; Ding, Xavier; Campo, Brice; Leroy, Didier; Rogers, M. John; Rathod, Pradipsinh K.; Burrows, Jeremy N.; Charman, Susan A.

2015-01-01

Malaria is one of the most significant causes of childhood mortality but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective towards DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200–400 mg. DSM265 was well tolerated in repeat dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood and liver-stage activity, and predicted long human half-life position DSM265 as a new potential drug combination partner for either single-dose treatment or once weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive on the parasite liver-stage PMID:26180101

Assessment of the point-source method for estimating dose rates to members of the public from exposure to patients with 131I thyroid treatment

DOE PAGES

Dewji, Shaheen Azim; Bellamy, Michael B.; Hertel, Nolan E.; ...

2015-09-01

The U.S. Nuclear Regulatory Commission (USNRC) initiated a contract with Oak Ridge National Laboratory (ORNL) to calculate radiation dose rates to members of the public that may result from exposure to patients recently administered iodine-131 ( 131I) as part of medical therapy. The main purpose was to compare dose rate estimates based on a point source and target with values derived from more realistic simulations that considered the time-dependent distribution of 131I in the patient and attenuation of emitted photons by the patient’s tissues. The external dose rate estimates were derived using Monte Carlo methods and two representations of themore » Phantom with Movable Arms and Legs, previously developed by ORNL and the USNRC, to model the patient and a nearby member of the public. Dose rates to tissues and effective dose rates were calculated for distances ranging from 10 to 300 cm between the phantoms and compared to estimates based on the point-source method, as well as to results of previous studies that estimated exposure from 131I patients. The point-source method overestimates dose rates to members of the public in very close proximity to an 131I patient but is a broadly accurate method of dose rate estimation at separation distances of 300 cm or more at times closer to administration.« less

Dose-response-a challenge for allelopathy?

PubMed

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

2005-04-01

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

Analysis of Dose at the Site of Second Tumor Formation After Radiotherapy to the Central Nervous System

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

Galloway, Thomas J.; University of Florida Proton Therapy Institute, Jacksonville, FL; Indelicato, Daniel J., E-mail: dindelicato@floridaproton.org

Purpose: Second tumors are an uncommon complication of multimodality treatment of childhood cancer. The present analysis attempted to correlate the dose received as a component of primary treatment and the site of the eventual development of a second tumor. Methods and Materials: We retrospectively identified 16 patients who had received radiotherapy to sites in the craniospinal axis and subsequently developed a second tumor. We compared the historical fields and port films of the primary treatment with the modern imaging of the second tumor locations. We classified the location of the second tumors as follows: in the boost field; marginal tomore » the boost field, but in a whole-brain field; in a whole-brain field; marginal to the whole brain/primary treatment field; and distant to the field. We divided the dose received into 3 broad categories: high dose (>45 Gy), moderate dose (20-36 Gy), and low dose (<20 Gy). Results: The most common location of the second tumor was in the whole brain field (57%) and in the moderate-dose range (81%). Conclusions: Our data contradict previous publications that suggested that most second tumors develop in tissues that receive a low radiation dose. Almost all the second tumors in our series occurred in tissue within a target volume in the cranium that had received a moderate dose (20-36 Gy). These findings suggest that a major decrease in the brain volume that receives a moderate radiation dose is the only way to substantially decrease the second tumor rate after central nervous system radiotherapy.« less

Out-of-field doses and neutron dose equivalents for electron beams from modern Varian and Elekta linear accelerators.

PubMed

Cardenas, Carlos E; Nitsch, Paige L; Kudchadker, Rajat J; Howell, Rebecca M; Kry, Stephen F

2016-07-08

Out-of-field doses from radiotherapy can cause harmful side effects or eventually lead to secondary cancers. Scattered doses outside the applicator field, neutron source strength values, and neutron dose equivalents have not been broadly investigated for high-energy electron beams. To better understand the extent of these exposures, we measured out-of-field dose characteristics of electron applicators for high-energy electron beams on two Varian 21iXs, a Varian TrueBeam, and an Elekta Versa HD operating at various energy levels. Out-of-field dose profiles and percent depth-dose curves were measured in a Wellhofer water phantom using a Farmer ion chamber. Neutron dose was assessed using a combination of moderator buckets and gold activation foils placed on the treatment couch at various locations in the patient plane on both the Varian 21iX and Elekta Versa HD linear accelerators. Our findings showed that out-of-field electron doses were highest for the highest electron energies. These doses typically decreased with increasing distance from the field edge but showed substantial increases over some distance ranges. The Elekta linear accelerator had higher electron out-of-field doses than the Varian units examined, and the Elekta dose profiles exhibited a second dose peak about 20 to 30 cm from central-axis, which was found to be higher than typical out-of-field doses from photon beams. Electron doses decreased sharply with depth before becoming nearly constant; the dose was found to decrease to a depth of approximately E(MeV)/4 in cm. With respect to neutron dosimetry, Q values and neutron dose equivalents increased with electron beam energy. Neutron contamination from electron beams was found to be much lower than that from photon beams. Even though the neutron dose equivalent for electron beams represented a small portion of neutron doses observed under photon beams, neutron doses from electron beams may need to be considered for special cases.

Considerations for Clinical Review of Cellular Therapy Products: Perspectives of the China Food and Drug Administration Center for Drug Evaluation.

PubMed

Liu, Yantong; Zhao, Chenyang; Gao, Liucun; Yang, Huan; He, Ruyi; Gao, Chenyan

2018-02-01

With increasing numbers of technical developments and clinical studies, pioneering cellular/gene therapies are now available that could cure life-threatening disease. Cellular/gene therapy products are broad-ranging and complicated, and thereby bring challenges for clinical review by regulatory agencies. This review discusses principles for the clinical review of cellular therapy products, including protection of clinical trial populations, pharmacodynamics, pharmacokinetics, dose evaluation, clinical efficacy, clinical safety, and risk-management plans. Based on these principles, key points in the clinical review of chimeric antigen receptor T-cell therapy are also discussed.

Use of real-time PCR to detect canine parvovirus in feces of free-ranging wolves.

PubMed

Mech, L David; Almberg, Emily S; Smith, Douglas; Goyal, Sagar; Singer, Randall S

2012-04-01

Using real-time PCR, we tested 15 wolf (Canis lupus) feces from the Superior National Forest (SNF), Minnesota, USA, and 191 from Yellowstone National Park (YNP), USA, collected during summer and 13 during winter for canine parvovirus (CPV)-2 DNA. We also tested 20 dog feces for CPV-2 DNA. The PCR assay was 100% sensitive and specific with a minimum detection threshold of 10(4) 50% tissue culture infective dose. Virus was detected in two winter specimens but none of the summer specimens. We suggest applying the technique more broadly especially with winter feces.

A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice.

PubMed

Martín, V; Pascual, E; Avia, M; Rangel, G; de Molina, A; Alejo, A; Sevilla, N

2016-01-06

Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Use of real-time PCR to detect canine parvovirus in feces of free-ranging wolves

USGS Publications Warehouse

Mech, L. David; Almberg, Emily S.; Smith, Douglas; Goyal, Sagar; Singer, Randall S.

2012-01-01

Using real-time PCR, we tested 15 wolf (Canis lupus) feces from the Superior National Forest (SNF), Minnesota, USA, and 191 from Yellowstone National Park (YNP), USA, collected during summer and 13 during winter for canine parvovirus (CPV)-2 DNA. We also tested 20 dog feces for CPV-2 DNA. The PCR assay was 100% sensitive and specific with a minimum detection threshold of 104 50% tissue culture infective dose. Virus was detected in two winter specimens but none of the summer specimens. We suggest applying the technique more broadly especially with winter feces.

Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial.

PubMed

Mayer, Kenneth H; Seaton, Kelly E; Huang, Yunda; Grunenberg, Nicole; Isaacs, Abby; Allen, Mary; Ledgerwood, Julie E; Frank, Ian; Sobieszczyk, Magdalena E; Baden, Lindsey R; Rodriguez, Benigno; Van Tieu, Hong; Tomaras, Georgia D; Deal, Aaron; Goodman, Derrick; Bailer, Robert T; Ferrari, Guido; Jensen, Ryan; Hural, John; Graham, Barney S; Mascola, John R; Corey, Lawrence; Montefiori, David C

2017-11-01

VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 μg/ml (95% CI: 1,033, 1,340) and 420 μg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 μg/ml (95% CI: 10, 27) and 6 μg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits. VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials. Clinical Trials Registration: NCT02165267.

Fundamental Design Principles for Transcription-Factor-Based Metabolite Biosensors.

PubMed

Mannan, Ahmad A; Liu, Di; Zhang, Fuzhong; Oyarzún, Diego A

2017-10-20

Metabolite biosensors are central to current efforts toward precision engineering of metabolism. Although most research has focused on building new biosensors, their tunability remains poorly understood and is fundamental for their broad applicability. Here we asked how genetic modifications shape the dose-response curve of biosensors based on metabolite-responsive transcription factors. Using the lac system in Escherichia coli as a model system, we built promoter libraries with variable operator sites that reveal interdependencies between biosensor dynamic range and response threshold. We developed a phenomenological theory to quantify such design constraints in biosensors with various architectures and tunable parameters. Our theory reveals a maximal achievable dynamic range and exposes tunable parameters for orthogonal control of dynamic range and response threshold. Our work sheds light on fundamental limits of synthetic biology designs and provides quantitative guidelines for biosensor design in applications such as dynamic pathway control, strain optimization, and real-time monitoring of metabolism.

SU-F-T-125: Radial Dose Distributions From Carbon Ions of Therapeutic Energies Calculated with Geant4-DNA

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

Vassiliev, O

Purpose: Radial dose distribution D(r) is the dose as a function of lateral distance from the path of a heavy charged particle. Its main application is in modelling of biological effects of heavy ions, including applications to hadron therapy. It is the main physical parameter of a broad group of radiobiological models known as the amorphous track models. Our purpose was to calculate D(r) with Monte Carlo for carbon ions of therapeutic energies, find a simple formula for D(r) and fit it to the Monte Carlo data. Methods: All calculations were performed with Geant4-DNA code, for carbon ion energies frommore » 10 to 400 MeV/u (ranges in water: ∼ 0.4 mm to 27 cm). The spatial resolution of dose distribution in the lateral direction was 1 nm. Electron tracking cut off energy was 11 eV (ionization threshold). The maximum lateral distance considered was 10 µm. Over this distance, D(r) decreases with distance by eight orders of magnitude. Results: All calculated radial dose distributions had a similar shape dominated by the well-known inverse square dependence on the distance. Deviations from the inverse square law were observed close to the beam path (r<10 nm) and at large distances (r >1 µm). At small and large distances D(r) decreased, respectively, slower and faster than the inverse square of distance. A formula for D(r) consistent with this behavior was found and fitted to the Monte Carlo data. The accuracy of the fit was better than 10% for all distances considered. Conclusion: We have generated a set of radial dose distributions for carbon ions that covers the entire range of therapeutic energies, for distances from the ion path of up to 10 µm. The latter distance is sufficient for most applications because dose beyond 10 µm is extremely low.« less

Enhancement of X-ray dose absorption for medical applications

NASA Astrophysics Data System (ADS)

Lim, Sara; Montenegro, Maximiliano; Nahar, Sultana; Pradhan, Anil; Barth, Rolf; Nakkula, Robin; Bell, Erica; Yu, Yan

2012-06-01

Interaction of high-Z (HZ) elements with X-rays occurs efficiently at specific resonant energies. Cross sections for photoionization rapidly decrease after the K-edge; higher energy X-rays are mostly Compton-scattered. These features restrict the energy range for the use of HZ moities for radiosensitization in cancer therapy. Conventional X-ray sources such as linear accelerators (LINAC) used in radiotherapy emit a broad spectrum up to MeV energies. We explore the dichotomy between X-ray radiotherapy in two ranges: (i) E < 100 keV including HZ sensitization, and (ii) E > 100 keV where sensitization is inefficient. We perform Monte Carlo numerical simulations of tumor tissue embedded with platinum compounds and gold nanoparticles and compute radiation dose enhancement factors (DEF) upon irradiation with 100 kV, 170 kV and 6 MV sources. Our results demonstrate that the DEF peak below 100 keV and fall sharply above 200 keV to very small values. Therefore most of the X-ray output from LINACs up to the MeV range is utilized very inefficiently. We also describe experimental studies for implementation of option (i) using Pt and Au reagents and selected cancer cell lines. Resultant radiation exposure to patients could be greatly reduced, yet still result in increased tumoricidal ability.

Development of a Non-Invasive Biomonitoring Approach to Determine Exposure to the Organophosphorus Insecticide Chlorpyrifos in Rat Saliva

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

Timchalk, Chuck; Campbell, James A.; Liu, Guodong

2007-03-01

Abstract Non-invasive biomonitoring approaches are being developed using reliable portable analytical systems to quantify dosimetry utilizing readily obtainable body fluids, such as saliva. In the current study, rats were given single oral gavage doses (1, 10 or 50 mg/kg) of the insecticide chlorpyrifos (CPF), saliva and blood were collected from groups of animals (4/time-point) at 3, 6, and 12 hr post-dosing, and the samples were analyzed for the CPF metabolite trichlorpyridinol (TCP). Trichlorpyridinol was detected in both blood and saliva at all doses and the TCP concentration in blood exceeded saliva, although the kinetics in blood and saliva were comparable.more » A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF incorporated a compartment model to describe the time-course of TCP in blood and saliva. The model adequately simulated the experimental results over the dose ranges evaluated. A rapid and sensitive sequential injection (SI) electrochemical immunoassay was developed to monitor TCP, and the reported detection limit for TCP in water was 6 ng/L. Computer model simulation in the range of the Allowable Daily Intake (ADI) or Reference Dose (RfD) for CPF (0.01-0.003 mg/kg/day) suggest that the electrochemical immunoassay had adequate sensitivity to detect and quantify TCP in saliva at these low exposure levels. To validate this approach further studies are needed to more fully understand the pharmacokinetics of CPF and TCP excretion in saliva. The utilization of saliva as a biomonitoring matrix, coupled to real-time quantitation and PBPK/PD modeling represents a novel approach with broad application for evaluating both occupational and environmental exposures to insecticides.« less

A microarray MEMS device for biolistic delivery of vaccine and drug powders.

PubMed

Pirmoradi, Fatemeh Nazly; Pattekar, Ashish V; Linn, Felicia; Recht, Michael I; Volkel, Armin R; Wang, Qian; Anderson, Greg B; Veiseh, Mandana; Kjono, Sandra; Peeters, Eric; Uhland, Scott A; Chow, Eugene M

2015-01-01

We report a biolistic technology platform for physical delivery of particle formulations of drugs or vaccines using parallel arrays of microchannels, which generate highly collimated jets of particles with high spatial resolution. Our approach allows for effective delivery of therapeutics sequentially or concurrently (in mixture) at a specified target location or treatment area. We show this new platform enables the delivery of a broad range of particles with various densities and sizes into both in vitro and ex vivo skin models. Penetration depths of ∼1 mm have been achieved following a single ejection of 200 µg high-density gold particles, as well as 13.6 µg low-density polystyrene-based particles into gelatin-based skin simulants at 70 psi inlet gas pressure. Ejection of multiple shots at one treatment site enabled deeper penetration of ∼3 mm in vitro, and delivery of a higher dose of 1 mg gold particles at similar inlet gas pressure. We demonstrate that particle penetration depths can be optimized in vitro by adjusting the inlet pressure of the carrier gas, and dosing is controlled by drug reservoirs that hold precise quantities of the payload, which can be ejected continuously or in pulses. Future investigations include comparison between continuous versus pulsatile payload deliveries. We have successfully delivered plasmid DNA (pDNA)-coated gold particles (1.15 µm diameter) into ex vivo murine and porcine skin at low inlet pressures of ∼30 psi. Integrity analysis of these pDNA-coated gold particles confirmed the preservation of full-length pDNA after each particle preparation and jetting procedures. This technology platform provides distinct capabilities to effectively deliver a broad range of particle formulations into skin with specially designed high-speed microarray ejector nozzles.

A microarray MEMS device for biolistic delivery of vaccine and drug powders

PubMed Central

Pirmoradi, Fatemeh Nazly; Pattekar, Ashish V; Linn, Felicia; Recht, Michael I; Volkel, Armin R; Wang, Qian; Anderson, Greg B; Veiseh, Mandana; Kjono, Sandra; Peeters, Eric; Uhland, Scott A; Chow, Eugene M

2015-01-01

We report a biolistic technology platform for physical delivery of particle formulations of drugs or vaccines using parallel arrays of microchannels, which generate highly collimated jets of particles with high spatial resolution. Our approach allows for effective delivery of therapeutics sequentially or concurrently (in mixture) at a specified target location or treatment area. We show this new platform enables the delivery of a broad range of particles with various densities and sizes into both in vitro and ex vivo skin models. Penetration depths of ∼1 mm have been achieved following a single ejection of 200 µg high-density gold particles, as well as 13.6 µg low-density polystyrene-based particles into gelatin-based skin simulants at 70 psi inlet gas pressure. Ejection of multiple shots at one treatment site enabled deeper penetration of ∼3 mm in vitro, and delivery of a higher dose of 1 mg gold particles at similar inlet gas pressure. We demonstrate that particle penetration depths can be optimized in vitro by adjusting the inlet pressure of the carrier gas, and dosing is controlled by drug reservoirs that hold precise quantities of the payload, which can be ejected continuously or in pulses. Future investigations include comparison between continuous versus pulsatile payload deliveries. We have successfully delivered plasmid DNA (pDNA)-coated gold particles (1.15 µm diameter) into ex vivo murine and porcine skin at low inlet pressures of ∼30 psi. Integrity analysis of these pDNA-coated gold particles confirmed the preservation of full-length pDNA after each particle preparation and jetting procedures. This technology platform provides distinct capabilities to effectively deliver a broad range of particle formulations into skin with specially designed high-speed microarray ejector nozzles. PMID:26090875

Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers

PubMed Central

Johnson, Matthew W.; Sewell, R. Andrew; Griffiths, Roland R.

2011-01-01

Background Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache. Methods This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30 mg/70 kg) on headache in 18 healthy participants. Results Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration. Conclusions Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research. PMID:22129843

Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers.

PubMed

Johnson, Matthew W; Sewell, R Andrew; Griffiths, Roland R

2012-06-01

Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache. This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30 mg/70 kg) on headache in 18 healthy participants. Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration. Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Laser-based irradiation apparatus and methods for monitoring the dose-rate response of semiconductor devices

DOEpatents

Horn, Kevin M [Albuquerque, NM

2006-03-28

A scanned, pulsed, focused laser irradiation apparatus can measure and image the photocurrent collection resulting from a dose-rate equivalent exposure to infrared laser light across an entire silicon die. Comparisons of dose-rate response images or time-delay images from before, during, and after accelerated aging of a device, or from periodic sampling of devices from fielded operational systems allows precise identification of those specific age-affected circuit structures within a device that merit further quantitative analysis with targeted materials or electrical testing techniques. Another embodiment of the invention comprises a broad-beam, dose rate-equivalent exposure apparatus. The broad-beam laser irradiation apparatus can determine if aging has affected the device's overall functionality. This embodiment can be combined with the synchronized introduction of external electrical transients into a device under test to simulate the electrical effects of the surrounding circuitry's response to a radiation exposure.

Overview of epidemiologic studies of radiation and cancer risk based on medical series

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

Howe, G.R.

1997-03-01

Epidemiologic studies of individuals exposed to ionizing radiation for medical reasons have made important contributions to understanding of the relationship between such radiation and subsequent cancer risk. In this paper the strengths and limitations of medical studies are considered and their future potential usefulness is discussed. Studies may be broadly classified into two types, namely, those of individuals exposed for therapeutic purposes such as the study of ankylosing spondylytics and those of individuals exposed for diagnostic or examination purposes such as those of tuberculosis patients routinely examined by chest fluoroscopy. In general, studies of therapeutic exposures tend to involve highmore » doses of radiation given at high dose rates and in a relatively small number of fractions, whereas studies of diagnostic exposures tend to involve relatively low doses, low dose rates and many fractions. However, these generalizations are not always true: for example, in the fluoroscopy studies some patients received doses to organs such as breast and lung which were substantially higher than those experienced in the atomic bomb survivors study and in a study of Israeli children treated with radiation for tinea capitis the average thyroid dose was reported to be low, and only about 0.09 gray. These studies illustrate one of the most important advantages of medical series, namely the variety of such studies in terms of the characteristics of the radiation involved (linear energy transfer characteristics, dose range, dose rate, and fractionation), the organs exposed and hence potentially at risk, and the characteristics of those exposed to such radiation.« less

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

Determining organ doses from computed tomography scanners using cadaveric subjects

NASA Astrophysics Data System (ADS)

Griglock, Thomas M.

The use of computed tomographic (CT) imaging has increased greatly since its inception in 1972. Technological advances have increased both the applicability of CT exams for common health problems as well as the radiation doses used to perform these exams. The increased radiation exposures have garnered much attention in the media and government agencies, and have brought about numerous attempts to quantify the amount of radiation received by patients. While the overwhelming majority of these attempts have focused on creating models of the human body (physical or computational), this research project sought to directly measure the radiation inside an actual human being. Three female cadaveric subjects of varying sizes were used to represent live patients. Optically-stimulated luminescent (OSL) dosimeters were used to measure the radiation doses. A dosimeter placement system was developed, tested, and optimized to allow accurate and reproducible placement of the dosimeters within the cadaveric subjects. A broad-beam, 320-slice, volumetric CT scanner was utilized to perform all CT exams, including five torso exams, four cardiac exams, and three organ perfusion exams. Organ doses ranged in magnitude from less than 1 to over 120 mGy, with the largest doses measured for perfusion imaging. A methodology has been developed that allows fast and accurate measurement of actual organ doses resulting from CT exams. The measurements made with this methodology represent the first time CT organ doses have been directly measured within a human body. These measurements are of great importance because they allow comparison to the doses measured using previous methods, and can be used to more accurately assess the risks from CT imaging.

[BIOLOGICAL EFFECTIVENESS OF FISSION SPECTRUM NEUTRONS AND PROTONS WITH ENERGIES OF 60-126 MEV DURING ACUTE AND PROLONGED IRRADIATION].

PubMed

Shafirkin, A V

2015-01-01

Neutrons of the fission spectrum are characterized by relatively high values of linear energy transfer (LET). Data about their effects on biological objects are used to evaluate the risk of delayed effects of accelerated ions within the same LET range that serve as an experimental model of the nuclei component of galactic cosmic rays (GCR). Additionally, risks of delayed consequences to cosmonaut's health and average lifetime from certain GCR fluxes and secondary neutrons can be also prognosticated. The article deals with comparative analysis of the literature on reduction of average lifespan (ALS) of animals exposed to neutron reactor spectrum, 60-126 MeV protons, and X- and γ-rays in a broad range of radiation intensity and duration. It was shown that a minimal lifespan reduction by 5% occurs due to a brief exposure to neutrons with the absorbed dose of 5 cGy, whereas same lifespan reduction due to hard X- and γ-radiation occurs after absorption of a minimal dose of 100 cGy. Therefore, according to the estimated minimal ALS reduction in mice, neutron effectiveness is 20-fold higher. Biological effectiveness of protons as regards ALS reduction is virtually equal to that of standard types of radiation. Exposure to X- and γ-radiation with decreasing daily doses, and increasing number of fractions and duration gives rise to an apparent trend toward a less dramatic ALS reduction in mice; on the contrary, exposure to neutrons of varying duration had no effect on threshold doses for the specified ALS reductions. Factors of relative biological effectiveness of neutrons reached 40.

Broadly protective anti-hemagglutinin stalk antibodies induced by live attenuated influenza vaccine expressing chimeric hemagglutinin.

PubMed

Isakova-Sivak, Irina; Korenkov, Daniil; Smolonogina, Tatiana; Kotomina, Tatiana; Donina, Svetlana; Matyushenko, Victoria; Mezhenskaya, Daria; Krammer, Florian; Rudenko, Larisa

2018-05-01

The development of influenza vaccines that can provide broad protection against all drifted seasonal virus variants, zoonotic infections and emerging pandemic strains, has been a priority for two decades. Here we propose a strategy of inducing broadly-reactive anti-stalk antibody by sequential immunizations with live attenuated influenza vaccines (LAIVs) expressing chimeric HAs (cHAs). These vaccines are designed to contain identical hemagglutinin stalk domains from H1N1 virus but antigenically unrelated globular head domains from avian influenza virus subtypes H5, H8 and H9. Mouse experiments demonstrated enhanced cross-protection of cHA-containing LAIVs compared to the relevant vaccine viruses expressing natural HAs, and this enhanced protection was driven by stalk-HA-reactive IgG antibodies. The establishment of fully functional cross-protective immunity after two doses of cHA LAIV vaccination in naïve animals suggests that a similar effect might be expected after a single cHA LAIV dose in primed individuals, or after two to three doses in naïve children. Copyright © 2018 Elsevier Inc. All rights reserved.

Genome-wide transcription responses to synchrotron microbeam radiotherapy.

PubMed

Sprung, Carl N; Yang, Yuqing; Forrester, Helen B; Li, Jason; Zaitseva, Marina; Cann, Leonie; Restall, Tina; Anderson, Robin L; Crosbie, Jeffrey C; Rogers, Peter A W

2012-10-01

The majority of cancer patients achieve benefit from radiotherapy. A significant limitation of radiotherapy is its relatively low therapeutic index, defined as the maximum radiation dose that causes acceptable normal tissue damage to the minimum dose required to achieve tumor control. Recently, a new radiotherapy modality using synchrotron-generated X-ray microbeam radiotherapy has been demonstrated in animal models to ablate tumors with concurrent sparing of normal tissue. Very little work has been undertaken into the cellular and molecular mechanisms that differentiate microbeam radiotherapy from broad beam. The purpose of this study was to investigate and compare the whole genome transcriptional response of in vivo microbeam radiotherapy versus broad beam irradiated tumors. We hypothesized that gene expression changes after microbeam radiotherapy are different from those seen after broad beam. We found that in EMT6.5 tumors at 4-48 h postirradiation, microbeam radiotherapy differentially regulates a number of genes, including major histocompatibility complex (MHC) class II antigen gene family members, and other immunity-related genes including Ciita, Ifng, Cxcl1, Cxcl9, Indo and Ubd when compared to broad beam. Our findings demonstrate molecular differences in the tumor response to microbeam versus broad beam irradiation and these differences provide insight into the underlying mechanisms of microbeam radiotherapy and broad beam.

Systemic photoprotection in solar urticaria with α-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-α-MSH.

PubMed

Haylett, A K; Nie, Z; Brownrigg, M; Taylor, R; Rhodes, L E

2011-02-01

Solar urticaria is a rare photosensitivity disorder demonstrating a range of action spectra, which can inflict a very large impact on life quality despite available treatments. Melanin broadly reduces skin penetration by ultraviolet-visible wavelengths, thus increased melanization may protect in solar urticaria. To examine quantitatively for impact of the potent α-melanocyte stimulating hormone analogue afamelanotide ([Nle(4)-D-Phe(7)]-α-MSH, Scenesse(®); Clinuvel Pharmaceuticals Ltd, Melbourne, Vic., Australia) on the solar urticaria response and skin melanization. Five patients with solar urticaria received a single dose of 16 mg subcutaneous afamelanotide implant in winter time. Melanin density was assessed spectrophotometrically from day 0 to day 60. Detailed monochromated light testing to geometric dose series (increment ) of wavelengths 300-600 nm was performed at 0, 30 and 60 days, with assessment of weal and flare area and minimum urticarial dose (MUD). Data were analysed by repeated-measures anova. Mean melanin density increased by day 7, peaked at day 15 and remained elevated at day 60 (P=0·03, 0·01, 0·02 vs. baseline, respectively). Baseline phototesting revealed action spectra of 320-400 (n=1), 320-500 (n=2), 300-600 (n=1) and 370-500 nm (n=1), and on afamelanotide mean rises in MUD of 1-12 and 1-3 dose increments were seen at the individual wavelengths tested, at 30 and 60 days, respectively. A significant fall in weal area occurred across responding wavelengths from 300 to 600 nm at 60 days postimplant (P=0·049 vs. baseline), accompanied by greater than twofold overall increase in MUD (P=0·058 vs. baseline). Melanization following afamelanotide is accompanied by reduction in solar urticaria response across a broad spectrum of wavelengths. Further study is warranted to assess clinical benefit under ambient conditions in summer. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

Luminescence studies of rare earth doped yttrium gadolinium mixed oxide phosphor

NASA Astrophysics Data System (ADS)

Som, S.; Choubey, A.; Sharma, S. K.

2012-09-01

This paper reports the photoluminescence and thermoluminescence properties of gamma ray induced rare earth doped yttrium gadolinium mixed oxide phosphor. The europium (Eu3+) was used as rare earth dopant. The phosphor was prepared by chemical co-precipitation method according to the formula (Y2-x-yGdx) O3: Euy3+ (x=0.5; y=0.05). The photoluminescence emission spectrum of the prepared phosphor shows intense peaks in the red region at 615 nm for 5D0→7F2 transitions and the photoluminescence excitation spectra show a broad band located around 220-270 nm for the emission wavelength fixed at 615 nm. The thermoluminescence studies were carried out after irradiating the phosphor by gamma rays in the dose range from 100 Gy to 1 KGy. In the thermoluminescence glow curves, one single peak was observed at about 300 °C of which the intensity increases linearly in the studied dose range of gamma rays. The glow peak was deconvoluted by GlowFit program and the kinetic parameters associated with the deconvoluted peaks were calculated. The kinetic parameters were also calculated by various glow curve shape and heating rate methods.

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

PubMed Central

Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe

2017-01-01

ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.) PMID:28784673

A versatile indirect detector design for hard X-ray microimaging

NASA Astrophysics Data System (ADS)

Douissard, P.-A.; Cecilia, A.; Rochet, X.; Chapel, X.; Martin, T.; van de Kamp, T.; Helfen, L.; Baumbach, T.; Luquot, L.; Xiao, X.; Meinhardt, J.; Rack, A.

2012-09-01

Indirect X-ray detectors are of outstanding importance for high resolution imaging, especially at synchrotron light sources: while consisting mostly of components which are widely commercially available, they allow for a broad range of applications in terms of the X-ray energy employed, radiation dose to the detector, data acquisition rate and spatial resolving power. Frequently, an indirect detector consists of a thin-film single crystal scintillator and a high-resolution visible light microscope as well as a camera. In this article, a novel modular-based indirect design is introduced, which offers several advantages: it can be adapted for different cameras, i.e. different sensor sizes, and can be trimmed to work either with (quasi-)monochromatic illumination and the correspondingly lower absorbed dose or with intense white beam irradiation. In addition, it allows for a motorized quick exchange between different magnifications / spatial resolutions. Developed within the European project SCINTAX, it is now commercially available. The characteristics of the detector in its different configurations (i.e. for low dose or for high dose irradiation) as measured within the SCINTAX project will be outlined. Together with selected applications from materials research, non-destructive evaluation and life sciences they underline the potential of this design to make high resolution X-ray imaging widely available.

Carbendazim-induced haematological, biochemical and histopathological changes to the liver and kidney of male rats.

PubMed

Selmanoglu, G; Barlas, N; Songür, S; Koçkaya, E A

2001-12-01

Carbendazim is a systemic broad-spectrum fungicide controlling a wide range of pathogens. It is also used as a preservative in paint, textile, papermaking and leather industry, as well as a preservative of fruits. In the present study, carbendazim was administered at 0, 150, 300 and 600 mg/kg per day doses orally to male rats (Rattus rattus) for 15 weeks. At the end of the experiment, blood samples, liver and kidney tissues of each animal were taken. Serum enzyme activities, and haematological and biochemical parameters were analysed. In toxicological tests, 600 mg/kg per day doses of carbendazim caused an increase of albumin, glucose, creatinine and cholesterol levels. Also, at the same doses, white blood cell and lymphocyte counts decreased. However, mean cell hemoglobin and mean cell hemoglobin concentrations increased. Histopathological examinations revealed congestion, an enlargement of the sinusoids, an increase in the number of Kupffer cells, mononuclear cell infiltration and hydropic degeneration in the liver. At the highest doses, congestion, mononuclear cell infiltration, tubular degeneration and fibrosis were observed in the kidney tissue. These results indicate that 300 and 600 mg/kg per day carbendazim affected the liver and kidney tissue and caused some changes on haematological and biochemical parameters of rats.

Evaluation of the immunogenicity and safety of different doses and formulations of a broad spectrum influenza vaccine (FLU-v) developed by SEEK: study protocol for a single-center, randomized, double-blind and placebo-controlled clinical phase IIb trial.

PubMed

van Doorn, Eva; Pleguezuelos, Olga; Liu, Heng; Fernandez, Ana; Bannister, Robin; Stoloff, Gregory; Oftung, Fredrik; Norley, Stephen; Huckriede, Anke; Frijlink, Henderik W; Hak, Eelko

2017-04-04

Current influenza vaccines, based on antibodies against surface antigens, are unable to provide protection against newly emerging virus strains which differ from the vaccine strains. Therefore the population has to be re-vaccinated annually. It is thus important to develop vaccines which induce protective immunity to a broad spectrum of influenza viruses. This trial is designed to evaluate the immunogenicity and safety of FLU-v, a vaccine composed of four synthetic peptides with conserved epitopes from influenza A and B strains expected to elicit both cell mediated immunity (CMI) and humoral immunity providing protection against a broad spectrum of influenza viruses. In a single-center, randomized, double-blind and placebo-controlled phase IIb trial, 222 healthy volunteers aged 18-60 years will be randomized (2:2:1:1) to receive two injections of a suspension of 500 μg FLU-v in saline (arm 1), one dose of emulsified 500 μg FLU-v in Montanide ISA-51 and water for injection (WFI) followed by one saline dose (arm 2), two saline doses (arm 3), or one dose of Montanide ISA-51 and WFI emulsion followed by one saline dose (arm 4). All injections will be given subcutaneously. Primary endpoints are safety and FLU-v induced CMI, evaluated by cytokine production by antigen specific T cell populations (flow-cytometry and ELISA). Secondary outcomes are measurements of antibody responses (ELISA and multiplex), whereas exploratory outcomes include clinical efficacy and additional CMI assays (ELISpot) to show cross-reactivity. Broadly protective influenza vaccines able to provide protection against multiple strains of influenza are urgently needed. FLU-v is a promising vaccine which has shown to trigger the cell-mediated immune response. The dosages and formulations tested in this current trial are also estimated to induce antibody response. Therefore, both cellular and humoral immune responses will be evaluated. EudraCT number 2015-001932-38 ; retrospectively registered clinicaltrials.gov NCT02962908 (November 7th 2016).

Evaluation of DNA extraction methods and their clinical application for direct detection of causative bacteria in continuous ambulatory peritoneal dialysis culture fluids from patients with peritonitis by using broad-range PCR.

PubMed

Kim, Si Hyun; Jeong, Haeng Soon; Kim, Yeong Hoon; Song, Sae Am; Lee, Ja Young; Oh, Seung Hwan; Kim, Hye Ran; Lee, Jeong Nyeo; Kho, Weon-Gyu; Shin, Jeong Hwan

2012-03-01

The aims of this study were to compare several DNA extraction methods and 16S rDNA primers and to evaluate the clinical utility of broad-range PCR in continuous ambulatory peritoneal dialysis (CAPD) culture fluids. Six type strains were used as model organisms in dilutions from 10(8) to 10(0) colony-forming units (CFU)/mL for the evaluation of 5 DNA extraction methods and 5 PCR primer pairs. Broad-range PCR was applied to 100 CAPD culture fluids, and the results were compared with conventional culture results. There were some differences between the various DNA extraction methods and primer sets with regard to the detection limits. The InstaGene Matrix (Bio-Rad Laboratories, USA) and Exgene Clinic SV kits (GeneAll Biotechnology Co. Ltd, Korea) seem to have higher sensitivities than the others. The results of broad-range PCR were concordant with the results from culture in 97% of all cases (97/100). Two culture-positive cases that were broad-range PCR-negative were identified as Candida albicans, and 1 PCR-positive but culture-negative sample was identified as Bacillus circulans by sequencing. Two samples among 54 broad-range PCR-positive products could not be sequenced. There were differences in the analytical sensitivity of various DNA extraction methods and primers for broad-range PCR. The broad-range PCR assay can be used to detect bacterial pathogens in CAPD culture fluid as a supplement to culture methods.

Comparison of Effects Produced by Nicotine and the α4β2-Selective Agonist 5-I-A-85380 On Intracranial Self-Stimulation in Rats

PubMed Central

Freitas, Kelen; Carroll, F. Ivy; Negus, S. Stevens

2015-01-01

Intracranial self-stimulation (ICSS) is one type of preclinical procedure for research on pharmacological mechanisms that mediate abuse potential of drugs acting at various targets including nicotinic acetylcholine receptors (nAChRs). This study compared effects of the non-selective nAChR agonist nicotine (0.032-1.0 mg/kg) and the α4β2-selective nAChR agonist 5-I-A-85380 (0.01-1.0 mg/kg) on ICSS in male Sprague-Dawley rats. Rats were implanted with electrodes targeting the medial forebrain bundle at the level of the lateral hypothalamus and trained to respond under a fixed-ratio 1 schedule for a range of brain stimulation frequencies (158-56 Hz). A broad range of 5-I-A-85380 doses produced an abuse-related increase (or “facilitation”) of low ICSS rates maintained by low brain-stimulation frequencies, and this effect was blocked by both the nonselective nAChR antagonist mecamylamine and the selective α4β2 antagonist dihyrdo-ß-erythroidine (DHßE). Conversely, nicotine produced weaker ICSS facilitation across a narrower range of doses, and higher nicotine doses decreased high rates of ICSS maintained by high brain- stimulation frequencies. The rate-decreasing effects of a high nicotine dose were blocked by mecamylamine but not DHßE. Chronic nicotine treatment produced selective tolerance to rate-decreasing effects of nicotine but did not alter ICSS rate-increasing effects of nicotine. These results suggest that α4β2 receptors are sufficient to mediate abuse-related rate-increasing effects of nAChR agonists in this ICSS procedure. Conversely, nicotine effects at non-α4β2 nAChRs appear to oppose and limit abuse-related effects mediated by α4β2 receptors, although tolerance can develop to these non-α4β2 effects. Selective α4β2 agonists may have higher abuse potential than nicotine. PMID:26461167

In Vivo Pharmacodynamic Target Assessment of Eravacycline against Escherichia coli in a Murine Thigh Infection Model.

PubMed

Zhao, Miao; Lepak, Alexander J; Marchillo, Karen; VanHecker, Jamie; Andes, David R

2017-07-01

Eravacycline is a novel fluorocycline antibiotic with potent activity against a broad range of pathogens, including strains with tetracycline and other drug resistance phenotypes. The goal of the studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli isolates were utilized for the studies. MICs were determined using CLSI methods and ranged from 0.125 to 0.25 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after administration of 2.5, 5, 10, 20, 40, and 80 mg/kg of body weight. Pharmacokinetic studies exhibited maximum plasma concentration ( C max ) values of 0.34 to 2.58 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC 0-∞ ) values of 2.44 to 57.6 mg · h/liter, and elimination half-lives of 3.9 to 17.6 h. Dose fractionation studies were performed using total drug doses of 6.25 mg/kg to 100 mg/kg fractionated into 6-, 8-, 12-, or 24-h regimens. Nonlinear regression analysis demonstrated that the 24-h free drug AUC/MIC ( f AUC/MIC) was the PK/PD parameter that best correlated with efficacy ( R 2 = 0.80). In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of eravacycline varied among pathogens. Mice were treated with 2-fold increasing doses (range, 3.125 to 50 mg/kg) of eravacycline every 12 h. The mean f AUC/MIC magnitudes associated with the net stasis and the 1-log-kill endpoints were 27.97 ± 8.29 and 32.60 ± 10.85, respectively. Copyright © 2017 American Society for Microbiology.

78 FR 23826 - Information Collection Activities (Complaints, Petitions for Declaratory Orders, and Petitions...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-22

.... Under these statutory and regulatory sections, the Board provides procedures for persons to make a broad range of claims and to seek a broad range of remedies before the Board. The information collections... terminate a controversy or remove uncertainty. Because petitions for a declaratory order cover a broad range...

Broad-range PCR: past, present, or future of bacteriology?

PubMed

Renvoisé, A; Brossier, F; Sougakoff, W; Jarlier, V; Aubry, A

2013-08-01

PCR targeting the gene encoding 16S ribosomal RNA (commonly named broad-range PCR or 16S PCR) has been used for 20 years as a polyvalent tool to study prokaryotes. Broad-range PCR was first used as a taxonomic tool, then in clinical microbiology. We will describe the use of broad-range PCR in clinical microbiology. The first application was identification of bacterial strains obtained by culture but whose phenotypic or proteomic identification remained difficult or impossible. This changed bacterial taxonomy and allowed discovering many new species. The second application of broad-range PCR in clinical microbiology is the detection of bacterial DNA from clinical samples; we will review the clinical settings in which the technique proved useful (such as endocarditis) and those in which it did not (such as characterization of bacteria in ascites, in cirrhotic patients). This technique allowed identifying the etiological agents for several diseases, such as Whipple disease. This review is a synthesis of data concerning the applications, assets, and drawbacks of broad-range PCR in clinical microbiology. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Radiation dose and second cancer risk in patients treated for cancer of the cervix

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

Boice, J.D. Jr.; Engholm, G.; Kleinerman, R.A.

1988-10-01

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder (relative risk (RR) = 4.0),more » rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors.« less

Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

PubMed Central

2010-01-01

Background YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies. Methods This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death. Results Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks. Conclusions The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. Trial registration ClinicalTrials.gov unique identifier: NCT00633490 PMID:20923544

A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew).

PubMed

Kwiatkowska, Magdalena; Parker, Linda A; Burton, Page; Mechoulam, Raphael

2004-07-01

The 5-HT3 antagonist, ondansetron (OND), and the cannabinoid, delta9-tetrahydrocannabinol (delta9-THC), have been shown to interfere with emesis; however, their relative and/or combined effectiveness in suppressing vomiting produced by the chemotherapeutic agent, cisplatin, is unknown. To evaluate the potential of: 1) a broad range of doses of delta9-THC and OND to prevent cisplatin-induced vomiting and retching in the Suncus murinus (house musk shrew), 2) combined treatment with ineffective individual doses of delta9-THC and OND to prevent cisplatin-induced vomiting and retching, 3) the CB1 receptor antagonist, SR141716, to reverse the antiemetic effects of OND, and 4) cannabidiol (CBD), the principal non-psychoactive component of marijuana, to reverse cisplatin-induced vomiting in the shrew. Shrews were injected with various doses of OND (0.02-6.0 mg/kg), delta9-THC (1.25-10 mg/kg) and a combination of ineffective doses of each (0.02 mg/kg OND+1.25 mg/kg delta9-THC) prior to being injected with cisplatin (20 mg/kg) which induces vomiting. Shrews were also injected with CBD (5 mg/kg and 40 mg/kg) prior to an injection of cisplatin. OND and delta9-THC both dose-dependently suppressed cisplatin-induced vomiting and retching. Furthermore, a combined pretreatment of doses of the two drugs that were ineffective alone completely suppressed vomiting and retching. CBD produced a biphasic effect, suppressing vomiting at 5 mg/kg and potentiating it at 40 mg/kg. A low dose of the non-intoxicating cannabinoid CBD may be an effective anti-emetic treatment and combined doses of OND and delta9-THC that are ineffective alone suppresses cisplatin-induced emetic reactions in shrews.

A population pharmacokinetic modeling approach shows that serum penicillin G concentrations are below inhibitory concentrations by two weeks after benzathine penicillin G injection in the majority of young adults.

PubMed

Neely, Michael; Kaplan, Edward L; Blumer, Jeffrey L; Faix, Dennis J; Broderick, Michael P

2014-11-01

Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

PubMed Central

Kaplan, Edward L.; Blumer, Jeffrey L.; Faix, Dennis J.; Broderick, Michael P.

2014-01-01

Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks. PMID:25182635

TU-F-CAMPUS-T-04: An Evaluation of Out-Of-Field Doses for Electron Beams From Modern Varian and Elekta Linear Accelerators

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

Cardenas, C; Nitsch, P; Kudchadker, R

2015-06-15

Purpose: Accurately determining out-of-field doses when using electron beam radiotherapy is of importance when treating pregnant patients or patients with implanted electronic devices. Scattered doses outside of the applicator field in electron beams have not been broadly investigated, especially since manufacturers have taken different approaches in applicator designs. Methods: In this study, doses outside of the applicator field were measured for electron beams produced by a 10×10 applicator on two Varian 21iXs operating at 6, 9, 12, 16, and 20 MeV, a Varian TrueBeam operating at 6, 9, 12, 16, and 20 MeV, and an Elekta Versa HD operating atmore » 6, 9, 12 and 15 MeV. Peripheral dose profiles and percent depth doses were measured in a Wellhofer water phantom at 100 cm SSD with a Farmer ion chamber. Doses were compared to peripheral photon doses from AAPM’s Task Group #36 report. Results: Doses were highest for the highest electron energies. Doses typically decreased with increasing distance from the field edge but showed substantial increases over some distance ranges. Substantial dose differences were observed between different accelerators; the Elekta accelerator had much higher doses than any Varian unit examined. Surprisingly, doses were often similar to, and could be much higher than, doses from photon therapy. Doses decreased sharply with depth before becoming nearly constant; the dose was found to decrease to a depth of approximately E(MeV)/4 in cm. Conclusion: The results of this study indicate that proper shielding may be very important when utilizing electron beams, particularly on a Versa HD, while treating pregnant patients or those with implanted electronic devices. Applying a water equivalent bolus of Emax(MeV)/4 thickness (cm) on the patient would reduce fetal dose drastically for all clinical energies and is a practical solution to manage the potentially high peripheral doses seen from modern electron beams. Funding from NIH Grant number: #CA180803.« less

Cumulative clinical trial data on atorvastatin for reducing cardiovascular events: the clinical impact of atorvastatin.

PubMed

Bybee, Kevin A; Lee, John H; O'Keefe, James H

2008-04-01

Since the 1990s a multitude of statin trials have definitively demonstrated the ability of statin therapy to reduce the risk of adverse coronary heart disease (CHD) events. Among these, the Atorvastatin Landmarks program - a group of 32 major atorvastatin trials - has assessed the efficacy and safety of atorvastatin across its full dose range and has helped illustrate its effectiveness in treatment of cardiovascular disease and its related disorders and also in non-cardiovascular outcomes. This paper will review the major atorvastatin clinical trials and report the important findings and their clinical significance. Clinical trials with atorvastatin have established significant reductions in cardiovascular events in patients with and without CHD. Studies show that high-dose atorvastatin will reduce LDL to approximately 70 mg/dL in many patients and improve cardiac outcomes. Current evidence suggests that high-dose atorvastatin can halt and, in some cases, reverse atherosclerotic progression. A study of diabetic patients showed atorvastatin decreased the occurrence of acute CHD events, coronary revascularizations, and stroke. Atorvastatin has been found to be effective for reducing nonfatal myocardial infarctions and fatal CHD in hypertensive patients with three or more additional risk factors. High-dose atorvastatin was found to be effective in reducing risk of recurrent stroke in patients with prior cerebrovascular events, has been shown to benefit patients suffering a recent acute coronary syndrome, and to slow cognitive decline in preliminary studies of patients with Alzheimer's disease. Atorvastatin has been associated with reduced progression of mild chronic kidney disease; however, in a randomized trial of patients with end stage renal disease on hemodialysis, atorvastatin showed no statistically significant benefit. Limitations of this review include lack of generalizability of the atorvastatin trial data to other statins, lack of head to head outcome trials involving the newer more potent statins, and the relatively short study durations (none exceeded 5 years) when atherosclerosis is typically a decades-long disease. A compelling body of evidence documents that atorvastatin reduces major cardiovascular events in both secondary and primary prevention of CHD and in a broad range of patients and disease conditions. Furthermore, throughout its dose range, atorvastatin is safe and well tolerated.

Effect of gamma irradiation on antinutritional factors in broad bean

NASA Astrophysics Data System (ADS)

Al-Kaisey, Mahdi T.; Alwan, Abdul-Kader H.; Mohammad, Manal H.; Saeed, Amjed H.

2003-06-01

The effect of gamma irradiation on the level of antinutritional factors (trypsin inhibitor (TI), phytic acid and oligosaccharides) of broad bean was investigated. The seeds were subjected to gamma irradiation at 0, 2.5, 5, 7.5 and 10 kGy, respectively using cobalt-60 gamma radiation with a dose rate 2.37 kGy/h. TI activity was reduced by 4.5%, 6.7%, 8.5% and 9.2% at 2.5, 5, 7.5 and 10 kGy, respectively. Meanwhile, irradiation at 10.2, 12.3, 15.4 and 18.2 kGy reduced the phytic acid content. The flatulence causing oligosaccharides were decreased as the radiation dose increased. The chemical composition (protein, oil, ash and total carbohydrates) of the tested seeds was determined. Gamma radiation seems to be a good procedure to improve the quality of broad bean from the nutritional point of view.

MONTE CARLO STUDY OF THE CARDIAC ABSORBED DOSE DURING X-RAY EXAMINATION OF AN ADULT PATIENT.

PubMed

Kadri, O; Manai, K; Alfuraih, A

2016-12-01

The computational voxel phantom 'High-Definition Reference Korean-Man (HDRK-Man)' was implemented into the Monte Carlo transport toolkit Geant4. The voxel model, adjusted to the Reference Korean Man, is 171 cm in height and 68 kg in weight and composed of ∼30 million voxels whose size is 1.981 × 1.981 × 2.0854 mm 3 The Geant4 code is then utilised to compute the dose conversion coefficients (DCCs) expressed in absorbed dose per air kerma free in air for >30 tissues and organs, including almost all organs required in the new recommendation of the ICRP 103, due to a broad parallel beam of monoenergetic photons impinging in antero-postero direction with energy ranging from 10 to 150 keV. The computed DCCs of different organs are found to be in good agreement with data published using other simulation codes. Also, the influence of patient size on DCC values was investigated for a representative body size of the adult Korean patient population. The study was performed using five different sizes covering the range of 0.8-1.2 magnification order of the original HDRK-Man. It focussed on the computation of DCC for the human heart. Moreover, the provided DCCs were used to present an analytical parameterisation for the calculation of the cardiac absorbed dose for any arbitrary X-ray spectrum and for those patient sizes. Thus, the present work can be considered as an enhancement of the continuous studies performed by medical physicist as part of quality control tests and radiation protection dosimetry. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A neonicotinoid impairs olfactory learning in Asian honey bees (Apis cerana) exposed as larvae or as adults

PubMed Central

Tan, Ken; Chen, Weiwen; Dong, Shihao; Liu, Xiwen; Wang, Yuchong; Nieh, James C.

2015-01-01

Xenobiotics such as the neonicotinoid pesticide, imidacloprid, are used globally, but their effects on native bee species are poorly understood. We studied the effects of sublethal doses of imidacloprid on olfactory learning in the native honey bee species, Apis cerana, an important pollinator of agricultural and native plants throughout Asia. We provide the first evidence that imidacloprid can impair learning in A. cerana workers exposed as adults or as larvae. Adults that ingested a single imidacloprid dose as low as 0.1 ng/bee had significantly reduced olfactory learning acquisition, which was 1.6-fold higher in control bees. Longer-term learning (1-17 h after the last learning trial) was also impaired. Bees exposed as larvae to a total dose of 0.24 ng/bee did not have reduced survival to adulthood. However, these larval-treated bees had significantly impaired olfactory learning when tested as adults: control bees exhibited up to 4.8-fold better short-term learning acquisition, though longer-term learning was not affected. Thus, sublethal cognitive deficits elicited by neonicotinoids on a broad range of native bee species deserve further study. PMID:26086769

EPR and photoluminescence study of irradiated anion-defective alumina single crystals

NASA Astrophysics Data System (ADS)

Kortov, V. S.; Ananchenko, D. V.; Konev, S. F.; Pustovarov, V. A.

2017-09-01

Electron paramagnetic resonance (EPR) and photoluminescence (PL) spectra of anion-defective alumina single crystals were measured. Exposure to a dose 10 Gy-1 kGy causes isotropic EPR signal of a complex form, this signal contains narrow and broad components. At the same time, in the PL spectrum alongside with a band of F+-centers (3.8 eV) an additional emission band with the maximum of 2.25 eV is registered. This band corresponds to aggregate F22+-centers which were create under irradiation. By comparing measurements in EPR and PL spectra with further stepped annealing in the temperature range of 773-1473 K of the samples exposed to the same doses, we were able to conclude that a narrow component of isotropic EPR signal is associated with the formation of paramagnetic F22+-centers under irradiation. A wide component can be caused by deep hole traps which are created by a complex defect (VAl2- - F+) with a localized hole.

Long-term Radiation-Related Health Effects in a Unique Human Population: Lessons Learned from the Atomic Bomb Survivors of Hiroshima and Nagasaki

PubMed Central

Douple, Evan B.; Mabuchi, Kiyohiko; Cullings, Harry M.; Preston, Dale L.; Kodama, Kazunori; Shimizu, Yukiko; Fujiwara, Saeko; Shore, Roy E.

2014-01-01

For 63 years scientists in the Atomic Bomb Casualty Commission and its successor, the Radiation Effects Research Foundation, have been assessing the long-term health effects in the survivors of the atomic bombings of Hiroshima and Nagasaki and in their children. The identification and follow-up of a large population (approximately a total of 200 000, of whom more than 40% are alive today) that includes a broad range of ages and radiation exposure doses, and healthy representatives of both sexes; establishment of well-defined cohorts whose members have been studied longitudinally, including some with biennial health examinations and a high survivor participation rate; and careful reconstructions of individual radiation doses have resulted in reliable excess relative risk estimates for radiation-related health effects, including cancer and noncancer effects in humans, for the benefit of the survivors and for all humankind. This article reviews those risk estimates and summarizes what has been learned from this historic and unique study. PMID:21402804

Correct titration of non-drugs and some other methodological issues.

PubMed

Beneke, M; Rasmus, W; Rød, I S; Fritze, J

1994-01-01

Doctors' prescription and dosing behaviour was investigated using data from 9 clinical trials in 550 patients treated with psychotropics. 7 trials were conducted under double- and 2 under single-blind conditions. In 3 of these trials, oral and i.m. preparations were used demanding a double-dummy design. All patients were evaluated on a weekly or 2-week basis using psychopathological rating scales (i.e. Hamilton Anxiety Scale, Hamilton Depression Scale, Clinical Global Impressions, Simpson and Angus EPS). It was found that (a) oral-medication titration was 3- to 4-fold more broad-ranging than i.m. medication titration, (b) oral placebo was titrated to the same extent as the oral investigational drugs, and (c) the titration schedule did not follow protocol requirements. Moreover, the average doses in all drug and placebo groups were the same. Concomitant medication like sleep inducers was found to be more closely related to doctors' habits than to actual medical need. Independent of trial and investigational drug, 10-33% of all patients received additional sleep inducers.

Absorbed dose in AgBr in direct film for photon energies ( < 150 keV): relation to optical density. Theoretical calculation and experimental evaluation.

PubMed

Helmrot, E; Alm Carlsson, G

1996-01-01

In the radiological process it is necessary to develop tools so as to explore how X-rays can be used in the most effective way. Evaluation of models to derive measures of image quality and risk-related parameters is one possibility of getting such a tool. Modelling the image receptor, an important part of the imaging chain, is then required. The aim of this work was to find convenient and accurate ways of describing the blackening of direct dental films by X-rays. Since the beginning of the 20th century, the relation between optical density and photon interactions in the silver bromide in X-ray films has been investigated by many authors. The first attempts used simple quantum theories with no consideration of underlying physical interaction processes. The theories were gradually made more realistic by the introduction of dosimetric concepts and cavity theory. A review of cavity theories for calculating the mean absorbed dose in the AgBr grains of the film emulsion is given in this work. The cavity theories of GREENING (15) and SPIERS-CHARLTON (37) were selected for calculating the mean absorbed dose in the AgBr grains relative to the air collision kerma (Kc,air) of the incident photons of Ultra-speed and Ektaspeed (intraoral) films using up-to-date values of interaction coefficients. GREENING'S theory is a multi-grain theory and the results depend on the relative amounts of silver bromide and gelatine in the emulsion layer. In the single grain theory of SPIERS-CHARLTON, the shape and size of the silver bromide grain are important. Calculations of absorbed dose in the silver bromide were compared with measurements of optical densities in Ultra-speed and Ektaspeed films for a broad range (25-145 kV) of X-ray energy. The calculated absorbed dose values were appropriately averaged over the complete photon energy spectrum, which was determined experimentally using a Compton spectrometer. For the whole range of tube potentials used, the measured optical densities of the films were found to be proportional to the mean absorbed dose in the AgBr grains calculated according to GREENING'S theory. They were also found to be proportional to the collision kerma in silver bromide (Kc,AgBr) indicating proportionality between Kc,AgBr and the mean absorbed dose in silver bromide. While GREENING'S theory shows that the quotient of the mean absorbed dose in silver bromide and Kc,AgBr varies with photon energy, this is not apparent when averaged over the broad (diagnostic) X-ray energy spectra used here. Alternatively, proportionality between Kc,AgBr and the mean absorbed dose in silver bromide can be interpreted as resulting from a combination of the SPIERS-CHARLTON theory, valid at low photon energies ( < 30 keV) and GREENING'S theory, which is strictly valid at energies above 50 keV. This study shows that the blackening of non-screen films can be related directly to the energy absorbed in the AgBr grains of the emulsion layer and that, for the purpose of modelling the imaging chain in intraoral radiography, film response can be represented by Kc,AgBr (at the position of the film) independent of photon energy. The importance of taking the complete X-ray energy spectrum into full account in deriving Kc,AgBr is clearly demonstrated, showing that the concept of effective energy must be used with care.

EXPOSURE DOMAINS: ROLE OF TIMING, PATTERN AND MAGNITUDE OF EXPOSURE ON HEALTH RISKS

EPA Science Inventory

Environmental health risk assessment may be broadly separated into assessment of risks from exposures to agents affecting health endpoints for which it may be presumed there is no dose threshold, and to agents affecting endpoints that more likely have a dose threshold. For hea...

Changes in the Peripheral Blood Gene Expression Profile Induced by 3 Months of Valproate Treatment in Patients with Newly Diagnosed Epilepsy

PubMed Central

Rakitin, Aleksei; Kõks, Sulev; Reimann, Ene; Prans, Ele; Haldre, Sulev

2015-01-01

Valproic acid (VPA) is a widely used antiepileptic drug with a broad range of effects and broad clinical efficacy. As a well-known histone deacetylase (HDAC) inhibitor, VPA regulates epigenetic programming by altering the expression of many genes. The aim of study was to analyze differences in gene expression profiles before and after the start of VPA treatment in patients with newly diagnosed epilepsy. RNA sequencing was used to compare whole-genome gene expression patterns of peripheral blood from nine patients with epilepsy before and 3 months after the start of treatment with VPA. Of the 23,099 analyzed genes, only 11 showed statistically significant differential expression with false discovery rate-adjusted p-values below 0.1. Functional annotation and network analyses showed activation of only one genetic network (enrichment score = 30), which included genes for cardiovascular system development and function, cell morphology, and hematological system development and function. The finding of such a small number of differently expressed genes between before and after the start of treatment suggests a lack of HDAC inhibition in these patients, which could be explained by the relatively low doses of VPA that were used. In conclusion, VPA at standard therapeutic dosages modulates the expression of a small number of genes. Therefore, to minimize the potential side effects of HDAC inhibition, it is recommended that the lowest effective dose of VPA be used for treating epilepsy. PMID:26379622

In Vivo Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Streptococcus suis Serotype 2 at Varied Initial Inoculum Sizes

PubMed Central

Guo, Chunna; Liao, Xiaoping; Wang, Mingru; Wang, Feng; Yan, Chaoqun; Xiao, Xia; Sun, Jiang

2015-01-01

Streptococcus suis serotype 2 is an emerging zoonotic pathogen and causes severe disease in both pigs and human beings. Cefquinome (CEQ), a fourth-generation cephalosporin, exhibits broad-spectrum activity against Gram-positive bacteria such as S. suis. This study evaluated the in vitro and in vivo antimicrobial activities of CEQ against four strains of S. suis serotype 2 in a murine neutropenic thigh infection model. We investigated the effect of varied inoculum sizes (106 to 108 CFU/thigh) on the pharmacokinetic (PK)/pharmacodynamic (PD) indices and magnitudes of a particular PK/PD index or dose required for efficacy. Dose fractionation studies included total CEQ doses ranging from 0.625 to 640 mg/kg/24 h. Data were analyzed via a maximum effect (Emax) model using nonlinear regression. The PK/PD studies demonstrated that the percentage of time that serum drug levels were above the MIC of free drug (%ƒT>MIC) in a 24-h dosing interval was the primary index driving the efficacy of both inoculum sizes (R2 = 91% and R2 = 63%). CEQ doses of 2.5 and 40 mg/kg body weight produced prolonged postantibiotic effects (PAEs) of 2.45 to 8.55 h. Inoculum sizes had a significant influence on CEQ efficacy. Compared to the CEQ exposure and dosages in tests using standard inocula, a 4-fold dose (P = 0.006) and a 2-fold exposure time (P = 0.01) were required for a 1-log kill using large inocula of 108 CFU/thigh. PMID:26666923

Biodosimetric quantification of short-term synchrotron microbeam versus broad-beam radiation damage to mouse skin using a dermatopathological scoring system

PubMed Central

Priyadarshika, R C U; Crosbie, J C; Kumar, B; Rogers, P A W

2011-01-01

Objectives Microbeam radiotherapy (MRT) with wafers of microscopically narrow, synchrotron generated X-rays is being used for pre-clinical cancer trials in animal models. It has been shown that high dose MRT can be effective at destroying tumours in animal models, while causing unexpectedly little damage to normal tissue. The aim of this study was to use a dermatopathological scoring system to quantify and compare the acute biological response of normal mouse skin with microplanar and broad-beam (BB) radiation as a basis for biological dosimetry. Method The skin flaps of three groups of mice were irradiated with high entrance doses (200 Gy, 400 Gy and 800 Gy) of MRT and BB and low dose BB (11 Gy, 22 Gy and 44 Gy). The mice were culled at different time-points post-irradiation. Skin sections were evaluated histologically using the following parameters: epidermal cell death, nuclear enlargement, spongiosis, hair follicle damage and dermal inflammation. The fields of irradiation were identified by γH2AX-positive immunostaining. Results The acute radiation damage in skin from high dose MRT was significantly lower than from high dose BB and, importantly, similar to low dose BB. Conclusion The integrated MRT dose was more relevant than the peak or valley dose when comparing with BB fields. In MRT-treated skin, the apoptotic cells of epidermis and hair follicles were not confined to the microbeam paths. PMID:21849367

Incidence of salivary gland tumors among atomic bomb survivors, 1950-1987. Evaluation of radiation-related risk

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

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

1996-07-01

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

Cancer Mortality Following Radiotherapy for Benign Gynecologic Disorders

PubMed Central

Sakata, Ritsu; Kleinerman, Ruth A.; Mabuchi, Kiyohiko; Stovall, Marilyn; Smith, Susan A.; Weathers, Rita; Wactawski-Wende, Jean; Cookfair, Diane L.; Boice, John D.; Inskip, Peter D.

2012-01-01

The purpose of this study is to quantify cancer mortality in relationship to organ-specific radiation dose among women irradiated for benign gynecologic disorders. Included in this study are 12,955 women treated for benign gynecologic disorders at hospitals in the Northeastern U.S. between 1925 and 1965; 9,770 women treated by radiation and 3,186 women treated by other methods. The average age at treatment was 45.9 years (range, 13–88 years), and the average follow-up period was 30.1 years (maximum, 69.9 years). Radiation doses to organs and active bone marrow were reconstructed by medical physicists using original radiotherapy records. The highest doses were received by the uterine cervix (median, 120 Gy) and uterine corpus (median, 34 Gy), followed by the bladder, rectum and colon (median, 1.7–7.2 Gy), with other abdominal organs receiving median doses ≤1 Gy and organs in the chest and head receiving doses <0.1 Gy. Standardized mortality rate ratios relative to the general U.S. population were calculated. Radiation-related risks were estimated in internal analyses using Poisson regression models. Mortality was significantly elevated among irradiated women for cancers of the uterine corpus, ovary, bladder, rectum, colon and brain, as well as for leukemia (exclusive of chronic lymphocytic leukemia) but not for cancer of the cervix, Hodgkin or non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Evidence of a dose-response was seen for cancers of the ovary [excess relative risk (ERR) 0.31/Gy, P < 0.001], bladder (ERR = 0.21/Gy, P = 0.02) and rectum (ERR = 0.23/Gy, P = 0.05) and suggested for colon (ERR = 0.09/Gy, P = 0.10), but not for cancers of the uterine corpus or brain nor for non-chronic lymphocytic leukemia. Relative risks of mortality due to cancers of the stomach, pancreas, liver and kidney were close to 1.0, with no evidence of dose-response over the range of 0–1.5 Gy. Breast cancer was not significantly associated with dose to the breast or ovary. Mortality due to cancers of heavily irradiated organs remained elevated up to 40 years after irradiation. Significantly elevated radiation-related risk was seen for cancers of organs proximal to the radiation source or fields (bladder, rectum and ovary), as well as for non-chronic lymphocytic leukemia. Our results corroborate those from previous studies that suggest that cells of the uterine cervix and lymphopoietic system are relatively resistant to the carcinogenic effects of radiation. Studies of women irradiated for benign gynecologic disorders, together with studies of women treated with higher doses of radiation for uterine cancers, provide quantitative information on cancer risks associated with a broad range of pelvic radiation exposures. PMID:22856888

Cascaded systems analysis of noise and detectability in dual-energy cone-beam CT

PubMed Central

Gang, Grace J.; Zbijewski, Wojciech; Webster Stayman, J.; Siewerdsen, Jeffrey H.

2012-01-01

Purpose: Dual-energy computed tomography and dual-energy cone-beam computed tomography (DE-CBCT) are promising modalities for applications ranging from vascular to breast, renal, hepatic, and musculoskeletal imaging. Accordingly, the optimization of imaging techniques for such applications would benefit significantly from a general theoretical description of image quality that properly incorporates factors of acquisition, reconstruction, and tissue decomposition in DE tomography. This work reports a cascaded systems analysis model that includes the Poisson statistics of x rays (quantum noise), detector model (flat-panel detectors), anatomical background, image reconstruction (filtered backprojection), DE decomposition (weighted subtraction), and simple observer models to yield a task-based framework for DE technique optimization. Methods: The theoretical framework extends previous modeling of DE projection radiography and CBCT. Signal and noise transfer characteristics are propagated through physical and mathematical stages of image formation and reconstruction. Dual-energy decomposition was modeled according to weighted subtraction of low- and high-energy images to yield the 3D DE noise-power spectrum (NPS) and noise-equivalent quanta (NEQ), which, in combination with observer models and the imaging task, yields the dual-energy detectability index (d′). Model calculations were validated with NPS and NEQ measurements from an experimental imaging bench simulating the geometry of a dedicated musculoskeletal extremities scanner. Imaging techniques, including kVp pair and dose allocation, were optimized using d′ as an objective function for three example imaging tasks: (1) kidney stone discrimination; (2) iodine vs bone in a uniform, soft-tissue background; and (3) soft tissue tumor detection on power-law anatomical background. Results: Theoretical calculations of DE NPS and NEQ demonstrated good agreement with experimental measurements over a broad range of imaging conditions. Optimization results suggest a lower fraction of total dose imparted by the low-energy acquisition, a finding consistent with previous literature. The selection of optimal kVp pair reveals the combined effect of both quantum noise and contrast in the kidney stone discrimination and soft-tissue tumor detection tasks, whereas the K-edge effect of iodine was the dominant factor in determining kVp pairs in the iodine vs bone task. The soft-tissue tumor task illustrated the benefit of dual-energy imaging in eliminating anatomical background noise and improving detectability beyond that achievable by single-energy scans. Conclusions: This work established a task-based theoretical framework that is predictive of DE image quality. The model can be utilized in optimizing a broad range of parameters in image acquisition, reconstruction, and decomposition, providing a useful tool for maximizing DE-CBCT image quality and reducing dose. PMID:22894440

33 CFR 334.480 - Archers Creek, Ribbon Creek and Broad River, S.C.; U.S. Marine Corps Recruit Depot rifle and...

Code of Federal Regulations, 2011 CFR

2011-07-01

... Broad River, S.C.; U.S. Marine Corps Recruit Depot rifle and pistol ranges, Parris Island. 334.480... DEFENSE DANGER ZONE AND RESTRICTED AREA REGULATIONS § 334.480 Archers Creek, Ribbon Creek and Broad River... navigation: (1) At the rifle range. Archers Creek between Broad River and Beaufort River and Ribbon Creek...

33 CFR 334.480 - Archers Creek, Ribbon Creek and Broad River, S.C.; U.S. Marine Corps Recruit Depot rifle and...

Code of Federal Regulations, 2010 CFR

2010-07-01

... Broad River, S.C.; U.S. Marine Corps Recruit Depot rifle and pistol ranges, Parris Island. 334.480... DEFENSE DANGER ZONE AND RESTRICTED AREA REGULATIONS § 334.480 Archers Creek, Ribbon Creek and Broad River... navigation: (1) At the rifle range. Archers Creek between Broad River and Beaufort River and Ribbon Creek...

NEURAL NETWORK MODELLING OF CARDIAC DOSE CONVERSION COEFFICIENT FOR ARBITRARY X-RAY SPECTRA.

PubMed

Kadri, O; Manai, K

2016-12-01

In this article, an approach to compute the dose conversion coefficients (DCCs) is described for the computational voxel phantom 'High-Definition Reference Korean-Man' (HDRK-Man) using artificial neural networks (ANN). For this purpose, the voxel phantom was implemented into the Monte Carlo (MC) transport toolkit GEANT4, and the DCCs for more than 30 tissues and organs, due to a broad parallel beam of monoenergetic photons with energy ranging from 15 to 150 keV by a step of 5 keV, were calculated. To study the influence of patient size on DCC values, DCC calculation was performed, for a representative body size population, using five different sizes covering the range of 80-120 % magnification of the original HDRK-Man. The focus of the present study was on the computation of DCC for the human heart. ANN calculation and MC simulation results were compared, and good agreement was observed showing that ANNs can be used as an efficient tool for modelling DCCs for the computational voxel phantom. ANN approach appears to be a significant advance over the time-consuming MC methods for DCC calculation. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B

PubMed Central

Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H.; Streatfield, Stephen J.; Herzog, Roland W.; Daniell, Henry

2015-01-01

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (~1mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ~2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP+ regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ~870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft2 per annum yielding 24,000–36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. PMID:26302233

Thermoluminescent properties of Dy doped calcium borate based glass for dose measurement subjected to photon irradiation

NASA Astrophysics Data System (ADS)

Tajuddin, H. A.; WanHassan, W. M. S.; Abdul Sani, S. F..; Shaharin, Nurul Syazlin

2017-10-01

This study presents the thermoluminescent (TL) dosimetric properties of calcium borate glass with various dopant concentration of dysprosium (Dy). Calcium borate glass is a new potential material to be used in radiation measurement with absorption coefficient that is close to human bone. A series of glasses based on chemical equation xCaO-(100-x) B2O3 system, x = 0.1, 0.2, 0.3, 0.4, 0.5 (0< x <100) % weight have been prepared by melt quenching method. The X-ray diffraction analysis of glass samples were carried out and the result showed a broad peak, which confirmed the amorphous nature of the glass. The 70B2O3-30CaO glass sample was found as the most stable among other glass samples studied. Present work focuses on 70B2O3-30CaO glass of (0.01-0.4) mol% Dy-doped in order to investigate the thermoluminescence (TL) properties, in particular, dose-response and fading. The glass samples were irradiated to dose range of 0.5-4.0 Gy subjected to 6MV photon irradiations of LINAC Primus MLC 3339. TL response of 0.3 mol% Dy-doped 70B2O3-30CaO glass was found to produce highest response, with good linear dose- response relationship.

Shielding properties of lead-free protective clothing and their impact on radiation doses

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

Schlattl, Helmut; Zankl, Maria; Eder, Heinrich

2007-11-15

The shielding properties of two different lead-free materials--tin and a compound of 80% tin and 20% bismuth--for protective clothing are compared with those of lead for three typical x-ray spectra generated at tube voltages of 60, 75, and 120 kV. Three different quantities were used to compare the shielding capability of the different materials: (1) Air-kerma attenuation factors in narrow-beam geometry, (2) air-kerma attenuation factors in broad-beam geometry, and (3) ratios of organ and effective doses in the human body for a whole-body irradiation with a parallel beam directed frontally at the body. The thicknesses of tin (0.45 mm) andmore » the tin/bismuth compound (0.41 mm) to be compared against lead correspond to a lead equivalence value of 0.35 mm for the 75 kV spectrum. The narrow-beam attenuation factors for 0.45 mm tin are 54% and 32% lower than those for 0.35 mm lead for 60 and 120 kV; those for 0.41 mm tin/bismuth are 12% and 32% lower, respectively. The decrease of the broad-beam air-kerma attenuation factors compared to lead is 74%, 46%, and 41% for tin and 42%, 26%, and 33% for tin/bismuth and the spectra at 60, 75, and 120 kV, respectively. Therefore, it is recommended that the characterization of the shielding potential of a material should be done by measurements in broad-beam geometry. Since the secondary radiation that is mainly responsible for the shielding reduction in broad-beam geometry is of low penetrability, only more superficially located organs receive significantly enhanced doses. The increase for the dose to the glandular breast tissue (female) compared to being shielded by lead is 143%, 37%, and 45% when shielded by tin, and 35%, 15%, and 39% when shielded by tin/bismuth for 60, 75, and 120 kV, respectively. The effective dose rises by 60%, 6%, and 38% for tin, and 14%, 3% and, 35% for tin/bismuth shielding, respectively.« less

Robust determination of effective atomic numbers for electron interactions with TLD-100 and TLD-100H thermoluminescent dosimeters

NASA Astrophysics Data System (ADS)

Taylor, M. L.

2011-04-01

Lithium fluoride thermoluminescent dosimeters (TLD) are the most commonly implemented for clinical dosimetry. The small physical magnitude of TLDs makes them attractive for applications such as small field measurement, in vivo dosimetry and measurement of out-of-field doses to critical structures. The most broadly used TLD is TLD-100 (LiF:Mg,Ti) and, for applications requiring higher sensitivity to low-doses, TLD-100H (LiF:Mg,Cu,P) is frequently employed. The radiological properties of these TLDs are therefore of significant interest. For the first time, in this study effective atomic numbers for radiative, collisional and total electron interaction processes are calculated for TLD-100 and TLD-100H dosimeters over the energy range 1 keV-100 MeV. This is undertaken using a robust, energy-dependent method of calculation rather than typical power-law approximations. The influence of dopant concentrations and unwanted impurities is also investigated. The two TLDs exhibit similar effective atomic numbers, ranging from approximately 5.77-6.51. Differences arising from the different dopants are most pronounced in low-energy radiative effects. The TLDs have atomic numbers approximately 1.48-2.06 times that of water. The effective atomic number of TLD-100H is consistently higher than that of TLD-100 over a broad energy range, due to the greater influence of the higher- Z dopants on the electron interaction cross sections. Typical variation in dopant concentration does not significantly influence the effective atomic number. The influence on TLD-100H is comparatively more pronounced than that on TLD-100. Contrariwise, unwanted hydroxide impurities influence TLD-100 more than TLD-100H. The effective atomic number is a key parameter that influences the radiological properties and energy response of TLDs. Although many properties of these TLDs have been studied rigorously, as yet there has been no investigation of their effective atomic numbers for electron interactions. The discrepancy between the effective atomic numbers of the TLDs and water is significantly higher than would be indicated by comparing effective atomic numbers calculated via the common - but dubious - power-law method. The mean effective numbers over the full energy range are 6.06, 6.09, 3.34 and 3.37 for TLD-100, TLD-100H, soft tissue and water respectively.

Risk Factors, Pathophysiology, and Treatment of Hot Flashes in Cancer

PubMed Central

Fisher, William I.; Johnson, Aimee K.; Elkins, Gary R.; Otte, Julie L.; Burns, Debra S.; Yu, Menggang; Carpenter, Janet S.

2012-01-01

Hot flashes are prevalent and severe symptoms that can interfere with mood, sleep, and quality of life for women and men with cancer. The purpose of this article is to review existing literature on the risk factors, pathophysiology, and treatment of hot flashes in persons with cancer. Electronic searches were conducted to identify relevant, English-language literature published through June 15, 2012. Results indicated that risk factors for hot flashes in cancer include patient-related factors (eg, age, race/ethnicity, educational level, smoking history, cardiovascular risk including BMI, and genetics) and disease-related factors (eg, cancer diagnosis, and dose/type of treatment). In addition, although the pathophysiology of hot flashes has remained elusive, these symptoms are likely attributable to disruptions in thermoregulation and neurochemicals. Therapies that have been offered or tested fall into 4 broad categories: pharmacological, nutraceutical, surgical, and complementary/behavioral strategies. The evidence base for this broad range of therapies varies, with some treatments not yet having been fully tested or showing equivocal results. The evidence base surrounding all therapies is evaluated to enhance hot flash treatment decision making by clinicians and patients. PMID:23355109

Effect of gentamicin and levels of ambient sound on hearing screening outcomes in the neonatal intensive care unit: A pilot study.

PubMed

Garinis, Angela C; Liao, Selena; Cross, Campbell P; Galati, Johnathan; Middaugh, Jessica L; Mace, Jess C; Wood, Anna-Marie; McEvoy, Lindsey; Moneta, Lauren; Lubianski, Troy; Coopersmith, Noe; Vigo, Nicholas; Hart, Christopher; Riddle, Artur; Ettinger, Olivia; Nold, Casey; Durham, Heather; MacArthur, Carol; McEvoy, Cynthia; Steyger, Peter S

2017-06-01

Hearing loss rates in infants admitted to neonatal intensive care units (NICU) run at 2-15%, compared to 0.3% in full-term births. The etiology of this difference remains poorly understood. We examined whether the level of ambient sound and/or cumulative gentamicin (an aminoglycoside) exposure affect NICU hearing screening results, as either exposure can cause acquired, permanent hearing loss. We hypothesized that higher levels of ambient sound in the NICU, and/or gentamicin dosing, increase the risk of referral on the distortion product otoacoustic emission (DPOAE) assessments and/or automated auditory brainstem response (AABR) screens. This was a prospective pilot outcomes study of 82 infants (<37 weeks gestational age) admitted to the NICU at Oregon Health & Science University. An ER-200D sound pressure level dosimeter was used to collect daily sound exposure in the NICU for each neonate. Gentamicin dosing was also calculated for each infant, including the total daily dose based on body mass (mg/kg/day), as well as the total number of treatment days. DPOAE and AABR assessments were conducted prior to discharge to evaluate hearing status. Exclusion criteria included congenital infections associated with hearing loss, and congenital craniofacial or otologic abnormalities. The mean level of ambient sound was 62.9 dBA (range 51.8-70.6 dBA), greatly exceeding American Academy of Pediatrics (AAP) recommendation of <45.0 dBA. More than 80% of subjects received gentamicin treatment. The referral rate for (i) AABRs, (frequency range: ∼1000-4000 Hz), was 5%; (ii) DPOAEs with a broad F2 frequency range (2063-10031 Hz) was 39%; (iii) DPOAEs with a low-frequency F2 range (<4172 Hz) was 29%, and (iv) DPOAEs with a high-frequency F2 range (>4172 Hz) was 44%. DPOAE referrals were significantly greater for infants receiving >2 days of gentamicin dosing compared to fewer doses (p = 0.004). The effect of sound exposure and gentamicin treatment on hearing could not be determined due to the low number of NICU infants without gentamicin exposure (for control comparisons). All infants were exposed to higher levels of ambient sound that substantially exceed AAP guidelines. More referrals were generated by DPOAE assessments than with AABR screens, with significantly more DPOAE referrals with a high-frequency F2 range, consistent with sound- and/or gentamicin-induced cochlear dysfunction. Adding higher frequency DPOAE assessments to existing NICU hearing screening protocols could better identify infants at-risk for ototoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of Gentamicin and Levels of Ambient Sound on Hearing Screening Outcomes in the Neonatal Intensive Care Unit: A Pilot Study

PubMed Central

Garinis, Angela C.; Liao, Selena; Cross, Campbell P.; Galati, Johnathan; Middaugh, Jessica L.; Mace, Jess C.; Wood, Anna-Marie; McEvoy, Lindsey; Moneta, Lauren; Lubianski, Troy; Coopersmith, Noe; Vigo, Nicholas; Hart, Christopher; Riddle, Artur; Ettinger, Olivia; Nold, Casey; Durham, Heather; MacArthur, Carol; McEvoy, Cynthia; Steyger, Peter S.

2017-01-01

Objective Hearing loss rates in infants admitted to neonatal intensive care units (NICU) run at 2–15%, compared to 0.3% in full-term births. The etiology of this difference remains poorly understood. We examined whether the level of ambient sound and/or cumulative gentamicin (an aminoglycoside) exposure affect NICU hearing screening results, as either exposure can cause acquired, permanent hearing loss. We hypothesized that higher levels of ambient sound in the NICU, and/or gentamicin dosing, increase the risk of referral on the distortion product otoacoustic emission (DPOAE) assessments and/or automated auditory brainstem response (AABR) screens. Methods This was a prospective pilot outcomes study of 82 infants (<37 weeks gestational age) admitted to the NICU at Oregon Health & Science University. An ER-200D sound pressure level dosimeter was used to collect daily sound exposure in the NICU for each neonate. Gentamicin dosing was also calculated for each infant, including the total daily dose based on body mass (mg/kg/day), as well as the total number of treatment days. DPOAE and AABR assessments were conducted prior to discharge to evaluate hearing status. Exclusion criteria included congenital infections associated with hearing loss, and congenital craniofacial or otologic abnormalities. Results The mean level of ambient sound was 62.9 dBA (range 51.8–70.6 dBA), greatly exceeding American Academy of Pediatrics (AAP) recommendation of <45.0 dBA. More than 80% of subjects received gentamicin treatment. The referral rate for (i) AABRs, (frequency range: ~1000–4000 Hz), was 5%; (ii) DPOAEs with a broad F2 frequency range (2063–10031 Hz) was 39%; (iii) DPOAEs with a low-frequency F2 range (<4172 Hz) was 29%, and (iv) DPOAEs with a high-frequency F2 range (>4172 Hz) was 44%. DPOAE referrals were significantly greater for infants receiving >2 days of gentamicin dosing compared to fewer doses (p= 0.004). The effect of sound exposure and gentamicin treatment on hearing could not be determined due to the low number of NICU infants without gentamicin exposure (for control comparisons). Conclusion All infants were exposed to higher levels of ambient sound that substantially exceed AAP guidelines. More referrals were generated by DPOAE assessments than with AABR screens, with significantly more DPOAE referrals with a high-frequency F2 range, consistent with sound- and/or gentamicin-induced cochlear dysfunction. Adding higher frequency DPOAE assessments to existing NICU hearing screening protocols could better identify at-risk infants to be referred for diagnostic evaluation. PMID:28483249

Targeted analysis of 116 drugs in hair by UHPLC-MS/MS and its application to forensic cases.

PubMed

Wang, Xin; Johansen, Sys Stybe; Nielsen, Marie Katrine Klose; Linnet, Kristian

2017-08-01

A multi-target method that can detect a broad range of drugs in human hair, such as hypnotics, anxiolytics, analgesics, benzodiazepines, antihistamines, antidepressants, antipsychotics, and anticonvulsants, was developed based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The drugs were extracted from 10 mg of washed hair by incubation for 18 h in a 25:25:50 (v/v/v) mixture of methanol/acetonitrile/2 mM ammonium formate (8% acetonitrile, pH 5.3). For 51% of the basic drugs, the lower limits of quantification (LLOQs) were in the range of 0.05-0.5 pg/mg, and the majority (98%) were ≤ 5 pg/mg. Linearity ranged from LLOQs to 100-500 pg/mg for all the basic drugs. For acid and neutral drugs, the LLOQs ranged from 0.4 to 500 pg/mg, and linearity ranged from LLOQs to 80-40 000 pg/mg. According to published reports on concentrations attained in single dose control studies, the present method is sensitive enough to detect single-dose drug exposure for many of the drugs. The accuracy was within 75-125% for the majority of drugs. Good precision was observed (relative standard deviations [RSD%] < 25%) for most of the compounds, including the prepared quality control (QC) hair samples. The method was applied to forensic cases and concentrations of rarely reported drugs in hair in 25 post-mortem forensic cases were presented. Hair concentrations of amisulpride, gabapentin, mianserin, mepyramine, orphenadrine, and xylometazoline have not been previously reported. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Space: The Final Frontier-Research Relevant to Mars.

PubMed

Boice, John D

2017-04-01

A critically important gap in knowledge surrounds the health consequences of exposure to radiation received gradually over time. Much is known about the health effects of brief high-dose exposures, such as from the atomic bombings in Japan, but the concerns today focus on the frequent low-dose exposures received by members of the public, workers, and, as addressed in this paper, astronauts. Additional guidance is needed by the National Aeronautics and Space Administration (NASA) for planning long-term missions where the rate of radiation exposure is gradual over years and the cumulative amounts high. The direct study of low doses and low-dose rates is of immeasurable value in understanding the possible range of health effects from gradual exposures and in providing guidance for radiation protection, not only of workers and the public but also astronauts. The ongoing Million Person Study (MPS) is 10 times larger than the study of the Japanese atomic bomb survivors of 86,000 survivors with estimated doses. The number of workers with >100 mSv career dose is substantially greater. The large study size, broad range of doses, and long follow-up indicate substantial statistical ability to quantify the risk of exposures that are received gradually over time. The study consists of 360,000 U.S. Department of Energy workers from the Manhattan Project; 150,000 nuclear utility workers from the inception of the nuclear age; 115,000 atomic veterans who participated in above-ground atmospheric tests at the Nevada Test Site and the Bikini and Enewetak Atolls and Johnston Island in the Pacific Proving Grounds (PPG); 250,000 radiologists and medical workers; and 130,000 industrial radiographers. NASA uses an individual risk-based system for radiation protection in contrast to the system of dose limits for occupational exposures used by terrestrial-based organizations. The permissible career exposure limit set by NASA for each astronaut is a 3% risk of exposure-induced death (REID) from cancer at a 95% confidence level to account for uncertainties in risk projections. The large size of the MPS will reduce the uncertainty in the risk estimates, narrowing the 95% confidence interval, and thus allow more time in space for astronauts. Further differences between men and women in their response to radiation can be more fully examined, and non-cancer outcomes, such as neurological disorders and cardiovascular disease, can be evaluated in a way not hitherto possible.

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model.

PubMed

Lepak, Alexander J; Andes, David R

2016-08-01

Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0-∞), 2.8 to 152 mg · h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10 CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10 CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2 log10 to more than 4 log10 The median free-drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. AUC/MIC targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin demonstrated in vitro and in vivo potency against a diverse group of pathogens, including those with phenotypic drug resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

PubMed Central

Lepak, Alexander J.

2016-01-01

Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae. Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0–∞), 2.8 to 152 mg · h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10 CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10 CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2 log10 to more than 4 log10. The median free-drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. AUC/MIC targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin demonstrated in vitro and in vivo potency against a diverse group of pathogens, including those with phenotypic drug resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens. PMID:27216072

Evaluation of an empirical monitor output estimation in carbon ion radiotherapy.

PubMed

Matsumura, Akihiko; Yusa, Ken; Kanai, Tatsuaki; Mizota, Manabu; Ohno, Tatsuya; Nakano, Takashi

2015-09-01

A conventional broad beam method is applied to carbon ion radiotherapy at Gunma University Heavy Ion Medical Center. According to this method, accelerated carbon ions are scattered by various beam line devices to form 3D dose distribution. The physical dose per monitor unit (d/MU) at the isocenter, therefore, depends on beam line parameters and should be calibrated by a measurement in clinical practice. This study aims to develop a calculation algorithm for d/MU using beam line parameters. Two major factors, the range shifter dependence and the field aperture effect, are measured via PinPoint chamber in a water phantom, which is an identical setup as that used for monitor calibration in clinical practice. An empirical monitor calibration method based on measurement results is developed using a simple algorithm utilizing a linear function and a double Gaussian pencil beam distribution to express the range shifter dependence and the field aperture effect. The range shifter dependence and the field aperture effect are evaluated to have errors of 0.2% and 0.5%, respectively. The proposed method has successfully estimated d/MU with a difference of less than 1% with respect to the measurement results. Taking the measurement deviation of about 0.3% into account, this result is sufficiently accurate for clinical applications. An empirical procedure to estimate d/MU with a simple algorithm is established in this research. This procedure allows them to use the beam time for more treatments, quality assurances, and other research endeavors.

SU-F-T-476: Performance of the AS1200 EPID for Periodic Photon Quality Assurance

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

DeMarco, J; Fraass, B; Yang, W

2016-06-15

Purpose: To assess the dosimetric performance of a new amorphous silicon flat-panel electronic portal imaging device (EPID) suitable for high-intensity, flattening-filter-free delivery mode. Methods: An EPID-based QA suite was created with automation to periodically monitor photon central-axis output and two-dimensional beam profile constancy as a function of gantry angle and dose-rate. A Varian TrueBeamTM linear accelerator installed with Developer Mode was used to customize and deliver XML script routines for the QA suite using the dosimetry mode image acquisition for an aS1200 EPID. Automatic post-processing software was developed to analyze the resulting DICOM images. Results: The EPID was used tomore » monitor photon beam output constancy (central-axis), flatness, and symmetry over a period of 10 months for four photon beam energies (6x, 15x, 6xFFF, and 10xFFF). EPID results were consistent to those measured with a standard daily QA check device. At the four cardinal gantry angles, the standard deviation of the EPID central-axis output was <0.5%. Likewise, EPID measurements were independent for the wide range of dose rates (including up to 2400 mu/min for 10xFFF) studied with a standard deviation of <0.8% relative to the nominal dose rate for each energy. Also, profile constancy and field size measurements showed good agreement with the reference acquisition of 0° gantry angle and nominal dose rate. XML script files were also tested for MU linearity and picket-fence delivery. Using Developer Mode, the test suite was delivered in <60 minutes for all 4 photon energies with 4 dose rates per energy and 5 picket-fence acquisitions. Conclusion: Dosimetry image acquisition using a new EPID was found to be accurate for standard and high-intensity photon beams over a broad range of dose rates over 10 months. Developer Mode provided an efficient platform to customize the EPID acquisitions by using custom script files which significantly reduced the time. This work was funded in part by Varian Medical Systems.« less

A light-weight compact proton gantry design with a novel dose delivery system for broad-energetic laser-accelerated beams

NASA Astrophysics Data System (ADS)

Masood, U.; Cowan, T. E.; Enghardt, W.; Hofmann, K. M.; Karsch, L.; Kroll, F.; Schramm, U.; Wilkens, J. J.; Pawelke, J.

2017-07-01

Proton beams may provide superior dose-conformity in radiation therapy. However, the large sizes and costs limit the widespread use of proton therapy (PT). The recent progress in proton acceleration via high-power laser systems has made it a compelling alternative to conventional accelerators, as it could potentially reduce the overall size and cost of the PT facilities. However, the laser-accelerated beams exhibit different characteristics than conventionally accelerated beams, i.e. very intense proton bunches with large divergences and broad-energy spectra. For the application of laser-driven beams in PT, new solutions for beam transport, such as beam capture, integrated energy selection, beam shaping and delivery systems are required due to the specific beam parameters. The generation of these beams are limited by the low repetition rate of high-power lasers and this limitation would require alternative solutions for tumour irradiation which can efficiently utilize the available high proton fluence and broad-energy spectra per proton bunch to keep treatment times short. This demands new dose delivery system and irradiation field formation schemes. In this paper, we present a multi-functional light-weight and compact proton gantry design for laser-driven sources based on iron-less pulsed high-field magnets. This achromatic design includes improved beam capturing and energy selection systems, with a novel beam shaping and dose delivery system, so-called ELPIS. ELPIS system utilizes magnetic fields, instead of physical scatterers, for broadening the spot-size of broad-energetic beams while capable of simultaneously scanning them in lateral directions. To investigate the clinical feasibility of this gantry design, we conducted a treatment planning study with a 3D treatment planning system augmented for the pulsed beams with optimizable broad-energetic widths and selectable beam spot sizes. High quality treatment plans could be achieved with such unconventional beam parameters, deliverable via the presented gantry and ELPIS dose delivery system. The conventional PT gantries are huge and require large space for the gantry to rotate the beam around the patient, which could be reduced up to 4 times with the presented pulse powered gantry system. The further developments in the next generation petawatt laser systems and laser-targets are crucial to reach higher proton energies. However, if proton energies required for therapy applications are reached it could be possible in future to reduce the footprint of the PT facilities, without compromising on clinical standards.

A light-weight compact proton gantry design with a novel dose delivery system for broad-energetic laser-accelerated beams.

PubMed

Masood, U; Cowan, T E; Enghardt, W; Hofmann, K M; Karsch, L; Kroll, F; Schramm, U; Wilkens, J J; Pawelke, J

2017-07-07

Proton beams may provide superior dose-conformity in radiation therapy. However, the large sizes and costs limit the widespread use of proton therapy (PT). The recent progress in proton acceleration via high-power laser systems has made it a compelling alternative to conventional accelerators, as it could potentially reduce the overall size and cost of the PT facilities. However, the laser-accelerated beams exhibit different characteristics than conventionally accelerated beams, i.e. very intense proton bunches with large divergences and broad-energy spectra. For the application of laser-driven beams in PT, new solutions for beam transport, such as beam capture, integrated energy selection, beam shaping and delivery systems are required due to the specific beam parameters. The generation of these beams are limited by the low repetition rate of high-power lasers and this limitation would require alternative solutions for tumour irradiation which can efficiently utilize the available high proton fluence and broad-energy spectra per proton bunch to keep treatment times short. This demands new dose delivery system and irradiation field formation schemes. In this paper, we present a multi-functional light-weight and compact proton gantry design for laser-driven sources based on iron-less pulsed high-field magnets. This achromatic design includes improved beam capturing and energy selection systems, with a novel beam shaping and dose delivery system, so-called ELPIS. ELPIS system utilizes magnetic fields, instead of physical scatterers, for broadening the spot-size of broad-energetic beams while capable of simultaneously scanning them in lateral directions. To investigate the clinical feasibility of this gantry design, we conducted a treatment planning study with a 3D treatment planning system augmented for the pulsed beams with optimizable broad-energetic widths and selectable beam spot sizes. High quality treatment plans could be achieved with such unconventional beam parameters, deliverable via the presented gantry and ELPIS dose delivery system. The conventional PT gantries are huge and require large space for the gantry to rotate the beam around the patient, which could be reduced up to 4 times with the presented pulse powered gantry system. The further developments in the next generation petawatt laser systems and laser-targets are crucial to reach higher proton energies. However, if proton energies required for therapy applications are reached it could be possible in future to reduce the footprint of the PT facilities, without compromising on clinical standards.

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.

A comparison of simple and realistic eye models for calculation of fluence to dose conversion coefficients in a broad parallel beam incident of protons

NASA Astrophysics Data System (ADS)

Sakhaee, Mahmoud; Vejdani-Noghreiyan, Alireza; Ebrahimi-Khankook, Atiyeh

2015-01-01

Radiation induced cataract has been demonstrated among people who are exposed to ionizing radiation. To evaluate the deterministic effects of ionizing radiation on the eye lens, several papers dealing with the eye lens dose have been published. ICRP Publication 103 states that the lens of the eye may be more radiosensitive than previously considered. Detailed investigation of the response of the lens showed that there are strong differences in sensitivity to ionizing radiation exposure with respect to cataract induction among the tissues of the lens of the eye. This motivated several groups to look deeper into issue of the dose to a sensitive cell population within the lens, especially for radiations with low energy penetrability that have steep dose gradients inside the lens. Two sophisticated mathematical models of the eye including the inner structure have been designed for the accurate dose estimation in recent years. This study focuses on the calculations of the absorbed doses of different parts of the eye using the stylized models located in UF-ORNL phantom and comparison with the data calculated with the reference computational phantom in a broad parallel beam incident of protons with energies between 20 MeV and 10 GeV. The obtained results indicate that the total lens absorbed doses of reference phantom has good compliance with those of the more sensitive regions of stylized models. However, total eye absorbed dose of these models greatly differ with each other for lower energies.

Improvement of the Cramer classification for oral exposure using the database TTC RepDose - A strategy description

EPA Science Inventory

The present report describes a strategy to refine the current Cramer classification of the TTC concept using a broad database (DB) termed TTC RepDose. Cramer classes 1-3 overlap to some extent, indicating a need for a better separation of structural classes likely to be toxic, mo...

Foreword

NASA Astrophysics Data System (ADS)

Bradley, D. A.

2017-11-01

We live in a world in which the risks and benefits of the various influences impacting upon our lives are constantly being revisited and weighed against each other. Radiation, the issue with which we are concerned herein, forms one example of such a two-edged sword, offering immense benefits under well-controlled conditions but posing risks to health as well as more generally to the environment when controls are poor or absent. It is a truism, non the less true in its re-stating, that the extent to which control is successful can be measured through the amount of radiation imparted, the name accorded to the endeavour of measurement being 'radiation dosimetry'. It forms the basis of numerous technological approaches, passive or active. Passive forms of dosimeter will for instance include thermoluminescence, radioluminesence, optically stimulated luminescence, and numerous other diverse forms, offering advantages and disadvantages in accord with the particular applications. And here too the interests are manifold, ranging from the very low doses (for example the dose-rates of the undisturbed terrestrial environment or single bite-wing dental radiographs), through to general radiography (that of the chest for instance), highly specialised radiography (mammography, CT, PET/CT, fluoroscopy, angiography), the entire range of nuclear medicine, the various radiotherapies (eg external beam and brachytherapy), food irradiations and radiation processing. The range-change across this diverse set of interests approaches of the order of 1012 (from μGy through to in excess of 100 kGy) and yet there are technologies and the supporting science that can be demonstrated to serve that need. Undoubtedly there exists the need for highly versatile technologies, placing minimal demand on allied technological support and human resource. Clearly there is need to demonstrate useful response of dosimeters to a broad range of radiations, from the ultraviolet and low-energy x-rays, to electrons, gamma, alpha, proton, neutron and heavy ion irradiations as well as the need in unison to develop high throughput readout systems that perfectly augment the dosimetric devices that are on offer. No less desirable is the need for reusable/long lifetime systems that can be applied in highly inhospitable environments, including at elevated temperatures and in aqueous systems. These Proceedings are intended to showcase the various issues and solutions, also providing an awareness of state-of-the-art systems that can serve such a broad range of radiation dosimetry needs, adaptable to the less well endowed budget and modest desires through to applications involving highly sophisticated beam manipulations.

Nanoparticle formulations of cisplatin for cancer therapy

PubMed Central

Duan, Xiaopin; He, Chunbai; Kron, Stephen J.; Lin, Wenbin

2016-01-01

The genotoxic agent cisplatin, used alone or in combination with radiation and/or other chemotherapeutic agents, is an important first-line chemotherapy for a broad range of cancers. The clinical utility of cisplatin is limited both by intrinsic and acquired resistance and dose-limiting normal tissue toxicity. That cisplatin shows little selectivity for tumor versus normal tissue may be a critical factor limiting its value. To overcome the low therapeutic ratio of the free drug, macromolecular, liposomal and nanoparticle drug delivery systems have been explored toward leveraging the enhanced permeability and retention (EPR) effect and promoting delivery of cisplatin to tumors. Here, we survey recent advances in nanoparticle formulations of cisplatin, focusing on agents that show promise in preclinical or clinical settings. PMID:26848041

In Vivo Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Streptococcus suis Serotype 2 at Varied Initial Inoculum Sizes.

PubMed

Guo, Chunna; Liao, Xiaoping; Wang, Mingru; Wang, Feng; Yan, Chaoqun; Xiao, Xia; Sun, Jiang; Liu, Yahong

2016-02-01

Streptococcus suis serotype 2 is an emerging zoonotic pathogen and causes severe disease in both pigs and human beings. Cefquinome (CEQ), a fourth-generation cephalosporin, exhibits broad-spectrum activity against Gram-positive bacteria such as S. suis. This study evaluated the in vitro and in vivo antimicrobial activities of CEQ against four strains of S. suis serotype 2 in a murine neutropenic thigh infection model. We investigated the effect of varied inoculum sizes (10(6) to 10(8) CFU/thigh) on the pharmacokinetic (PK)/pharmacodynamic (PD) indices and magnitudes of a particular PK/PD index or dose required for efficacy. Dose fractionation studies included total CEQ doses ranging from 0.625 to 640 mg/kg/24 h. Data were analyzed via a maximum effect (Emax) model using nonlinear regression. The PK/PD studies demonstrated that the percentage of time that serum drug levels were above the MIC of free drug (%ƒT>MIC) in a 24-h dosing interval was the primary index driving the efficacy of both inoculum sizes (R(2) = 91% and R(2) = 63%). CEQ doses of 2.5 and 40 mg/kg body weight produced prolonged postantibiotic effects (PAEs) of 2.45 to 8.55 h. Inoculum sizes had a significant influence on CEQ efficacy. Compared to the CEQ exposure and dosages in tests using standard inocula, a 4-fold dose (P = 0.006) and a 2-fold exposure time (P = 0.01) were required for a 1-log kill using large inocula of 10(8) CFU/thigh. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Comparison of two methods for measuring γ-H2AX nuclear fluorescence as a marker of DNA damage in cultured human cells: applications for microbeam radiation therapy

NASA Astrophysics Data System (ADS)

Anderson, D.; Andrais, B.; Mirzayans, R.; Siegbahn, E. A.; Fallone, B. G.; Warkentin, B.

2013-06-01

Microbeam radiation therapy (MRT) delivers single fractions of very high doses of synchrotron x-rays using arrays of microbeams. In animal experiments, MRT has achieved higher tumour control and less normal tissue toxicity compared to single-fraction broad beam irradiations of much lower dose. The mechanism behind the normal tissue sparing of MRT has yet to be fully explained. An accurate method for evaluating DNA damage, such as the γ-H2AX immunofluorescence assay, will be important for understanding the role of cellular communication in the radiobiological response of normal and cancerous cell types to MRT. We compare two methods of quantifying γ-H2AX nuclear fluorescence for uniformly irradiated cell cultures: manual counting of γ-H2AX foci by eye, and an automated, MATLAB-based fluorescence intensity measurement. We also demonstrate the automated analysis of cell cultures irradiated with an array of microbeams. In addition to offering a relatively high dynamic range of γ-H2AX signal versus irradiation dose ( > 10 Gy), our automated method provides speed, robustness, and objectivity when examining a series of images. Our in-house analysis facilitates the automated extraction of the spatial distribution of the γ-H2AX intensity with respect to the microbeam array — for example, the intensities in the peak (high dose area) and valley (area between two microbeams) regions. The automated analysis is particularly beneficial when processing a large number of samples, as is needed to systematically study the relationship between the numerous dosimetric and geometric parameters involved with MRT (e.g., microbeam width, microbeam spacing, microbeam array dimensions, peak dose, valley dose, and geometric arrangement of multiple arrays) and the resulting DNA damage.

NF-κB dynamics show digital activation and analog information processing in cells

NASA Astrophysics Data System (ADS)

Tay, Savas; Hughey, Jake; Lee, Timothy; Lipniacki, Tomasz; Covert, Markus; Quake, Stephen

2010-03-01

Cells operate in ever changing environments using extraordinary communication capabilities. Cell-to-cell communication is mediated by signaling molecules that form spatiotemporal concentration gradients, which requires cells to respond to a wide range of signal intensities. We used high-throughput microfluidic cell culture, quantitative gene expression analysis and mathematical modeling to investigate how single mammalian cells respond to different concentrations of the signaling molecule TNF-α via the transcription factor NF-κB. We measured NF-κB activity in thousands of live cells under TNF-α doses covering four orders of magnitude. In contrast to population studies, the activation is a stochastic, switch-like process at the single cell level with fewer cells responding at lower doses. The activated cells respond fully and express early genes independent of the TNF-α concentration, while only high dose stimulation results in the expression of late genes. Cells also encode a set of analog parameters such as the NF-κB peak intensity, response time and number of oscillations to modulate the outcome. We developed a stochastic model that reproduces both the digital and analog dynamics as well as the gene expression profiles at all measured conditions, constituting a broadly applicable model for TNF-α induced NF-κB signaling in various types of cells.

Ultrasound-guided corticosteroid injection therapy for juvenile idiopathic arthritis: 12-year care experience.

PubMed

Young, Cody M; Shiels, William E; Coley, Brian D; Hogan, Mark J; Murakami, James W; Jones, Karla; Higgins, Gloria C; Rennebohm, Robert M

2012-12-01

Intra-articular corticosteroid injections are a safe and effective treatment for patients with juvenile idiopathic arthritis. The potential scope of care in ultrasound-guided corticosteroid therapy in children and a joint-based corticosteroid dose protocol designed to optimize interdisciplinary care are not found in the current literature. The purpose of this study was to report the spectrum of care, technique and safety of ultrasound-guided corticosteroid injection therapy in patients with juvenile idiopathic arthritis and to propose an age-weight-joint-based corticosteroid dose protocol. A retrospective analysis was performed of 198 patients (ages 21 months to 28 years) referred for treatment of juvenile idiopathic arthritis with corticosteroid therapy. Symptomatic joints and tendon sheaths were treated as prescribed by the referring rheumatologist. An age-weight-joint-based dose protocol was developed and utilized for corticosteroid dose prescription. A total of 1,444 corticosteroid injections (1,340 joints, 104 tendon sheaths) were performed under US guidance. Injection sites included small, medium and large appendicular skeletal joints (upper extremity 497, lower extremity 837) and six temporomandibular joints. For patients with recurrent symptoms, 414 repeat injections were performed, with an average time interval of 17.7 months (range, 0.5-101.5 months) between injections. Complications occurred in 2.6% of injections and included subcutaneous tissue atrophy, skin hypopigmentation, erythema and pruritis. US-guided corticosteroid injection therapy provides dynamic, precise and safe treatment of a broad spectrum of joints and tendon sheaths throughout the entire pediatric musculoskeletal system. An age-weight-joint-based corticosteroid dose protocol is effective and integral to interdisciplinary care of patients with juvenile idiopathic arthritis.

A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

PubMed

van Iersel, Marlou L P S; Rossenu, Stefaan; de Greef, Rik; Waskin, Hetty

2018-04-30

A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia vs allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (single dose vs multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/l) to a broad range of patients at high risk for invasive fungal disease. Copyright © 2018 American Society for Microbiology.

A Characterization of the Radiation from a Rod-Pinch Diode

NASA Astrophysics Data System (ADS)

Swanekamp, Stephen B.; Allen, Raymond J.; Hinshelwood, David D.; Mosher, David; Schumer, Joseph W.

2002-12-01

Coupled PIC-Monte-Carlo simulations of the electron-flow and radiation production in a rod-pinch diode show that multiple scatterings in the rod produce incident electron energies that ranging from zero to slightly higher than the applied voltage. It is speculated that those electrons that gain energy do so by remaining in phase with a rapidly varying electric field near the tip of the rod. The simulations also show that multiple passes in the rod produce a wide spread in incident electron angles. For diode voltages of V=2 MV, the angular distribution of electrons incident on the rod is broad and peaked near 90° to the axis of the rod with a larger fraction of electrons striking the rod at angles less than 90°. The electron angular distribution for V=4 MV is narrower and peaked at 105° with a larger fraction of electrons incident on the rod with angles greater than 90°. The photon distributions are peaked along the direction of the high-energy electrons. For V=2 MV the dose filtered through 21/4-cm thick Plexiglas is peaked at 90° and is 1.8 times higher than the forward-directed [0°] dose. For V=4 MV the dose filtered through 21/4-cm thick Plexiglas is peaked at 120° and is 2.3 times higher than the forward-directed dose. Similar angular variation of the dose has been observed on the 4-MV Asterix accelerator [2] and on 1-2 MV accelerators at the Atomic Weapons Establishment [8].

Comparison of effects produced by nicotine and the α4β2-selective agonist 5-I-A-85380 on intracranial self-stimulation in rats.

PubMed

Freitas, Kelen; Carroll, F Ivy; Negus, S Stevens

2016-02-01

Intracranial self-stimulation (ICSS) is one type of preclinical procedure for research on pharmacological mechanisms that mediate abuse potential of drugs acting at various targets, including nicotinic acetylcholine receptors (nAChRs). This study compared effects of the nonselective nAChR agonist nicotine (0.032-1.0 mg/kg) and the α4β2-selective nAChR agonist 5-I-A-85380 (0.01-1.0 mg/kg) on ICSS in male Sprague-Dawley rats. Rats were implanted with electrodes targeting the medial forebrain bundle at the level of the lateral hypothalamus and trained to respond under a fixed-ratio 1 schedule for a range of brain stimulation frequencies (158-56 Hz). A broad range of 5-I-A-85380 doses produced an abuse-related increase (or "facilitation") of low ICSS rates maintained by low brain-stimulation frequencies, and this effect was blocked by both the nonselective nAChR antagonist mecamylamine and the selective α4β2 antagonist dihyrdo-β-erythroidine (DHβE). Conversely, nicotine produced weaker ICSS facilitation across a narrower range of doses, and higher nicotine doses decreased high rates of ICSS maintained by high brain-stimulation frequencies. The rate-decreasing effects of a high nicotine dose were blocked by mecamylamine but not DHβE. Chronic nicotine treatment produced selective tolerance to rate-decreasing effects of nicotine but did not alter ICSS rate-increasing effects of nicotine. These results suggest that α4β2 receptors are sufficient to mediate abuse-related rate-increasing effects of nAChR agonists in this ICSS procedure. Conversely, nicotine effects at non-α4β2 nAChRs appear to oppose and limit abuse-related effects mediated by α4β2 receptors, although tolerance can develop to these non-α4β2 effects. Selective α4β2 agonists may have higher abuse potential than nicotine. PsycINFO Database Record (c) 2016 APA, all rights reserved.

The Use of a Multidimensional Measure of Dialysis Adequacy—Moving beyond Small Solute Kinetics

PubMed Central

Perl, Jeffrey; Dember, Laura M.; Bargman, Joanne M.; Browne, Teri; Charytan, David M.; Flythe, Jennifer E.; Hickson, LaTonya J.; Hung, Adriana M.; Jadoul, Michel; Lee, Timmy Chang; Meyer, Klemens B.; Moradi, Hamid; Shafi, Tariq; Teitelbaum, Isaac; Wong, Leslie P.

2017-01-01

Urea removal has become a key measure of the intensity of dialysis treatment for kidney failure. Small solute removal, exemplified by Kt/Vurea, has been broadly applied as a means to quantify the dose of thrice weekly hemodialysis. Yet, the reliance on small solute clearances alone as a measure of dialysis adequacy fails fully to quantify the intended clinical effects of dialysis therapy. This review aims to (1) understand the strengths and limitations of small solute kinetics as a surrogate marker of dialysis dose, and (2) present the prospect of a more comprehensive construct for dialysis dose, one that considers more broadly the goals of ESRD care to maximize both quality of life and survival. On behalf of the American Society of Nephrology Dialysis Advisory Group, we propose the need to ascertain the validity and utility of a multidimensional measure that moves beyond small solute kinetics alone to quantify optimal dialysis derived from both patient-reported and comprehensive clinical and dialysis-related measures. PMID:28314806

Are higher doses of proton pump inhibitors better in acute peptic bleeding?

PubMed

Villalón, Alejandro; Olmos, Roberto; Rada, Gabriel

2016-06-24

Although there is broad consensus about the benefits of proton pump inhibitors in acute upper peptic bleeding, there is still controversy over their optimal dosing. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 27 randomized trials addressing this question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded high-dose proton pump inhibitors probably result in little or no difference in re-bleeding rate or mortality. The risk/benefit and cost/benefit balance probably favor use of low-doses.

Parthenolide Selectively Sensitizes Prostate Tumor Tissue to Radiotherapy while Protecting Healthy Tissues In Vivo.

PubMed

Morel, Katherine L; Ormsby, Rebecca J; Bezak, Eva; Sweeney, Christopher J; Sykes, Pamela J

2017-05-01

Radiotherapy is widely used in cancer treatment, however the benefits can be limited by radiation-induced damage to neighboring normal tissues. Parthenolide (PTL) exhibits anti-inflammatory and anti-tumor properties and selectively induces radiosensitivity in prostate cancer cell lines, while protecting primary prostate epithelial cell lines from radiation-induced damage. Low doses of radiation have also been shown to protect from subsequent high-dose-radiation-induced apoptosis as well as DNA damage. These properties of PTL and low-dose radiation could be used to improve radiotherapy by killing more tumor cells and less normal cells. Sixteen-week-old male Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) and C57BL/6J mice were treated with PTL (40 mg/kg), dimethylaminoparthenolide (DMAPT, a PTL analogue with increased bioavailability) (100 mg/kg), or vehicle control three times over one week prior to combinations of low (10 mGy) and high (6 Gy) doses of whole-body X-irradiation. Tissues were analyzed for apoptosis at a range of time points up to 72 h postirradiation. Both PTL and DMAPT protected normal tissues, but not prostate tumor tissues, from a significant proportion of high-dose-radiation-induced apoptosis. DMAPT provided superior protection compared to PTL in normal dorsolateral prostate (71.7% reduction, P = 0.026), spleen (48.2% reduction, P = 0.0001) and colorectal tissue (38.0% reduction, P = 0.0002), and doubled radiation-induced apoptosis in TRAMP prostate tumor tissue (101.3% increase, P = 0.039). Both drugs induced the greatest radiosensitivity in TRAMP prostate tissue in areas with higher grade prostatic intraepithelial neoplasia (PIN) lesions. A 10 mGy dose delivered 3 h prior to a 6 Gy dose induced a radioadaptive apoptosis response in normal C57Bl/6J prostate (28.4% reduction, P = 0.045) and normal TRAMP spleen (13.6% reduction, P = 0.047), however the low-dose-adaptive radioprotection did not significantly add to the PTL/DMAPT-induced protection in normal tissues, nor did it affect tumor kill. These results support the use of the more bioavailable DMAPT and low-dose radiation, alone or in combination as useful radioprotectors of normal tissues to alleviate radiotherapy-induced side-effects in patients. The enhanced radiosensitisation in prostate tissues displaying high-grade PIN suggests that DMAPT also holds promise for targeted therapy of advanced prostate cancer, which may go on to become metastatic. The redox mechanisms involved in the differential radioprotection observed here suggest that increased radiotherapy efficacy by DMAPT is more broadly applicable to a range of cancer types.

A phase I and pharmacokinetic study of a powder-filled capsule formulation of oral irinotecan (CPT-11) given daily for 5 days every 3 weeks in patients with advanced solid tumors.

PubMed

Pitot, Henry C; Adjei, Alex A; Reid, Joel M; Sloan, Jeff A; Atherton, Pamela J; Rubin, Joseph; Alberts, Steven R; Duncan, Barbara A; Denis, Louis; Schaaf, Larry J; Yin, Donghua; Sharma, Amarnath; McGovren, Patrick; Miller, Langdon L; Erlichman, Charles

2006-08-01

Intravenous (i.v.) irinotecan is a cytotoxic topoisomerase I inhibitor with broad clinical activity in metastatic colorectal cancer and other tumors. The development of an oral formulation of irinotecan could enhance convenience and lessen the expense of palliative irinotecan delivery. This phase I study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of irinotecan given as a powder-filled capsule (PFC) daily for 5 days every 3 weeks. Patients with advanced solid tumors received escalating doses of oral irinotecan daily for 5 days every 3 weeks. Plasma samples were collected following the first and fifth doses of irinotecan during Cycle 1 to determine the PK of irinotecan and its major circulating metabolites: SN-38, SN-38G, and APC. 20 patients (median age 61.5 years, range 40-75; M/F 12/8; ECOG PS 0=5, 1=11, 2=4) received oral irinotecan at dose levels of 30 (n=3), 40 (n=3), 50 (n=6), and 60 (n=8) mg/m(2)/day. Of the eight patients enrolled at 60 mg/m(2), three patients experienced DLT (> or = grade 3) consisting of nausea (three patients), vomiting (three patients), diarrhea (two patients), and febrile neutropenia (two patients) for which all the three patients required hospitalization. Treatment of six patients at the 50-mg/m(2) dose level resulted in no DLT. Other toxicities observed include abdominal pain, alopecia, anorexia, and asthenia. After oral administration, irinotecan was rapidly absorbed into systemic circulation and converted to the active metabolite SN-38. Increasing dose levels resulted in a dose-dependent increase in mean exposure parameters (Cmax and AUC) of irinotecan and metabolites. Systemic exposure parameters (Cmax and AUC(0-24)) of irinotecan and SN-38 were comparable between days 1 and 5. The extent of conversion from irinotecan to SN-38 was approximately threefold higher after the oral administration compared to that previously observed after i.v. administration. The exposure parameters of irinotecan or SN-38 are of limited value in predicting severity of Cycle 1 toxicities in the twofold dose range evaluated. Daily oral administration of irinotecan as the PFC formulation for 5 days every 3 weeks can safely deliver protracted exposure to SN-38, with the MTD of 50 mg/m(2)/d.

Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

NASA Technical Reports Server (NTRS)

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

1999-01-01

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

Structural and functional evidences for the interactions between nuclear hormone receptors and endocrine disruptors at low doses.

PubMed

Balaguer, Patrick; Delfosse, Vanessa; Grimaldi, Marina; Bourguet, William

Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system mainly by interacting with nuclear hormone receptors (NRs). Humans are generally exposed to low doses of pollutants, and current researches aim at deciphering the mechanisms accounting for the health impact of EDCs at environmental concentrations. Our correlative analysis of structural, interaction and cell-based data has revealed a variety of, sometimes unexpected, binding modes, reflecting a wide range of EDC affinities and specificities. Here, we present a few representative examples to illustrate various means by which EDCs achieve high-affinity binding to NRs. These examples include the binding of the mycoestrogen α-zearalanol to estrogen receptors, the covalent interaction of organotins with the retinoid X- and peroxisome proliferator-activated receptors, and the cooperative binding of two chemicals to the pregnane X receptor. We also discuss some hypotheses that could further explain low-concentration effects of EDCs with weaker affinity towards NRs. Copyright © 2017. Published by Elsevier Masson SAS.

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B.

PubMed

Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H; Streatfield, Stephen J; Herzog, Roland W; Daniell, Henry

2015-11-01

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP(+) regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft(2) per annum yielding 24,000-36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Efficacy of the nematode-trapping fungus Duddingtonia flagrans against three species of gastro-intestinal nematodes in laboratory faecal cultures from sheep and goats.

PubMed

Waghorn, T S; Leathwick, D M; Chen, L-Y; Skipp, R A

2003-12-30

The ability of the nematode-killing fungus Duddingtonia flagrans to reduce number of infective larvae of three species of gastro-intestinal parasitic nematodes developing in dung was investigated in both goats and sheep. Groups of lambs and kids (12-20 weeks old) were given mono-specific infections of Haemonchus contortus, Ostertagia (Teladorsagia) circumcincta or Trichostrongylus colubriformis. Following patency of the infections (t1) faecal samples were collected for determination of faecal nematode egg count (FEC) and culture of parasite larvae. Groups of animals were then dosed on 2 consecutive days with one of the two dose rates of the fungus (250,000 or 500,000 spores/kg liveweight). One (t2) and 5 (t3) days after the second dose of fungus samples were again collected for FEC and culture. The number of larvae recovered from the faecal cultures at t1 and t3 were used as controls to assess the efficacy of the experimental treatment at t2. Average efficacy was 78% with group means ranging from 40 to 93%. Dose rate of fungus appeared to influence efficacy against O. circumcincta but not against H. contortus or T. colubriformis. Overall, there were no differences in the efficacy of the fungus against any of the parasite species or in either host animal. The results of this trial indicate the potential use of this fungus as a broad spectrum anti-parasite agent for use in both goats and sheep.

Irradiation-induced defect formation and damage accumulation in single crystal CeO 2

DOE PAGES

Graham, Joseph T.; Zhang, Yanwen; Weber, William J.

2017-11-15

Here, the accumulation of irradiation-induced disorder in single crystal CeO 2 has been investigated over a wide range of ion fluences. Room temperature irradiations of epitaxial CeO 2 thin films using 2 MeV Au 2+ ions were carried out up to a total fluence of 1.3 x 10 16 cm –2 Post-irradiation disorder was characterized using ion channeling Rutherford backscattering spectrometry (RBS/C) and confocal Raman spectroscopy. The Raman measurements were interpreted by means of a phonon confinement model, which employed rigid ion calculations to determine the phonon correlation length in the irradiated material. Comparison between the dose dependent changes inmore » correlation length of the Raman measurements and the Ce disorder fraction from RBS/C provides complementary quantitative details on the rate of point and extended defect formation on the Ce and O sub-lattices over a broad range of ion fluences. Raman measurements, which are significantly more sensitive than RBS/C at low doses, reveal that the nucleation rate of defects is highest below 0.1 displacements per atom (dpa). Comparison between Raman and RBS/C measurements suggests that between 0.1 and 10 dpa the damage evolution is characterized by modest growth of point defects and/or small clusters, while above 10 dpa the preexisting defects rapidly grow into extended clusters and/or loops.« less

Irradiation-induced defect formation and damage accumulation in single crystal CeO2

NASA Astrophysics Data System (ADS)

Graham, Joseph T.; Zhang, Yanwen; Weber, William J.

2018-01-01

The accumulation of irradiation-induced disorder in single crystal CeO2 has been investigated over a wide range of ion fluences. Room temperature irradiations of epitaxial CeO2 thin films using 2 MeV Au2+ ions were carried out up to a total fluence of 1.3 ×1016 cm-2 Post-irradiation disorder was characterized using ion channeling Rutherford backscattering spectrometry (RBS/C) and confocal Raman spectroscopy. The Raman measurements were interpreted by means of a phonon confinement model, which employed rigid ion calculations to determine the phonon correlation length in the irradiated material. Comparison between the dose dependent changes in correlation length of the Raman measurements and the Ce disorder fraction from RBS/C provides complementary quantitative details on the rate of point and extended defect formation on the Ce and O sub-lattices over a broad range of ion fluences. Raman measurements, which are significantly more sensitive than RBS/C at low doses, reveal that the nucleation rate of defects is highest below 0.1 displacements per atom (dpa). Comparison between Raman and RBS/C measurements suggests that between 0.1 and 10 dpa the damage evolution is characterized by modest growth of point defects and/or small clusters, while above 10 dpa the preexisting defects rapidly grow into extended clusters and/or loops.

Irradiation-induced defect formation and damage accumulation in single crystal CeO 2

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

Graham, Joseph T.; Zhang, Yanwen; Weber, William J.

Here, the accumulation of irradiation-induced disorder in single crystal CeO 2 has been investigated over a wide range of ion fluences. Room temperature irradiations of epitaxial CeO 2 thin films using 2 MeV Au 2+ ions were carried out up to a total fluence of 1.3 x 10 16 cm –2 Post-irradiation disorder was characterized using ion channeling Rutherford backscattering spectrometry (RBS/C) and confocal Raman spectroscopy. The Raman measurements were interpreted by means of a phonon confinement model, which employed rigid ion calculations to determine the phonon correlation length in the irradiated material. Comparison between the dose dependent changes inmore » correlation length of the Raman measurements and the Ce disorder fraction from RBS/C provides complementary quantitative details on the rate of point and extended defect formation on the Ce and O sub-lattices over a broad range of ion fluences. Raman measurements, which are significantly more sensitive than RBS/C at low doses, reveal that the nucleation rate of defects is highest below 0.1 displacements per atom (dpa). Comparison between Raman and RBS/C measurements suggests that between 0.1 and 10 dpa the damage evolution is characterized by modest growth of point defects and/or small clusters, while above 10 dpa the preexisting defects rapidly grow into extended clusters and/or loops.« less

Wavelength dependent recovery of UV-mediated damage: Tying up the loose ends of optical based powdery mildew management.

PubMed

Suthaparan, Aruppillai; Pathak, Ranjana; Solhaug, Knut Asbjørn; Gislerød, Hans Ragnar

2018-01-01

Controlled environment chamber experiments at Petri dish level were conducted to examine the wavelength and dose dependent efficacy of ultraviolet (UV) radiation, the recovery action potential of optical radiation applied concomitantly/subsequently to effective UV treatment, and the lapse time between UV treatment and subsequent exposure to recovery wavelength on germination efficiency of Oidium neolycopersici conidia. Conidia of eight- to nine-day-old colonies were dusted on water agar surface in Petri dishes and exposed to UV treatments (without lid). Immediately after UV treatments, Petri dishes were sealed and incubated in darkness or differing optical environments generated using seven different radiation sources (range 290nm to 780nm). Twenty-four hours after UV treatment, fifty conidia from each sample were assessed for germination. Compared to non-UV controls, <10% of the conidia germinated after 30s of exposure to 254nm or 283nm UV and subsequent dark incubation. Conidia germination was almost negligible if the exposure duration increased to 4min. Germination was about 60% with broad spectrum UV after 1min of exposure, and about 35% after 2 to 4min of exposure. There was no reduction of conidia germination with the exposure of ≤4min with 310nm. With the tested wavelength and dose ranges, germination recovery was effective in the 350nm to 500nm range. Germination efficiency of conidia treated with effective UV was significantly higher (>73%) if incubated subsequently in the 350nm to 500nm range (germination recovery). Furthermore, germination recovery depends on the characteristics of UV treatment (wavelength, and duration of exposure) and the lapse time between UV treatment and subsequent exposure to optical radiation in the recovery range. The findings of this study provide key criteria for wavelength selection, combination and application time in the optical radiation range, enabling improved design of optical based management strategies against powdery mildews. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed Central

2014-01-01

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

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

PubMed Central

2016-01-01

Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics. PMID:27936709

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats.

PubMed

Schnakenberg Martin, Ashley M; OʼDonnell, Brian F; Millward, James B; Vohs, Jenifer L; Leishman, Emma; Bolbecker, Amanda R; Rass, Olga; Morzorati, Sandra L

2017-01-01

The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-D-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders. © 2017 S. Karger AG, Basel.

Effect of radiocesium transfer on ambient dose rate in forest environments affected by the Fukushima Nuclear Power Plant accident

NASA Astrophysics Data System (ADS)

Kato, H.

2015-12-01

We investigated the transfer of canopy-intercepted radiocesium to the forest floor during 3 years following the Fukushima Daiichi Nuclear Power Plant accident. The cesium-137 (Cs-137) contents in throughfall, stemflow, and litterfall were monitored in two coniferous stands (plantation of Japanese cedar) and a deciduous broad-leaved forest stand (Japanese oak with red pine). We also measured the ambient dose rate (ADR) at different heights in the forest using a survey meter and a portable Ge gamma-ray detector. Total Cs-137 deposition flux from the canopy to forest floor for the mature cedar, young cedar, and the mixed broad-leaved stands were 166 kBq/m2, 174 kBq/m2, and 60 kBq/m2, respectively. These values correspond to 38%, 40% and 13% of total atmospheric input after the accident. The ambient dose rate in forest exhibited height dependency and its vertical distribution varied with forest type and stand age. The ambient dose rate showed an exponential decrease with time for all the forest sites, however the decreasing trend differed depending on the height of dose measurement and forest type. The ambient dose rate at the canopy (approx. 10 m-height) decreased faster than that expected from physical decay of the two radiocesium isotopes, whereas those at the forest floor varied between the three forest stands. The radiocesium deposition via throughfall seemed to increase ambient dose rate during the first 200 days after the accident, however there was no clear relationship between litterfall and ambient dose rate since 400 days after the accident. These data suggested that the ambient dose rate in forest environment varied both spatially and temporally reflecting the transfer of radiocesium from canopy to forest floor. However, further monitoring investigation and analysis are required to determine the effect of litterfall on long-term trend of ambient dose rate in forest environments.

Computational Toxicology

EPA Science Inventory

‘Computational toxicology’ is a broad term that encompasses all manner of computer-facilitated informatics, data-mining, and modeling endeavors in relation to toxicology, including exposure modeling, physiologically based pharmacokinetic (PBPK) modeling, dose-response modeling, ...

Levofloxacin : a review of its use as a high-dose, short-course treatment for bacterial infection.

PubMed

Anderson, Vanessa R; Perry, Caroline M

2008-01-01

Levofloxacin (Levaquin) is a fluoroquinolone antibacterial that is the L-isomer of ofloxacin. A high-dose (750 mg) short-course (5 days) of once-daily levofloxacin is approved for use in the US in the treatment of community-acquired pneumonia (CAP), acute bacterial sinusitis (ABS), complicated urinary tract infections (UTI) and acute pyelonephritis (AP). The broad spectrum antibacterial profile of levofloxacin means that monotherapy is often a possibility in patients with CAP at times when other agents may require combination therapy, although levofloxacin can be used in combination therapy when necessary. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent bactericidal activity and may reduce the potential for resistance to emerge. In addition, this regimen lends itself to better compliance because of the shorter duration of treatment and the convenient once-daily administration schedule. Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation; importantly, patients can transition between the formulations, which results in more options in regards to the treatment regimen and the potential for patients with varying degrees of illness to be treated. Levofloxacin has good tissue penetration and an adequate concentration can be maintained in the urinary tract to treat uropathogens. Levofloxacin is generally well tolerated and has good efficacy in the treatment of patients with CAP, ABS, complicated UTI and AP. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP, ABS and UTIs is well established, and the high-dose, short-course levofloxacin regimen has been shown to be noninferior to the 10-day regimen in CAP and ABS, and to have a similar tolerability profile. Similarly, the high-dose, short-course levofloxacin regimen is noninferior to ciprofloxacin in patients with complicated UTI or AP. Thus, levofloxacin is a valuable antimicrobial agent that has activity against a wide range of bacterial pathogens; however, its use should be considered carefully so that the potential for resistance selection can be minimized and its usefulness in severe infections and against a range of penicillin- and macrolide-resistant pathogens can be maintained.

Magnitude of cyantraniliprole residues in tomato following open field application: pre-harvest interval determination and risk assessment.

PubMed

Malhat, Farag; Kasiotis, Konstantinos M; Shalaby, Shehata

2018-02-05

Cyantraniliprole is an anthranilic diamide insecticide, belonging to the ryanoid class, with a broad range of applications against several pests. In the presented work, a reliable analytical technique employing high-performance liquid chromatography coupled with photodiode array detector (HPLC-DAD) for analyzing cyantraniliprole residues in tomato was developed. The method was then applied to field-incurred tomato samples collected after applications under open field conditions. The latter aimed to ensure the safe application of cyantraniliprole to tomato and contribute the derived residue data to the risk assessment under field conditions. Sample preparation involved a single step extraction with acetonitrile and sodium chloride for partitioning. The extract was purified utilizing florisil as cleanup reagent. The developed method was further evaluated by comparing the analytical results with those obtained using the QuEChERS technique. The novel method outbalanced QuEChERS regarding matrix interferences in the analysis, while it met all guideline criteria. Hence, it showed excellent linearity over the assayed concentration and yielded satisfactory recovery rate in the range of 88.9 to 96.5%. The half-life of degradation of cyantraniliprole was determined at 2.6 days. Based on the Codex MRL, the pre-harvest interval (PHI) for cyantraniliprole on tomato was 3 days, after treatment at the recommended dose. To our knowledge, the present work provides the first record on PHI determination of cyantraniliprole in tomato under open field conditions in Egypt and the broad Mediterranean region.

Do Elite and Amateur Soccer Players Outperform Non-Athletes on Neurocognitive Functioning? A Study Among 8-12 Year Old Children.

PubMed

Verburgh, Lot; Scherder, Erik J A; Van Lange, Paul A M; Oosterlaan, Jaap

2016-01-01

Research suggested a positive association between physical fitness and neurocognitive functioning in children. Aim of the present study is to investigate possible dose-response relationships between diverse daily physical activities and a broad range of neurocognitive functions in preadolescent children. Furthermore, the relationship between several sedentary behaviours, including TV-watching, gaming and computer time, and neurocognitive functioning will be investigated in this group of children. A total of 168 preadolescent boys, aged 8 to 12 years, were recruited from various locations, including primary schools, an amateur soccer club, and a professional soccer club, to increase variability in the amount of participation in sports. All children performed neurocognitive tasks measuring inhibition, short term memory, working memory, attention and information processing speed. Regression analyses examined the predictive power of a broad range of physical activities, including sports, active transport to school, physical education (PE), outdoor play, and sedentary behaviour such as TV-watching and gaming, for neurocognitive functioning. Time spent in sports significantly accounted for the variance in inhibition, short term memory, working memory and lapses of attention, where more time spent in sports was associated with better performance. Outdoor play was also positively associated with working memory. In contrast, time spent on the computer was negatively associated with inhibition. Results of the current study suggest a positive relationship between participation in sports and several important neurocognitive functions. Interventions are recommended to increase sports participation and to reduce sedentary behaviour in preadolescent children.

A 12-month phase 3 study of pasireotide in Cushing's disease.

PubMed

Colao, Annamaria; Petersenn, Stephan; Newell-Price, John; Findling, James W; Gu, Feng; Maldonado, Mario; Schoenherr, Ulrike; Mills, David; Salgado, Luiz Roberto; Biller, Beverly M K

2012-03-08

Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).

Assessment of the actual light dose in photodynamic therapy.

PubMed

Schaberle, Fabio A

2018-06-09

Photodynamic therapy (PDT) initiates with the absorption of light, which depends on the spectral overlap between the light source emission and the photosensitizer absorption, resulting in the number of photons absorbed, the key parameter starting PDT processes. Most papers report light doses regardless if the light is only partially absorbed or shifted relatively to the absorption peak, misleading the actual light dose value and not allowing quantitative comparisons between photosensitizers and light sources. In this manuscript a method is presented to calculate the actual light dose delivered by any light source for a given photosensitizer. This method allows comparing light doses delivered for any combination of light source (broad or narrow band or daylight) and photosensitizer. Copyright © 2018. Published by Elsevier B.V.

Phase 2 Randomized Trial of the Safety and Efficacy of MHAA4549A, a Broadly Neutralizing Monoclonal Antibody, in a Human Influenza A Virus Challenge Model.

PubMed

McBride, Jacqueline M; Lim, Jeremy J; Burgess, Tracy; Deng, Rong; Derby, Michael A; Maia, Mauricio; Horn, Priscilla; Siddiqui, Omer; Sheinson, Daniel; Chen-Harris, Haiyin; Newton, Elizabeth M; Fillos, Dimitri; Nazzal, Denise; Rosenberger, Carrie M; Ohlson, Maikke B; Lambkin-Williams, Rob; Fathi, Hosnieh; Harris, Jeffrey M; Tavel, Jorge A

2017-11-01

MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID 50 ) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of ∼23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.). Copyright © 2017 American Society for Microbiology.

Behavioral phenotypes associated with MPTP induction of partial lesions in common marmosets (Callithrix jacchus).

PubMed

Phillips, Kimberley A; Ross, Corinna N; Spross, Jennifer; Cheng, Catherine J; Izquierdo, Alyssa; Biju, K C; Chen, Cang; Li, Senlin; Tardif, Suzette D

2017-05-15

Parkinson's disease is a chronic neurodegenerative disorder with the core motor features of resting tremor, bradykinesia, rigidity, and postural instability. Non-motor symptoms also occur, and include cognitive dysfunction, mood disorders, anosmia (loss of smell), and REM sleep disturbances. As the development of medications and other therapies for treatment of non-motor symptoms is ongoing, it is essential to have animal models that aid in understanding the neural changes underlying non-motor PD symptoms and serve as a testing ground for potential therapeutics. We investigated several non-motor symptoms in 10 adult male marmosets using the MPTP model, with both the full (n=5) and partial (n=5) MPTP dosing regimens. Baseline data in numerous domains were collected prior to dosing; assessments in these same domains occurred post-dosing for 12 weeks. Marmosets given the partial MPTP dose (designed to mimic the early stages of the disease) differed significantly from marmosets given the full MPTP dose in several ways, including behavior, olfactory discrimination, cognitive performance, and social responses. Importantly, while spontaneous recovery of PD motor symptoms has been previously reported in studies of MPTP monkeys and cats, we did not observe recovery of any non-motor symptoms. This suggests that the neurochemical mechanisms behind the non-motor symptoms of PD, which appear years before the onset of symptoms, are independent of the striatal dopaminergic transmission. We demonstrate the value of assessing a broad range of behavioral change to detect non-motor impairment, anosmia, and differences in socially appropriate responses, in the marmoset MPTP model of early PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Chlorinated Persistent Organic Pollutants, Obesity, and Type 2 Diabetes

PubMed Central

Porta, Miquel; Jacobs, David R.; Vandenberg, Laura N.

2014-01-01

Persistent organic pollutants (POPs) are lipophilic compounds that travel with lipids and accumulate mainly in adipose tissue. Recent human evidence links low-dose POPs to an increased risk of type 2 diabetes (T2D). Because humans are contaminated by POP mixtures and POPs possibly have nonmonotonic dose-response relations with T2D, critical methodological issues arise in evaluating human findings. This review summarizes epidemiological results on chlorinated POPs and T2D, and relevant experimental evidence. It also discusses how features of POPs can affect inferences in humans. The evidence as a whole suggests that, rather than a few individual POPs, background exposure to POP mixtures—including organochlorine pesticides and polychlorinated biphenyls—can increase T2D risk in humans. Inconsistent statistical significance for individual POPs may arise due to distributional differences in POP mixtures among populations. Differences in the observed shape of the dose-response curves among human studies may reflect an inverted U-shaped association secondary to mitochondrial dysfunction or endocrine disruption. Finally, we examine the relationship between POPs and obesity. There is evidence in animal studies that low-dose POP mixtures are obesogenic. However, relationships between POPs and obesity in humans have been inconsistent. Adipose tissue plays a dual role of promoting T2D and providing a relatively safe place to store POPs. Large prospective studies with serial measurements of a broad range of POPs, adiposity, and clinically relevant biomarkers are needed to disentangle the interrelationships among POPs, obesity, and the development of T2D. Also needed are laboratory experiments that more closely mimic real-world POP doses, mixtures, and exposure duration in humans. PMID:24483949

Benchmarking and validation of a Geant4-SHADOW Monte Carlo simulation for dose calculations in microbeam radiation therapy.

PubMed

Cornelius, Iwan; Guatelli, Susanna; Fournier, Pauline; Crosbie, Jeffrey C; Sanchez Del Rio, Manuel; Bräuer-Krisch, Elke; Rosenfeld, Anatoly; Lerch, Michael

2014-05-01

Microbeam radiation therapy (MRT) is a synchrotron-based radiotherapy modality that uses high-intensity beams of spatially fractionated radiation to treat tumours. The rapid evolution of MRT towards clinical trials demands accurate treatment planning systems (TPS), as well as independent tools for the verification of TPS calculated dose distributions in order to ensure patient safety and treatment efficacy. Monte Carlo computer simulation represents the most accurate method of dose calculation in patient geometries and is best suited for the purpose of TPS verification. A Monte Carlo model of the ID17 biomedical beamline at the European Synchrotron Radiation Facility has been developed, including recent modifications, using the Geant4 Monte Carlo toolkit interfaced with the SHADOW X-ray optics and ray-tracing libraries. The code was benchmarked by simulating dose profiles in water-equivalent phantoms subject to irradiation by broad-beam (without spatial fractionation) and microbeam (with spatial fractionation) fields, and comparing against those calculated with a previous model of the beamline developed using the PENELOPE code. Validation against additional experimental dose profiles in water-equivalent phantoms subject to broad-beam irradiation was also performed. Good agreement between codes was observed, with the exception of out-of-field doses and toward the field edge for larger field sizes. Microbeam results showed good agreement between both codes and experimental results within uncertainties. Results of the experimental validation showed agreement for different beamline configurations. The asymmetry in the out-of-field dose profiles due to polarization effects was also investigated, yielding important information for the treatment planning process in MRT. This work represents an important step in the development of a Monte Carlo-based independent verification tool for treatment planning in MRT.

Phase I Trial of Brentuximab Vedotin for Steroid-Refractory Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

PubMed

DeFilipp, Zachariah; Li, Shuli; Kempner, Maria E; Brown, Jami; Del Rio, Candice; Valles, Betsy; Hunnewell, Chrisa; Saylor, Meredith; Vanderklish, Julie; Dey, Bimalangshu R; El-Jawahri, Areej; McAfee, Steven L; Spitzer, Thomas R; Chen, Yi-Bin

2018-05-11

We conducted a phase I study of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3+3 study design was used with the primary endpoint to determine the maximum tolerated dose (MTD) of BV in this population. Escalating doses of BV were planned, starting with 0.6 mg/kg q3weeks (dose level 0) and increasing by 0.3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent prior to dosing. The median number of cycles of therapy was 4 (range, 1-16). Reasons for stopping therapy prematurely included toxicities (n=9), patient decision (n=3), lack of response (n=2), and death (n=1). There were 2 DLTs observed: PRES (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The MTD was not reached as the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to NIH cGVHD Response Criteria, 8 patients (47%) experienced a partial response while 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level prior to therapy was 61.5 ng/mL (range, 7.8-474.9), however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed. Copyright © 2018. Published by Elsevier Inc.

The Use of a Multidimensional Measure of Dialysis Adequacy-Moving beyond Small Solute Kinetics.

PubMed

Perl, Jeffrey; Dember, Laura M; Bargman, Joanne M; Browne, Teri; Charytan, David M; Flythe, Jennifer E; Hickson, LaTonya J; Hung, Adriana M; Jadoul, Michel; Lee, Timmy Chang; Meyer, Klemens B; Moradi, Hamid; Shafi, Tariq; Teitelbaum, Isaac; Wong, Leslie P; Chan, Christopher T

2017-05-08

Urea removal has become a key measure of the intensity of dialysis treatment for kidney failure. Small solute removal, exemplified by Kt/V urea, has been broadly applied as a means to quantify the dose of thrice weekly hemodialysis. Yet, the reliance on small solute clearances alone as a measure of dialysis adequacy fails fully to quantify the intended clinical effects of dialysis therapy. This review aims to ( 1 ) understand the strengths and limitations of small solute kinetics as a surrogate marker of dialysis dose, and ( 2 ) present the prospect of a more comprehensive construct for dialysis dose, one that considers more broadly the goals of ESRD care to maximize both quality of life and survival. On behalf of the American Society of Nephrology Dialysis Advisory Group, we propose the need to ascertain the validity and utility of a multidimensional measure that moves beyond small solute kinetics alone to quantify optimal dialysis derived from both patient-reported and comprehensive clinical and dialysis-related measures. Copyright © 2017 by the American Society of Nephrology.

Dose-volume parameters predict for the development of chest wall pain after stereotactic body radiation for lung cancer.

PubMed

Mutter, Robert W; Liu, Fan; Abreu, Andres; Yorke, Ellen; Jackson, Andrew; Rosenzweig, Kenneth E

2012-04-01

Chest wall (CW) pain has recently been recognized as an important adverse effect of stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC). We developed a dose-volume model to predict the development of this toxicity. A total of 126 patients with primary, clinically node-negative NSCLC received three to five fractions of SBRT to doses of 40-60 Gy and were prospectively followed. The dose-absolute volume histograms of two different definitions of the CW as an organ at risk (CW3cm and CW2cm) were examined for all 126 patients. With a median follow-up of 16 months, the 2-year estimated actuarial incidence of Grade ≥ 2 CW pain was 39%. The median time to onset of Grade ≥ 2 CW pain (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0) was 9 months. There was no predictive advantage for biologically corrected dose over physical dose. Neither fraction number (p = 0.07) nor prescription dose (p = 0.07) were significantly correlated with the development of Grade ≥ 2 CW pain. Cox Proportional Hazards analysis identified significant correlation with a broad range of dose-volume combinations, with the CW volume receiving 30 Gy (V30) as one of the strongest predictors (p < 0.001). CW2cm consistently enabled better prediction of CW toxicity. When a physical dose of 30 Gy was received by more than 70 cm(3) of CW2cm, there was a significant correlation with Grade ≥ 2 CW pain (p = 0.004). CW toxicity after SBRT is common and long-term follow-up is needed to identify affected patients. A volume of CW ≥ 70 cm(3) receiving 30 Gy is significantly correlated with Grade ≥ 2 CW pain. We are currently applying this constraint at our institution for patients receiving thoracic SBRT. An actuarial atlas of our data is provided as an electronic supplement to facilitate data-sharing and meta-analysis relating to CW pain. Copyright © 2012 Elsevier Inc. All rights reserved.

Dose-Volume Parameters Predict for the Development of Chest Wall Pain After Stereotactic Body Radiation for Lung Cancer

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

Mutter, Robert W.; Liu Fan; Abreu, Andres

Purpose: Chest wall (CW) pain has recently been recognized as an important adverse effect of stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC). We developed a dose-volume model to predict the development of this toxicity. Methods and Materials: A total of 126 patients with primary, clinically node-negative NSCLC received three to five fractions of SBRT to doses of 40-60 Gy and were prospectively followed. The dose-absolute volume histograms of two different definitions of the CW as an organ at risk (CW3cm and CW2cm) were examined for all 126 patients. Results: With a median follow-up of 16 months, themore » 2-year estimated actuarial incidence of Grade {>=} 2 CW pain was 39%. The median time to onset of Grade {>=} 2 CW pain (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0) was 9 months. There was no predictive advantage for biologically corrected dose over physical dose. Neither fraction number (p = 0.07) nor prescription dose (p = 0.07) were significantly correlated with the development of Grade {>=} 2 CW pain. Cox Proportional Hazards analysis identified significant correlation with a broad range of dose-volume combinations, with the CW volume receiving 30 Gy (V30) as one of the strongest predictors (p < 0.001). CW2cm consistently enabled better prediction of CW toxicity. When a physical dose of 30 Gy was received by more than 70 cm{sup 3} of CW2cm, there was a significant correlation with Grade {>=} 2 CW pain (p = 0.004). Conclusions: CW toxicity after SBRT is common and long-term follow-up is needed to identify affected patients. A volume of CW {>=} 70 cm{sup 3} receiving 30 Gy is significantly correlated with Grade {>=} 2 CW pain. We are currently applying this constraint at our institution for patients receiving thoracic SBRT. An actuarial atlas of our data is provided as an electronic supplement to facilitate data-sharing and meta-analysis relating to CW pain.« less

The response to selection for broad male response to female sex pheromone and its implications for divergence in close-range mating behavior in the European corn borer moth, Ostrinia nubilalis.

PubMed

Droney, David C; Musto, Callie J; Mancuso, Katie; Roelofs, Wendell L; Linn, Charles E

2012-12-01

Coordinated sexual communication systems, seen in many species of moths, are hypothesized to be under strong stabilizing natural selection. Stabilized communication systems should be resistant to change, but there are examples of species/populations that show great diversification. A possible solution is that it is directional sexual selection on variation in male response that drives evolution. We tested a component of this model by asking whether 'rare' males (ca. 5 % of all males in a population) of the European corn borer moth (ECB), Ostrinia nubilalis, that respond to the sex pheromones of both ECB and a different Ostrinia species (O. furnacalis, the Asian corn borer, ACB), might play an important role in diversification. We specifically tested, via artificial selection, whether this broad male response has an evolvable genetic component. We increased the frequency of broad male response from 5 to 70 % in 19 generations, showing that broad-responding males could be important for the evolution of novel communication systems in ECB. We did not find a broader range of mating acceptance of broad males by females of the base population, however, suggesting that broad response would be unlikely to increase in frequency without the involvement of other factors. However, we found that ECB selection-line females accepted a broader range of courting males, including those of ACB, than did females of the base population. Thus, a genetic correlation exists between broad, long-range response to female sex pheromone and the breadth of female acceptance of males at close range. These results are discussed in the context of evolution of novel communication systems in Ostrinia.

Radiation damage in Tb-implanted CaF 2 observed by channeling and luminescence measurements

NASA Astrophysics Data System (ADS)

Aono, K.; Kumagai, M.; Iwaki, M.; Aoyagi, Y.; Namba, S.

1993-06-01

The effects of 100 keV Tb ion implantation in CaF 2 single crystals have been investigated using Rutherford backscattering/channeling technique and luminescence spectra during ion implantation, depending on ion doses. Terbium ions were implanted into (111)-cut CaF 2 single crystals in random directions with doses ranging from 1 × 10 13 to 1 × 10 17 Tb +/cm 2 at -100°C, 25°C and 100°C. The luminescence signals were measured by 100 keV Ar ion beam irradiation at room temperature to Tb-implanted specimens in order to detect the ionic state of Tb. Two broad emission peaks (near 380 and 545 nm) in visible regions were observed, originating from Tb 3+ in CaF 2. The same luminescence was also observed even during Tb implantation to CaF 2. The luminescence near 380 nm is identified as an emission of 5D 3→ 7F 6 and that near 545 nm is 5D 4→ 7F 5. The emission peak intensities depend on ion dose. Channeling measurements suggest that most of the Tb atoms occupy substitutional lattice sites. Intensities of luminescence and Tb depth profiles depend on the target temperature. In conclusion, implanted Tb atoms occupy Ca lattice sites and emit green luminescence light.

Influence of the nucleus area distribution on the survival fraction after charged particles broad beam irradiation.

PubMed

Wéra, A-C; Barazzuol, L; Jeynes, J C G; Merchant, M J; Suzuki, M; Kirkby, K J

2014-08-07

It is well known that broad beam irradiation with heavy ions leads to variation in the number of hit(s) received by each cell as the distribution of particles follows the Poisson statistics. Although the nucleus area will determine the number of hit(s) received for a given dose, variation amongst its irradiated cell population is generally not considered. In this work, we investigate the effect of the nucleus area's distribution on the survival fraction. More specifically, this work aims to explain the deviation, or tail, which might be observed in the survival fraction at high irradiation doses. For this purpose, the nucleus area distribution was added to the beam Poisson statistics and the Linear-Quadratic model in order to fit the experimental data. As shown in this study, nucleus size variation, and the associated Poisson statistics, can lead to an upward survival trend after broad beam irradiation. The influence of the distribution parameters (mean area and standard deviation) was studied using a normal distribution, along with the Linear-Quadratic model parameters (α and β). Finally, the model proposed here was successfully tested to the survival fraction of LN18 cells irradiated with a 85 keV µm(- 1) carbon ion broad beam for which the distribution in the area of the nucleus had been determined.

Fresh broad (Vicia faba) tissue homogenate-based biosensor for determination of phenolic compounds.

PubMed

Ozcan, Hakki Mevlut; Sagiroglu, Ayten

2014-08-01

In this study, a novel fresh broad (Vicia faba) tissue homogenate-based biosensor for determination of phenolic compounds was developed. The biosensor was constructed by immobilizing tissue homogenate of fresh broad (Vicia faba) on to glassy carbon electrode. For the stability of the biosensor, general immobilization techniques were used to secure the fresh broad tissue homogenate in gelatin-glutaraldehyde cross-linking matrix. In the optimization and characterization studies, the amount of fresh broad tissue homogenate and gelatin, glutaraldehyde percentage, optimum pH, optimum temperature and optimum buffer concentration, thermal stability, interference effects, linear range, storage stability, repeatability and sample applications (Wine, beer, fruit juices) were also investigated. Besides, the detection ranges of thirteen phenolic compounds were obtained with the help of the calibration graphs. A typical calibration curve for the sensor revealed a linear range of 5-60 μM catechol. In reproducibility studies, variation coefficient (CV) and standard deviation (SD) were calculated as 1.59%, 0.64×10(-3) μM, respectively.

SU-F-T-157: Physics Considerations Regarding Dosimetric Accuracy of Analytical Dose Calculations for Small Field Proton Therapy: A Monte Carlo Study

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

Geng, C; Nanjing University of Aeronautics and Astronautics, Nanjing; Daartz, J

Purpose: To evaluate the accuracy of dose calculations by analytical dose calculation methods (ADC) for small field proton therapy in a gantry based passive scattering facility. Methods: 50 patients with intra-cranial disease were evaluated in the study. Treatment plans followed standard prescription and optimization procedures of proton stereotactic radiosurgery. Dose distributions calculated with the Monte Carlo (MC) toolkit TOPAS were used to represent delivered treatments. The MC dose was first adjusted using the output factor (OF) applied clinically. This factor is determined from the field size and the prescribed range. We then introduced a normalization factor to measure the differencemore » in mean dose between the delivered dose (MC dose with OF) and the dose calculated by ADC for each beam. The normalization was determined by the mean dose of the center voxels of the target area. We compared delivered dose distributions and those calculated by ADC in terms of dose volume histogram parameters and beam range distributions. Results: The mean target dose for a whole treatment is generally within 5% comparing delivered dose (MC dose with OF) and ADC dose. However, the differences can be as great as 11% for shallow and small target treated with a thick range compensator. Applying the normalization factor to the MC dose with OF can reduce the mean dose difference to less than 3%. Considering range uncertainties, the generally applied margins (3.5% of the prescribed range + 1mm) to cover uncertainties in range might not be sufficient to guarantee tumor coverage. The range difference for R90 (90% distal dose falloff) is affected by multiple factors, such as the heterogeneity index. Conclusion: This study indicates insufficient accuracy calculating proton doses using ADC. Our results suggest that uncertainties of target doses are reduced using MC techniques, improving the dosimetric accuracy for proton stereotactic radiosurgery. The work was supported by NIH/NCI under CA U19 021239. CG was partially supported by the Chinese Scholarship Council (CSC) and the National Natural Science Foundation of China (Grant No. 11475087).« less

Tertiary climates and floristic relationships at high latitudes in the northern hemisphere

USGS Publications Warehouse

Wolfe, J.A.

1980-01-01

During the Paleocene and Eocene, climates were characterized by a low mean annual range of temperature (a maximum of 10-15??C), a moderate to high mean annual temperature (10-20??C), and abundant precipitation; strong broad-leaved evergreen vegetation extended to almost lat. 60??N during the Paleocene and to well above 61??N during the Eocene. Poleward of the broad-leaved evergreen forests were forests that were broad-leaved deciduous; these deciduous forests, however, were unlike extant broad-leaved deciduous forests in general floristic composition and physiognomy. Coniferous forests probably occupied the northernmost latitudes. At the end of the Eocene, a major climatic deterioration resulted in a high (> 30??C) mean annual range of temperature and a low mean annual temperature (< 10??C). Vegetation represented temperate broad-leaved deciduous and coniferous forests. The Oligocene and Neogene climatic trends represent a decrease in both mean annual range of temperature and mean annual temperature. Tundra vegetation did not appear until late in the Neogene. The present distribution of broad-leaved evergreens concomitant with the principles of plant physiology indicates that present winter light conditions at high latitudes could not support broad-leaved evergreen forest. A possible solution to the problem is to increase winter light by lessening the inclination of the earth's rotational axis. ?? 1980.

Micropatterned Pyramidal Ionic Gels for Sensing Broad-Range Pressures with High Sensitivity.

PubMed

Cho, Sung Hwan; Lee, Seung Won; Yu, Seunggun; Kim, Hyeohn; Chang, Sooho; Kang, Donyoung; Hwang, Ihn; Kang, Han Sol; Jeong, Beomjin; Kim, Eui Hyuk; Cho, Suk Man; Kim, Kang Lib; Lee, Hyungsuk; Shim, Wooyoung; Park, Cheolmin

2017-03-22

The development of pressure sensors that are effective over a broad range of pressures is crucial for the future development of electronic skin applicable to the detection of a wide pressure range from acoustic wave to dynamic human motion. Here, we present flexible capacitive pressure sensors that incorporate micropatterned pyramidal ionic gels to enable ultrasensitive pressure detection. Our devices show superior pressure-sensing performance, with a broad sensing range from a few pascals up to 50 kPa, with fast response times of <20 ms and a low operating voltage of 0.25 V. Since high-dielectric-constant ionic gels were employed as constituent sensing materials, an unprecedented sensitivity of 41 kPa -1 in the low-pressure regime of <400 Pa could be realized in the context of a metal-insulator-metal platform. This broad-range capacitive pressure sensor allows for the efficient detection of pressure from a variety of sources, including sound waves, a lightweight object, jugular venous pulses, radial artery pulses, and human finger touch. This platform offers a simple, robust approach to low-cost, scalable device design, enabling practical applications of electronic skin.

Broad-Range 16S rDNA PCR on Heart Valves in Infective Endocarditis.

PubMed

Müller Premru, Manica; Lejko Zupanc, Tatjana; Klokočovnik, Tomislav; Ruzić Sabljić, Eva; Cerar, Tjaša

2016-03-01

Infective endocarditis (IE) is diagnosed by blood and/or resected valve cultivation and echocardiographic findings, as defined by the Duke criteria. Unfortunately, cultures may be negative due to prior antibiotic therapy or fastidious or slow-growing microorganisms. The study aim was to investigate the value of the broad-range polymerase chain reaction (PCR) in addition to blood and valve culture for the detection of causative microorganisms. Between February 2012 and March 2015, valve samples from 36 patients undergoing cardiac surgery were analyzed; of these patients, 26 had a preoperative diagnosis of IE and 10 served as controls. Multiple blood cultures were obtained from 34 patients before antibiotic therapy was commenced. Valve samples were inoculated on bacteriological media and underwent analysis using broad-range PCR (16S rDNA). IE was confirmed microbiologically in 21 of the 26 patients (80.7%); in 20 cases (76.9%) this was by positive blood cultures and in 16 (61.5%) by positive valves. Valves were positive in 15 blood culturepositive patients, and in one blood-culture negative patient. Broad-range PCR detected a microorganism in valves significantly more frequently (n = 14; 53.8%) compared to valve culture (n = 8; 30.7%) (chisquare 11.5, p <0.001). The predominant microorganisms were Staphylococcus aureus, Streptococcus of the viridans group, coagulasenegative staphylococci and Enterococcus faecalis. Blood, valve cultures and broad-range PCR were negative in five patients (19.3%) with IE, and in all 10 subjects of the control group. Broad-range PCR on valves was more sensitive than valve culture. However, blood culture, if taken before the start of antibiotic therapy, was the best method for detecting IE.

Spectral reconstruction of dental X-ray tubes using laplace inverse transform of the attenuation curve

NASA Astrophysics Data System (ADS)

Malezan, A.; Tomal, A.; Antoniassi, M.; Watanabe, P. C. A.; Albino, L. D.; Poletti, M. E.

2015-11-01

In this work, a spectral reconstruction methodology for diagnostic X-ray, using Laplace inverse transform of the attenuation, was successfully applied to dental X-ray equipments. The attenuation curves of 8 commercially available dental X-ray equipment, from 3 different manufactures (Siemens, Gnatus and Dabi Atlante), were obtained by using an ionization chamber and high purity aluminium filters, while the kVp was obtained with a specific meter. A computational routine was implemented in order to adjust a model function, whose inverse Laplace transform is analytically known, to the attenuation curve. This methodology was validated by comparing the reconstructed and the measured (using semiconductor detector of cadmium telluride) spectra of a given dental X-ray unit. The spectral reconstruction showed the Dabi Atlante equipments generating similar shape spectra. This is a desirable feature from clinic standpoint because it produces similar levels of image quality and dose. We observed that equipments from Siemens and Gnatus generate significantly different spectra, suggesting that, for a given operating protocol, these units will present different levels of image quality and dose. This fact claims for the necessity of individualized operating protocols that maximize image quality and dose. The proposed methodology is suitable to perform a spectral reconstruction of dental X-ray equipments from the simple measurements of attenuation curve and kVp. The simplified experimental apparatus and the low level of technical difficulty make this methodology accessible to a broad range of users. The knowledge of the spectral distribution can help in the development of operating protocols that maximize image quality and dose.

A review of the pharmacology and clinical efficacy of brivaracetam

PubMed Central

Klein, Pavel; Diaz, Anyzeila; Gasalla, Teresa; Whitesides, John

2018-01-01

Brivaracetam (BRV; Briviact) is a new antiepileptic drug (AED) approved for adjunctive treatment of focal (partial-onset) seizures in adults. BRV is a selective, high-affinity ligand for synaptic vesicle 2A (SV2A) with 15- to 30-fold higher affinity than levetiracetam, the first AED acting on SV2A. It has high lipid solubility and rapid brain penetration, with engagement of the target molecule, SV2A, within minutes of administration. BRV has potent broad-spectrum antiepileptic activity in animal models. Phase I studies indicated BRV was well tolerated and showed a favorable pharmacokinetic profile over a wide dose range following single (10–1,000 mg) and multiple (200–800 mg/day) oral dosing. Three pivotal Phase III studies have demonstrated promising efficacy and a good safety and tolerability profile across doses of 50–200 mg/day in the adjunctive treatment of refractory focal seizures. Long-term data indicate that the response to BRV is sustained, with good tolerability and retention rate. BRV is highly effective in patients experiencing secondarily generalized tonic–clonic seizures. Safety data to date suggest a favorable psychiatric adverse effect profile in controlled studies, although limited postmarketing data are available. BRV is easy to use, with no titration and little drug–drug interaction. It can be initiated at target dose with no titration. Efficacy is seen on day 1 of oral use in a significant percentage of patients. Intravenous administration in a 2-minute bolus and 15-minute infusion is well tolerated. Here, we review the pharmacology, pharmacokinetics, and clinical data of BRV. PMID:29403319

What Is the Optimal Target Convective Volume in On-Line Hemodiafiltration Therapy?

PubMed

Canaud, Bernard; Koehler, Katrin; Bowry, Sudhir; Stuard, Stefano

2017-01-01

Conventional diffusion-based dialysis modalities including high-flux hemodialysis are limited in their capacity to effectively remove large uremic toxins and to improve outcomes for end-stage chronic kidney disease (ESKD) patients. By increasing convective solute transport, hemodiafiltration (HDF) enhances solute removal capacity over a broad range of middle- and large-size uremic toxins implicated in the pathophysiology of chronic kidney disease. Furthermore, by offering flexible convection volume, on-line HDF permits customizing the treatment dose to the patient's needs. In addition, convective-based modalities have been shown to improve hemodynamic stability and to reduce patients' inflammation profile - both of which are implicated in CKD morbidity and mortality. Growing clinical evidence indicates that HDF-based modalities provide ESKD patients with a number of clinical and biological benefits, including improved outcomes. Interestingly, it has recently emerged that the clinical benefits associated with HDF are positively associated with the total ultrafiltered volume per session (and per week), namely convective dose. In this chapter, we revisit the concept of convective dose and discuss the threshold value above which an improvement in ESKD patient outcome can be expected. This particular point will be addressed by stratifying the level of efficacy of convective volumes, schematically defined as minimal, optimal, personalized, and maximal. In addition, factors and best clinical practices implicated in the achievement of an optimal convective dose are reviewed. To conclude, we show how HDF differs from standard hemodialysis and why HDF offers a paradigm shift in renal replacement therapy. © 2017 S. Karger AG, Basel.

PHARMACOKINETICS OF A SINGLE DOSE OF ORAL AND SUBCUTANEOUS ENROFLOXACIN IN CARIBBEAN FLAMINGOS (PHOENICOPTERUS RUBER RUBER).

PubMed

Nau, Melissa R; Carpenter, James W; KuKanich, Butch; Warner, Matt

2017-03-01

Enrofloxacin is a fluoroquinolone antimicrobial that is widely used in veterinary medicine because of its bactericidal activity and safety in a broad range of species. Caribbean flamingos, a member of the order Phoenicopteriformes, are popular in zoological collections and suffer from a variety of conditions that can result from or lead to bacterial infection. In this study, two groups of 7 adult captive Caribbean flamingos received a single dose of 15 mg/kg enrofloxacin, administered either orally or subcutaneously. Plasma concentrations of enrofloxacin and its metabolite, ciprofloxacin, were measured using liquid chromatography and mass spectrometry. Pharmacokinetic analysis was performed using noncompartmental methods. The pharmacokinetic parameters for both routes of administration were similar, with a mean peak plasma concentration (C max ) of 5.25 and 5.77 μg/ml, a mean time to peak plasma concentration (T max ) of 1.49 and 1.1 hr, a mean area under the curve (AUC) of 49.9 and 47.3 hr·μg/ml, and a mean terminal half-life (t 1/2 ) of 5.83 and 6.46 hr for oral and subcutaneous dosing, respectively. Conversion to ciprofloxacin was minimal, with the AUC of ciprofloxacin representing <3% of the enrofloxacin AUC for both routes of administration. Based on the results of the present study, a dose of 15 mg/kg enrofloxacin delivered either orally or subcutaneously in the Caribbean flamingo every 24 hr is recommended for susceptible bacterial pathogens with a minimal inhibitory concentration ≤ 0.25 μg/ml.

A Randomized Double-Blind, Placebo Controlled, Four-Arm Parallel Study Investigating the Effect of a Broad-Spectrum Wellness Beverage on Mood State in Healthy, Moderately Stressed Adults.

PubMed

Evans, Malkanthi; Antony, Joseph; Guthrie, Najla; Landes, Bernie; Aruoma, Okezie I

2018-01-01

The objective of this study was to investigate the effect of a broad-spectrum wellness beverage (Zeal Wellness [ZW]) on standardized measures of mood states, including overall feelings of vitality, in healthy, moderately stressed adults. A randomized, double-blind, placebo-controlled clinical trial was conducted among 99 eligible participants prescreened for moderate stress. Participants were randomized to one of four groups and received ZW once daily (1-dose-ZW; 14 g), ZW twice daily (2-dose-ZW; 28 g), placebo once daily (1-dose-placebo), or placebo twice daily (2-dose-placebo) for 4 weeks. A stress/vitality questionnaire assessed stress and the Profile of Moods (POMS) Questionnaire assessed vigor via mental/physical energy and global mood state. Safety was assessed by clinical chemistry, liver, kidney function, and anthropometric measures and adverse event reporting. Participants receiving 2-dose-ZW reported a 6.6% decrease in scores on POMS-Total Mood Disturbance (TMD; p < 0.05) and a 6.8% decrease in the anger-hostility mood state (p < 0.022) compared to the combined placebo group at day 29. The 2-dose-ZW provided a 12.8% greater improvement in POMS-TMD scores when compared to participants receiving 1-dose-ZW after 28 days of supplementation (p = 0.014). Within groups, there was a 22.4% and a 9.6% decrease in POMS-TMD scores in participants with 2-dose-ZW and 1-dose-ZW, respectively. In addition, participants receiving 2-dose-ZW showed significant improvements (p = 0.001) in the POMS t-score iceberg profile, which represented a shift to a more healthy profile. These data show that daily supplementation with 2-dose-ZW significantly decreased POMS-TMD scores and anger-hostility mood state and shifted the POMS iceberg profile to a healthy profile compared to the combined placebo, reflecting the functional benefit of rice-bran-fruit-vegetable extracts based beverage on health.

Triadimefon

EPA Science Inventory

Triadimefon (CAS 43121-43-3) is a broad spectrum systemic fungicide. The nervous system is the most sensitive target and serves as the basis for most regulatory assessments. Triadimefon is also a carcinogen and reproductive toxicant at high doses in rodent models.

Pharmacokinetic properties and tolerability of single-dose terbutaline in patients with severe asthma treated in the pediatric intensive care unit

PubMed Central

Lebovitz, Daniel J; Smith, Paul G; O'Riordan, MaryAnn; Reed, Michael D

2004-01-01

Background: Asthmatic children requiring treatment in the pediatric intensive care unit (PICU) receive aggressive drug therapy that may include IV administration of β2-receptor agonists to prevent progression to life-threatening respiratory failure. The only pharmacologic agent in this class currently available for parenteral use in the United States is terbutaline. Study of IV dosing of terbutaline in the pediatric population has been limited. Objective: The aim of this study was to determine the pharmacokinetic (PK) properties and tolerability of single-dose terbutaline in pediatric patients across a broad age range who were admitted to the PICU and were receiving maximal conventional asthma drug therapy. Methods: This study was conducted at the PICU at Rainbow Babies and Children's Hospital (Cleveland, Ohio). Patients aged 6 months to 16 years with severe exacerbation of reactive airways disease and who were undergoing maximal conventional therapy and had an arterial catheter were enrolled. Patients were arbitrarily assigned to receive a single IV infusion of 1 of 3 doses of terbutaline (10, 20, or 30 μg/kg), infused over 5 minutes. Blood samples were obtained for the determination of plasma terbutaline concentrations just before terbutaline was administered (baseline), immediately on completion of the IV infusion, and at 10, 20, and 40 minutes and 1, 2, 4, 8, 16, 32, 48, and 72 hours after the 5-minute infusion. PK properties (elimination half-life [tl2], mean residence time [MRT], apparent steady-state volume of distribution [Vdss], and total body clearance [CI]) were determined and adverse effects were recorded. Results: The determination of terbutaline PK properties was possible in 50 of 56 enrolled patients (31 boys, 19 girls; mean [SD] age, 6.5 [4.5] years). The PK properties of terbutaline were linear over the dose range studied and, with the exception of the expected dose-dependent increases in peak terbutaline plasma concentration and area under the terbutaline plasma concentration-time curve, no statistically significant differences were observed in PK relative to dose. Therefore, we pooled the data for all subsequent analyses. Statistically significant correlations with patient age were observed with tl2 (r = 0.4, P < 0.006), MRT (r = 0.4, P < 0.002), and Vdss (r = 0.33, P < 0.02), but not C1 (r = −0.03, P = NS). Single-dose terbutaline administration was generally well tolerated. Conclusions: Single-dose IV terbutaline was well tolerated in this study. In maximally treated asthmatic patients in the PICU, terbutaline elimination may be more rapid than in nonacutely ill children. These PK data suggest that if the drug is to be administered intravenously, the continuous IV infusion method, including loading doses for any subsequent dose escalations, may be the most appropriate. The influence of age and safety of long-term, continuous terbutaline IV infusion requires further study. PMID:24936108

Contemporary Business Administration Curricula

ERIC Educational Resources Information Center

Gleason, James R.

2006-01-01

The National Association of State Directors of Career Technical Education Consortium (NASDCTEc) career clusters initiative was designed to research and foster development of curicula and assessments for each of 16 broad occupational groupings known as career clusters. These clusters encompass a broad range of careers, ranging from agriculture to…

Effects of ionizing radiations on a pharmaceutical compound, chloramphenicol

NASA Astrophysics Data System (ADS)

Varshney, L.; Patel, K. M.

1994-05-01

Chloramphenicol, a broad spectrum antibiotic, has been irradiated using Cobalt-60 γ radiation and electron beam at graded radiation doses upto 100 kGy. Several degradation products and free radicals are formed on irradiation. Purity, degradation products, free radicals, discolouration, crystallinity, solubility and entropy of radiation processing have been investigated. Aqueous solutions undergo extensive radiolysis even at low doses. Physico-chemical, microbiological and toxicological tests do not show significant degradation at sterilization dose. High performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), UV-spectrophotometry, diffuse reflectance spectroscopy (DRS) and electron spin resonance spectroscopy (ESR) techniques were employed for the investigations.

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.

Evaluation of 16 genotype-guided Warfarin Dosing Algorithms in 310 Korean Patients Receiving Warfarin Treatment: Poor Prediction Performance in VKORC1 1173C Carriers.

PubMed

Yang, Mina; Choi, Rihwa; Kim, June Soo; On, Young Keun; Bang, Oh Young; Cho, Hyun-Jung; Lee, Soo-Youn

2016-12-01

The purpose of this study was to evaluate the performance of 16 previously published warfarin dosing algorithms in Korean patients. The 16 algorithms were selected through a literature search and evaluated using a cohort of 310 Korean patients with atrial fibrillation or cerebral infarction who were receiving warfarin therapy. A large interindividual variation (up to 11-fold) in warfarin dose was observed (median, 25 mg/wk; range, 7-77 mg/wk). Estimated dose and actual maintenance dose correlated well overall (r range, 0.52-0.73). Mean absolute error (MAE) of the 16 algorithms ranged from -1.2 to -20.1 mg/wk. The percentage of patients whose estimated dose fell within 20% of the actual dose ranged from 1.0% to 49%. All algorithms showed poor accuracy with increased MAE in a higher dose range. Performance of the dosing algorithms was worse in patients with VKORC1 1173TC or CC than in total (r range, 0.38-0.61 vs 0.52-0.73; MAE range, -2.6 to -28.0 mg/wk vs -1.2 to -20.1 mg/wk). The algorithms had comparable prediction abilities but showed limited accuracy depending on ethnicity, warfarin dose, and VKORC1 genotype. Further studies are needed to develop genotype-guided warfarin dosing algorithms with greater accuracy in the Korean population. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Luminescence study of Dy or Ce activated LiCaBO3 phosphor for γ-ray and C5+ ion beam irradiation.

PubMed

Oza, Abha H; Dhoble, N S; Lochab, S P; Dhoble, S J

2015-11-01

The photoluminescence and thermoluminescence characteristics of rare earths (Dy or Ce) activated LiCaBO3 phosphors have been studied. Phosphors were synthesized by modified solid state synthesis. The phosphors were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), photoluminescence (PL) and thermoluminescence (TL) for structural, morphological and luminescence studies. Dy(3+) activated LiCaBO3 shows emission at 486 and 577 nm due to (4) F9/2 →(6) H15/2 and (4) F9/2 → (6) H13/2 transition, respectively, whereas the PL emission spectra of Ce(3+) activated LiCaBO3 phosphor shows a broad band peaking at 432 nm, which is due to the transition from 5d level to the ground state of the Ce(3+) ion. The thermoluminescence study was also carried out for both these phosphors for γ-ray irradiation and carbon beam irradiation. Linearity was studied for a 0.4-3.1 Rad dose γ-rays. Linear behaviour over this dose range was observed. Gamma ray-irradiated phosphors were shown to be negligible fading upon storage. All the samples were also studied for 75 MeV C(5+) ion beam exposure in the range of 3.75 × 10(12) - 7.5 × 10(13) ion cm(-2) fluence. In addition to this, trapping parameters of all the samples were also calculated using Chen's peak shape method. Copyright © 2015 John Wiley & Sons, Ltd.

Lung Cancer Risk from Plutonium: A Pooled Analysis of the Mayak and Sellafield Worker Cohorts.

PubMed

Gillies, Michael; Kuznetsova, Irina; Sokolnikov, Mikhail; Haylock, Richard; O'Hagan, Jackie; Tsareva, Yulia; Labutina, Elena

2017-12-01

In this study, lung cancer risk from occupational plutonium exposure was analyzed in a pooled cohort of Mayak and Sellafield workers, two of the most informative cohorts in the world with detailed plutonium urine monitoring programs. The pooled cohort comprised 45,817 workers: 23,443 Sellafield workers first employed during 1947-2002 with follow-up until the end of 2005 and 22,374 Mayak workers first employed during 1948-1982 with follow-up until the end of 2008. In the pooled cohort 1,195 lung cancer deaths were observed (789 Mayak, 406 Sellafield) but only 893 lung cancer incidences (509 Mayak, 384 Sellafield, due to truncated follow-up in the incidence analysis). Analyses were performed using Poisson regression models, and were based on doses derived from individual radiation monitoring data using an updated dose assessment methodology developed in the study. There was clear evidence of a linear association between cumulative internal plutonium lung dose and risk of both lung cancer mortality and incidence in the pooled cohort. The pooled point estimates of the excess relative risk (ERR) from plutonium exposure for both lung cancer mortality and incidence were within the range of 5-8 per Gy for males at age 60. The ERR estimates in relationship to external gamma radiation were also significantly raised and in the range 0.2-0.4 per Gy of cumulative gamma dose to the lung. The point estimates of risk, for both external and plutonium exposure, were comparable between the cohorts, which suggests that the pooling of these data was valid. The results support point estimates of relative biological effectiveness (RBE) in the range of 10-25, which is in broad agreement with the value of 20 currently adopted in radiological protection as the radiation weighting factor for alpha particles, however, the uncertainty on this value (RBE = 21; 95% CI: 9-178) is large. The results provide direct evidence that the plutonium risks in each cohort are of the same order of magnitude but the uncertainty on the Sellafield cohort plutonium risk estimates is large, with observed risks consistent with no plutonium risk, and risks five times larger than those observed in the Mayak cohort.

Theory of the spatial resolution of (scanning) transmission electron microscopy in liquid water or ice layers.

PubMed

de Jonge, Niels

2018-04-01

The sample dependent spatial resolution was calculated for transmission electron microscopy (TEM) and scanning TEM (STEM) of objects (e.g., nanoparticles, proteins) embedded in a layer of liquid water or amorphous ice. The theoretical model includes elastic- and inelastic scattering, beam broadening, and chromatic aberration. Different contrast mechanisms were evaluated as function of the electron dose, the detection angle, and the sample configuration. It was found that the spatial resolution scales with the electron dose to the -1/4th power. Gold- and carbon nanoparticles were examined in the middle of water layers ranging from 0.01--10 µm thickness representing relevant classes of experiments in both materials science and biology. The optimal microscope settings differ between experimental configurations. STEM performs the best for gold nanoparticles for all layer thicknesses, while carbon is best imaged with phase-contrast TEM for thin layers but bright field STEM is preferred for thicker layers. The resolution was also calculated for a water layer enclosed between thin membranes. The influence of chromatic aberration correction for TEM was examined as well. The theory is broadly applicable to other types of materials and sample configurations. Copyright © 2018 Elsevier B.V. All rights reserved.

Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic.

PubMed

Stollenwerk, Ariane; Sohns, Melanie; Heisig, Fabian; Elling, Christian; von Zabern, Detlef

2018-01-01

Tapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009. This is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials. The first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses. More than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population. Grünenthal GmbH.

Ion-induced nuclear radiotherapy

DOEpatents

Horn, K.M.; Doyle, B.L.

1996-08-20

Ion-induced Nuclear Radiotherapy (INRT) is a technique for conducting radiosurgery and radiotherapy with a very high degree of control over the spatial extent of the irradiated volume and the delivered dose. Based upon the concept that low energy, ion induced atomic and nuclear reactions can be used to produce highly energetic reaction products at the site of a tumor, the INRT technique is implemented through the use of a conduit-needle or tube which conducts a low energy ion beam to a position above or within the intended treatment area. At the end of the conduit-needle or tube is a specially fabricated target which, only when struck by the ion beam, acts as a source of energetic radiation products. The inherent limitations in the energy, and therefore range, of the resulting reaction products limits the spatial extent of irradiation to a pre-defined volume about the point of reaction. Furthermore, since no damage is done to tissue outside this irradiated volume, the delivered dose may be made arbitrarily large. INRT may be used both as a point-source of radiation at the site of a small tumor, or as a topical bath of radiation to broad areas of diseased tissue. 25 figs.

Ion-induced nuclear radiotherapy

DOEpatents

Horn, Kevin M.; Doyle, Barney L.

1996-01-01

Ion-induced Nuclear Radiotherapy (INRT) is a technique for conducting radiosurgery and radiotherapy with a very high degree of control over the spatial extent of the irradiated volume and the delivered dose. Based upon the concept that low energy, ion induced atomic and nuclear reactions can be used to produce highly energetic reaction products at the site of a tumor, the INRT technique is implemented through the use of a conduit-needle or tube which conducts a low energy ion beam to a position above or within the intended treatment area. At the end of the conduit-needle or tube is a specially fabricated target which, only when struck by the ion beam, acts as a source of energetic radiation products. The inherent limitations in the energy, and therefore range, of the resulting reaction products limits the spatial extent of irradiation to a pre-defined volume about the point of reaction. Furthermore, since no damage is done to tissue outside this irradiated volume, the delivered dose may be made arbitrarily large. INRT may be used both as a point-source of radiation at the site of a small tumor, or as a topical bath of radiation to broad areas of diseased tissue.

Synthesis and luminescence behavior of SrGd1.76Eu0.24O4 host for display and dosimetric applications

NASA Astrophysics Data System (ADS)

Singh, Jyoti; Manam, J.; Singh, Fouran

2018-05-01

Novel SrGd1.76Eu0.24O4 materials were synthesized by conventional high-temperature solid-state reaction method in air ambiance. The structural and luminescence properties of as-prepared phosphors were explored by XRD, FESEM, TEM, PL and TL techniques. The confirmation of orthorhombic phase formation was obtained by XRD studies. The agglomerated ginger-like morphology of as-synthesized SrGd1.76Eu0.24O4 samples was unfolded by FESEM and TEM studies. Upon 276 and 395 nm UV excitation, SrGd1.76Eu0.24O4 phosphors showed intense red emission. The TL glow curve of SrGd1.76Eu0.24O4 irradiated with γ-rays exhibits two well-resolved peaks at 393 K and 598 K having a shoulder at 537 K. Linearity in a wide dose range 500 Gy-3 kGy are observed in the as-formed SrGd1.76Eu0.24O4 samples. Intense red emission, linear dose response and high reproducibility of SrGd1.76Eu0.24O4 samples broadly indicated its suitability for display and TL dosimetry applications.

SU-F-J-193: Efficient Dose Extinction Method for Water Equivalent Path Length (WEPL) of Real Tissue Samples for Validation of CT HU to Stopping Power Conversion

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

Zhang, R; Baer, E; Jee, K

Purpose: For proton therapy, an accurate model of CT HU to relative stopping power (RSP) conversion is essential. In current practice, validation of these models relies solely on measurements of tissue substitutes with standard compositions. Validation based on real tissue samples would be much more direct and can address variations between patients. This study intends to develop an efficient and accurate system based on the concept of dose extinction to measure WEPL and retrieve RSP in biological tissue in large number of types. Methods: A broad AP proton beam delivering a spread out Bragg peak (SOBP) is used to irradiatemore » the samples with a Matrixx detector positioned immediately below. A water tank was placed on top of the samples, with the water level controllable in sub-millimeter by a remotely controlled dosing pump. While gradually lowering the water level with beam on, the transmission dose was recorded at 1 frame/sec. The WEPL were determined as the difference between the known beam range of the delivered SOBP (80%) and the water level corresponding to 80% of measured dose profiles in time. A Gammex 467 phantom was used to test the system and various types of biological tissue was measured. Results: RSP for all Gammex inserts, expect the one made with lung-450 material (<2% error), were determined within ±0.5% error. Depends on the WEPL of investigated phantom, a measurement takes around 10 min, which can be accelerated by a faster pump. Conclusion: Based on the concept of dose extinction, a system was explored to measure WEPL efficiently and accurately for a large number of samples. This allows the validation of CT HU to stopping power conversions based on large number of samples and real tissues. It also allows the assessment of beam uncertainties due to variations over patients, which issue has never been sufficiently studied before.« less

Application of fluence field modulation to proton computed tomography for proton therapy imaging.

PubMed

Dedes, G; De Angelis, L; Rit, S; Hansen, D; Belka, C; Bashkirov, V; Johnson, R P; Coutrakon, G; Schubert, K E; Schulte, R W; Parodi, K; Landry, G

2017-07-12

This simulation study presents the application of fluence field modulated computed tomography, initially developed for x-ray CT, to proton computed tomography (pCT). By using pencil beam (PB) scanning, fluence modulated pCT (FMpCT) may achieve variable image quality in a pCT image and imaging dose reduction. Three virtual phantoms, a uniform cylinder and two patients, were studied using Monte Carlo simulations of an ideal list-mode pCT scanner. Regions of interest (ROI) were selected for high image quality and only PBs intercepting them preserved full fluence (FF). Image quality was investigated in terms of accuracy (mean) and noise (standard deviation) of the reconstructed proton relative stopping power compared to reference values. Dose calculation accuracy on FMpCT images was evaluated in terms of dose volume histograms (DVH), range difference (RD) for beam-eye-view (BEV) dose profiles and gamma evaluation. Pseudo FMpCT scans were created from broad beam experimental data acquired with a list-mode pCT prototype. FMpCT noise in ROIs was equivalent to FF images and accuracy better than  -1.3%(-0.7%) by using 1% of FF for the cylinder (patients). Integral imaging dose reduction of 37% and 56% was achieved for the two patients for that level of modulation. Corresponding DVHs from proton dose calculation on FMpCT images agreed to those from reference images and 96% of BEV profiles had RD below 2 mm, compared to only 1% for uniform 1% of FF. Gamma pass rates (2%, 2 mm) were 98% for FMpCT while for uniform 1% of FF they were as low as 59%. Applying FMpCT to preliminary experimental data showed that low noise levels and accuracy could be preserved in a ROI, down to 30% modulation. We have shown, using both virtual and experimental pCT scans, that FMpCT is potentially feasible and may allow a means of imaging dose reduction for a pCT scanner operating in PB scanning mode. This may be of particular importance to proton therapy given the low integral dose found outside the target.

Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity.

PubMed

Murthy, Bindu; Schmitt-Hoffmann, Anne

2008-01-01

Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference has been attributed to bodyweight. However, the pharmacodynamics of ceftobiprole are similar in males and females, and dosing adjustments are not required based on gender. In patients with moderate to severe renal impairment, systemic clearance of ceftobiprole correlated well with creatinine clearance. For these patients, dose adjustments for the treatment of infections caused by target pathogens, including MRSA, should be based on creatinine clearance. Ceftobiprole is undergoing clinical evaluation in phase III trials in patients with complicated skin and skin structure infections, patients with nosocomial pneumonia, and community-acquired pneumonia in hospitalized patients.

Characterization of extended range Bonner Sphere Spectrometers in the CERF high-energy broad neutron field at CERN

NASA Astrophysics Data System (ADS)

Agosteo, S.; Bedogni, R.; Caresana, M.; Charitonidis, N.; Chiti, M.; Esposito, A.; Ferrarini, M.; Severino, C.; Silari, M.

2012-12-01

The accurate determination of the ambient dose equivalent in the mixed neutron-photon fields encountered around high-energy particle accelerators still represents a challenging task. The main complexity arises from the extreme variability of the neutron energy, which spans over 10 orders of magnitude or more. Operational survey instruments, which response function attempts to mimic the fluence-to-ambient dose equivalent conversion coefficient up to GeV neutrons, are available on the market, but their response is not fully reliable over the entire energy range. Extended range rem counters (ERRC) do not require the exact knowledge of the energy distribution of the neutron field and the calibration can be done with a source spectrum. If the actual neutron field has an energy distribution different from the calibration spectrum, the measurement is affected by an added uncertainty related to the partial overlap of the fluence-to-ambient dose equivalent conversion curve and the response function. For this reason their operational use should always be preceded by an "in-field" calibration, i.e. a calibration made against a reference instrument exposed in the same field where the survey-meter will be employed. In practice the extended-range Bonner Sphere Spectrometer (ERBSS) is the only device which can serve as reference instrument in these fields, because of its wide energy range and the possibility to assess the neutron fluence and the ambient dose equivalent (H*(10)) values with the appropriate accuracy. Nevertheless, the experience gained by a number of experimental groups suggests that mandatory conditions for obtaining accurate results in workplaces are: (1) the use of a well-established response matrix, thus implying validation campaigns in reference monochromatic neutrons fields, (2) the expert and critical use of suitable unfolding codes, and (3) the performance test of the whole system (experimental set-up, elaboration and unfolding procedures) in a well controlled workplace field. The CERF (CERN-EU high-energy reference field) facility is a unique example of such a field, where a number of experimental campaigns and Monte Carlo simulations have been performed over the past years. With the aim of performing this kind of workplace performance test, four different ERBSS with different degrees of validation, operated by three groups (CERN, INFN-LNF and Politecnico of Milano), were exposed in two fixed positions at CERF. Using different unfolding codes (MAXED, GRAVEL, FRUIT and FRUIT SGM), the experimental data were analyzed to provide the neutron spectra and the related dosimetric quantities. The results allow assessing the overall performance of each ERBSS and of the unfolding codes, as well as comparing the performance of three ERRCs when used in a neutron field with energy distribution different from the calibration spectrum.

Broad-Spectrum Molecular Detection of Fungal Nucleic Acids by PCR-Based Amplification Techniques.

PubMed

Czurda, Stefan; Lion, Thomas

2017-01-01

Over the past decade, the incidence of life-threatening invasive fungal infections has dramatically increased. Infections caused by hitherto rare and emerging fungal pathogens are associated with significant morbidity and mortality among immunocompromised patients. These observations render the coverage of a broad range of clinically relevant fungal pathogens highly important. The so-called panfungal or, perhaps more correctly, broad-range nucleic acid amplification techniques do not only facilitate sensitive detection of all clinically relevant fungal species but are also rapid and can be applied to analyses of any patient specimens. They have therefore become valuable diagnostic tools for sensitive screening of patients at risk of invasive fungal infections. This chapter summarizes the currently available molecular technologies employed in testing of a wide range of fungal pathogens, and provides a detailed workflow for patient screening by broad-spectrum nucleic acid amplification techniques.

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013.

PubMed

Taylor, Carolyn W; Wang, Zhe; Macaulay, Elizabeth; Jagsi, Reshma; Duane, Frances; Darby, Sarah C

2015-11-15

Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this "mean heart dose." In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose. Copyright © 2015 Elsevier Inc. All rights reserved.

Depletion of florfenicol amine, marker residue of florfenicol, from the edible fillet of tilapia (Oreochromis niloticus x O. niloticus and O. niloticus x O. aureus) following florfenicol administration in feed

USGS Publications Warehouse

Gaikowski, M.P.; Mushtaq, M.; Cassidy, P.; Meinertz, J.R.; Schleis, S.M.; Sweeney, D.; Endris, R.G.

2010-01-01

Aquaflor??, a 50% feed premix containing the broad spectrum antibacterial agent florfenicol is available globally to control mortality associated with economically significant systemic bacterial diseases of fish. Florfenicol (FFC) is effective in controlling mortality associated with Streptococcus iniae in tilapia Oreochromis sp. when administered in medicated feed at a dose of 15 mg/kg bodyweight (BW)/d for 10 consecutive days. Our objective was to characterize the depletion of the FFC marker residue, florfenicol amine (FFA), from the edible tissue of market-weight Nile tilapia O. niloticus x O. niloticus and hybrid tilapia O. niloticus x O. aureus offered feed medicated with FFC at a nominal dose rate of 15 mg/kg BW/d for 12 days. Near market-weight tilapia were obtained from a commercial tilapia farm, distributed to 2 single pass (one for Nile tilapia and one for hybrid tilapia), flow-through systems and maintained at 27 ??C under a 15 h light:9 h dark photoperiod over a 41-d pre-dosing period. During the dosing period, tilapia were offered feed medicated with FFC at a concentration of 1.479 g/kg at 1% BW daily divided in three equal offerings. The initial 10-d dosing period was extended to 12 d because one tank did not consume > 75% of the feed offered during the first two dosing days. The total dose consumed by fish in each of the 2 tanks ranged from 147 to 167 mg/kg. Once during the pre-dose period and on days 1, 2, 4, 7, 14, 21, and 28 of the post-dose period, groups of fish were indiscriminately removed from each tank, measured for weight and length, scaled, filleted, and the skin-on fillets stored at <-70 ??C. Frozen fillets were individually homogenized, extracted, and FFA concentration was determined by high-performance liquid chromatography with UV detection. Florfenicol amine is rapidly eliminated from tilapia fillet after withdrawal from medication and depletion followed first-order kinetics with an estimated half-life of 2.32 d. The FFA tolerance limit, calculated as the 99th percentile of the potential residue level at 95% confidence, had depleted to less than the 1 ??g/g maximum residue level by 6.14 d after the dosing period.

Device and method for generating a beam of acoustic energy from a borehole, and applications thereof

DOEpatents

Vu, Cung Khac; Sinha, Dipen N; Pantea, Cristian; Nihei, Kurt T; Schmitt, Denis P; Skelt, Christopher

2013-10-01

In some aspects of the invention, a method of generating a beam of acoustic energy in a borehole is disclosed. The method includes generating a first broad-band acoustic pulse at a first broad-band frequency range having a first central frequency and a first bandwidth spread; generating a second broad-band acoustic pulse at a second broad-band frequency range different than the first frequency range having a second central frequency and a second bandwidth spread, wherein the first acoustic pulse and second acoustic pulse are generated by at least one transducer arranged on a tool located within the borehole; and transmitting the first and the second broad-band acoustic pulses into an acoustically non-linear medium, wherein the composition of the non-linear medium produces a collimated pulse by a non-linear mixing of the first and second acoustic pulses, wherein the collimated pulse has a frequency equal to the difference in frequencies between the first central frequency and the second central frequency and a bandwidth spread equal to the sum of the first bandwidth spread and the second bandwidth spread.

Flexible Ferroelectric Sensors with Ultrahigh Pressure Sensitivity and Linear Response over Exceptionally Broad Pressure Range.

PubMed

Lee, Youngoh; Park, Jonghwa; Cho, Soowon; Shin, Young-Eun; Lee, Hochan; Kim, Jinyoung; Myoung, Jinyoung; Cho, Seungse; Kang, Saewon; Baig, Chunggi; Ko, Hyunhyub

2018-04-24

Flexible pressure sensors with a high sensitivity over a broad linear range can simplify wearable sensing systems without additional signal processing for the linear output, enabling device miniaturization and low power consumption. Here, we demonstrate a flexible ferroelectric sensor with ultrahigh pressure sensitivity and linear response over an exceptionally broad pressure range based on the material and structural design of ferroelectric composites with a multilayer interlocked microdome geometry. Due to the stress concentration between interlocked microdome arrays and increased contact area in the multilayer design, the flexible ferroelectric sensors could perceive static/dynamic pressure with high sensitivity (47.7 kPa -1 , 1.3 Pa minimum detection). In addition, efficient stress distribution between stacked multilayers enables linear sensing over exceptionally broad pressure range (0.0013-353 kPa) with fast response time (20 ms) and high reliability over 5000 repetitive cycles even at an extremely high pressure of 272 kPa. Our sensor can be used to monitor diverse stimuli from a low to a high pressure range including weak gas flow, acoustic sound, wrist pulse pressure, respiration, and foot pressure with a single device.

Evaluation Of Microdosing Strategies For Studies In Preclinical Drug Development: Demonstration Of Linear Pharmacokinetics In Dogs Of A Nucleoside Analogue Over A 50-Fold Dose Range

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

Sandhu, P; Vogel, J S; Rose, M J

The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Thus, Compound A displayed multiphasic kinetics and possessed low plasma clearancemore » (4.4 mL/min/kg), a long terminal elimination half-life (19.4 hr) and high oral bioavailability (82%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the pharmacokinetics of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the kinetics of absorption, distribution and elimination in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques. The applications of accelerator mass spectrometry (AMS) are broad ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil and water (Hughen et al., 2000; Beck et al., 2001; Keith-Roach et al., 2001; Mironov et al., 2002), to archaeology and volcanology (Stafford et al., 1984; Vogel et al., 1990; Smith et al., 1999) to its use as a bioanalytical tool for nutritional research (Buchholz et al., 1999; Deuker et al., 2000; Weaver and Liebman, 2002). Biomedical applications of AMS and its use in the arena of pharmaceutical research also have been detailed in review articles (Barker and Garner, 1999; Garner, 2000; Turteltaub and Vogel, 2000). To date, most studies on the metabolism and disposition of xenobiotics by AMS have focused on how carcinogens bind to DNA and proteins to form adducts (Turteltaub et al., 1990, 1997; Frantz et al., 1995; Dingley et al., 1999; Li et al., 2003). Its application to the field of pharmaceutical sciences has been limited to a few studies (Kaye et al., 1997; Young et al., 2001; Garner et al., 2002). However, the pharmaceutical industry is becoming increasingly aware of the potential benefits that may accrue from the ultra high sensitivity afforded by AMS in terms of evaluating the pharmacokinetics of lead drug candidates in early development. Specifically, AMS allows administration of sub-pharmacological doses (microdoses) of carbon-14 or tritium-labeled investigational drugs to animals or humans at radiologically insignificant levels with the goal of obtaining preliminary information regarding the absorption, distribution, metabolism, and excretion of test compounds (Turteltaub and Vogel, 2000). An unresolved issue, however, is whether the pharmacokinetics determined following a microdose are representative of those following a conventional (pharmacological) dose (Lappin and Garner, 2003). This paper examines the linearity of kinetics of an antiviral nucleoside analogue, Compound A, across sub-pharmacological and pharmacological dose ranges in the dog prior to initiation of a human microdose study. The specific objectives of this study, therefore, were (1) to assess the pharmacokinetics of Compound A in dogs by a conventional dosing approach utilizing LC-MS/MS for sample analysis, (2) to assess the pharmacokinetics of Compound A in dogs by the microdose approach utilizing AMS for sample analysis, (3) to compare the pharmacokinetics of Compound A at a microdose versus a pharmacological dose, and (4) to validate AMS for this application and to compare the sensitivity of AMS to that of LC-MS/MS.« less

Vertebral Osteomyelitis Caused by Helicobacter cinaedi Identified Using Broad-range Polymerase Chain Reaction with Sequencing of the Biopsied Specimen.

PubMed

Hase, Ryota; Hirooka, Takuya; Itabashi, Takashi; Endo, Yasunobu; Otsuka, Yoshihito

2018-05-15

A 65-year-old man presented with gradually exacerbating low back pain. Magnetic resonance imaging revealed vertebral osteomyelitis in the Th11-L2 vertebral bodies and discs. The patient showed negative findings on conventional cultures. Direct broad-range polymerase chain reaction (PCR) with sequencing of the biopsied specimen had the highest similarity to the 16S rRNA gene of Helicobacter cinaedi. This case suggests that direct broad-range PCR with sequencing should be considered when conventional cultures cannot identify the causative organism of vertebral osteomyelitis, and that this method may be particularly useful when the pathogen is a fastidious organism, such as H. cinaedi.

Laser-induced periodic surface structures nanofabricated on poly(trimethylene terephthalate) spin-coated films.

PubMed

Martín-Fabiani, I; Rebollar, E; Pérez, S; Rueda, D R; García-Gutiérrez, M C; Szymczyk, A; Roslaniec, Z; Castillejo, M; Ezquerra, T A

2012-05-22

Here we present a precise morphological description of laser-induced periodic surface structures (LIPSS) nanofabricated on spin-coated poly(trimethylene terephthalate) (PTT) films by irradiation with 266 nm, 6 ns laser pulses and by using a broad range of fluences and number of pulses. By accomplishing real and reciprocal space measurements by means of atomic force microscopy and grazing incidence wide- and small-angle X-ray scattering respectively on LIPSS samples, the range of optimum structural order has been established. For a given fluence, an increase in the number of pulses tends to improve LIPSS in PTT. However, as the pulse doses increase above a certain limit, a distortion of the structures is observed and a droplet-like morphology appears. It is proposed that this effect could be related to a plausible decrease of the molecular weight of PTT due to laser-induced chain photo-oxidation by irradiation with a high number of pulses. A concurrent decrease in viscosity enables destabilization of LIPSS by the formation of droplets in a process similar to surface-limited dewetting.

Stress Exposure and Physical, Mental, and Behavioral Health among American Indian Adults with Type 2 Diabetes.

PubMed

Walls, Melissa L; Sittner, Kelley J; Aronson, Benjamin D; Forsberg, Angie K; Whitbeck, Les B; al'Absi, Mustafa

2017-09-16

American Indian (AI) communities experience disproportionate exposure to stressors and health inequities including type 2 diabetes. Yet, we know little about the role of psychosocial stressors for AI diabetes-related health outcomes. We investigated associations between a range of stressors and psychological, behavioral, and physical health for AIs with diabetes. This community-based participatory research with 5 AI tribes includes 192 AI adult type 2 diabetes patients recruited from clinical records at tribal clinics. Data are from computer-assisted interviews and medical charts. We found consistent bivariate relationships between chronic to discrete stressors and mental and behavioral health outcomes; several remained even after accounting for participant age, gender, and income. Fewer stressors were linked to physical health. We also document a dose-response relationship between stress accumulation and worse health. Findings underscore the importance of considering a broad range of stressors for comprehensive assessment of stress burden and diabetes. Policies and practices aimed at reducing stress exposure and promoting tools for stress management may be mechanisms for optimal health for AI diabetes patients.

SU-F-T-194: Analyzing the Effect of Range Shifter Air Gap On TPS Dose Modeling Accuracy in Superficial PBS Proton Therapy

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

Shirey, R; Wu, H

2016-06-15

Purpose: Treatment planning systems (TPS) may not accurately model superficial dose distributions of range shifted proton pencil beam scanning (PBS) treatments. Numerous patient-specific QA tests performed on superficially treated PBS plans have shown a consistent overestimate of dose by the TPS. This study quantifies variations between TPS planned dose and measured dose as a function of range shifter air gap and treatment depths up to 5 cm. Methods: PBS treatment plans were created in the TPS to uniformly irradiate a volume of solid water. One plan was created for each range shifter position analyzed, and all plans utilized identical dosemore » optimization parameters. Each optimized plan was analyzed in the TPS to determine the planned dose at varying depths. A PBS proton therapy system with a 3.5 cm lucite range shifter delivered the treatment plans, and a parallel plate chamber embedded in RW3 solid water measured dose at shallow depths for each air gap. Differences between measured and planned doses were plotted and analyzed. Results: The data show that the TPS more accurately models superficial dose as the air gap between the range shifter and patient surface decreases. Air gaps less than 10 cm have an average dose difference of only 1.6%, whereas air gaps between 10 and 20 cm differ by 3.0% and gaps greater than 20 cm differ by 4.4%. Conclusion: This study has shown that the TPS is unable to accurately model superficial dose with a large range shifter air gap. Dose differences greater than 3% will likely cause QA failure, as many institutions analyze patient QA with a 3%/3mm gamma analysis. For superficial PBS therapy, range shifter positions should be chosen to keep the air gap less then 10 cm when patient setup and gantry geometry allow.« less

Binaural pitch fusion: Comparison of normal-hearing and hearing-impaired listenersa)

PubMed Central

Reiss, Lina A. J.; Shayman, Corey S.; Walker, Emily P.; Bennett, Keri O.; Fowler, Jennifer R.; Hartling, Curtis L.; Glickman, Bess; Lasarev, Michael R.; Oh, Yonghee

2017-01-01

Binaural pitch fusion is the fusion of dichotically presented tones that evoke different pitches between the ears. In normal-hearing (NH) listeners, the frequency range over which binaural pitch fusion occurs is usually <0.2 octaves. Recently, broad fusion ranges of 1–4 octaves were demonstrated in bimodal cochlear implant users. In the current study, it was hypothesized that hearing aid (HA) users would also exhibit broad fusion. Fusion ranges were measured in both NH and hearing-impaired (HI) listeners with hearing losses ranging from mild-moderate to severe-profound, and relationships of fusion range with demographic factors and with diplacusis were examined. Fusion ranges of NH and HI listeners averaged 0.17 ± 0.13 octaves and 1.7 ± 1.5 octaves, respectively. In HI listeners, fusion ranges were positively correlated with a principal component measure of the covarying factors of young age, early age of hearing loss onset, and long durations of hearing loss and HA use, but not with hearing threshold, amplification level, or diplacusis. In NH listeners, no correlations were observed with age, hearing threshold, or diplacusis. The association of broad fusion with early onset, long duration of hearing loss suggests a possible role of long-term experience with hearing loss and amplification in the development of broad fusion. PMID:28372056

The Small Intestine in Experimental Acute Iron Poisoning

PubMed Central

Hosking, C. S.

1971-01-01

A histological examination of the small intestine of rats following acute iron poisoning by ingestion of ferrous sulphate solution is presented. The changes that occur depend on the dose and can be broadly divided into 2 classes. When a very large dose is given (greater than 0·3 mg. Fe/g.), there is gross shrinkage of the villi, sub-epithelial oedema and eventual loss of epithelium. With doses less than 0·2 mg. Fe/g., contraction of villi was not so obvious, but as the animals survive longer with the lower dose, the changes often progressed to gross destruction of the villous stalk. Some of the animals given smaller doses survived and in those that were killed after 24 hr, the mucosa of the small intestine was essentially normal. ImagesFigs. 1-4Figs. 5-7Figs. 8-11 PMID:5547659

Structural and optical properties of CuO in zinc phosphate glasses and effects of gamma irradiation

NASA Astrophysics Data System (ADS)

Ouis, M. A.; ElBatal, H. A.; Abdelghany, A. M.; Hammad, Ahmed H.

2016-01-01

Collective optical and infrared measurements have been employed to investigate the state of increasing copper ions in host 0.5ZnO-0.5P2O5 glass composition. The same spectral measurements were repeated after gamma irradiation with a dose of 20 and 80 KGy. Optical absorption spectra reveal strong UV absorption due to trace ferric ions present as unavoidable impurities within the chemicals used in the preparation of the glasses. Copper containing glasses show an additional broad visible-near infrared band due to distorted octahedrally coordinated Cu2+ ions which at high CuO contents exhibit splitting to several component absorption peaks. Gamma irradiation causes several variations between the response of the base host zinc phosphate glass and effect of increasing CuO. These changes are correlated with both the formation of induced defects through suggested photochemical reactions in the UV region and some shielding effects with increasing CuO in the visible-near infrared spectrum. Infrared absorption spectra reveal repetitive vibrational bands due to phosphate groups mainly from metaphosphate units and the spectra show some variations with the increase of CuO content visualize by the increase of the intensity of the mid broad band extending in the range 800-1500 cm-1.

Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

PubMed Central

WILCOX, CHRISTOPHER S.; PEARLMAN, ADAM

2009-01-01

Nitroxides can undergo one- or two-electron reduction reactions to hydroxylamines or oxammonium cations, respectively, which themselves are interconvertible, thereby providing redox metabolic actions. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) is the most extensively studied nitroxide. It is a cell membrane-permeable amphilite that dismutates superoxide catalytically, facilitates hydrogen peroxide metabolism by catalase-like actions, and limits formation of toxic hydroxyl radicals produced by Fenton reactions. It is broadly effective in detoxifying these reactive oxygen species in cell and animal studies. When administered intravenously to hypertensive rodent models, tempol caused rapid and reversible dose-dependent reductions in blood pressure in 22 of 26 studies. This was accompanied by vasodilation, increased nitric oxide activity, reduced sympathetic nervous system activity at central and peripheral sites, and enhanced potassium channel conductance in blood vessels and neurons. When administered orally or by infusion over days or weeks to hypertensive rodent models, it reduced blood pressure in 59 of 68 studies. This was accompanied by correction of salt sensitivity and endothelial dysfunction and reduced agonist-evoked oxidative stress and contractility of blood vessels, reduced renal vascular resistance, and increased renal tissue oxygen tension. Thus, tempol is broadly effective in reducing blood pressure, whether given by acute intravenous injection or by prolonged administration, in a wide range of rodent models of hypertension. PMID:19112152

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

Regulation of Cortical Dynamic Range by Background Synaptic Noise and Feedforward Inhibition

PubMed Central

Khubieh, Ayah; Ratté, Stéphanie; Lankarany, Milad; Prescott, Steven A.

2016-01-01

The cortex encodes a broad range of inputs. This breadth of operation requires sensitivity to weak inputs yet non-saturating responses to strong inputs. If individual pyramidal neurons were to have a narrow dynamic range, as previously claimed, then staggered all-or-none recruitment of those neurons would be necessary for the population to achieve a broad dynamic range. Contrary to this explanation, we show here through dynamic clamp experiments in vitro and computer simulations that pyramidal neurons have a broad dynamic range under the noisy conditions that exist in the intact brain due to background synaptic input. Feedforward inhibition capitalizes on those noise effects to control neuronal gain and thereby regulates the population dynamic range. Importantly, noise allows neurons to be recruited gradually and occludes the staggered recruitment previously attributed to heterogeneous excitation. Feedforward inhibition protects spike timing against the disruptive effects of noise, meaning noise can enable the gain control required for rate coding without compromising the precise spike timing required for temporal coding. PMID:26209846

Pharmacy sales data versus ward stock accounting for the surveillance of broad-spectrum antibiotic use in hospitals

PubMed Central

2011-01-01

Background Antibiotic consumption in hospitals is commonly measured using the accumulated amount of drugs delivered from the pharmacy to ward held stocks. The reliability of this method, particularly the impact of the length of the registration periods, has not been evaluated and such evaluation was aim of the study. Methods During 26 weeks, we performed a weekly ward stock count of use of broad-spectrum antibiotics - that is second- and third-generation cephalosporins, carbapenems, and quinolones - in five hospital wards and compared the data with corresponding pharmacy sales figures during the same period. Defined daily doses (DDDs) for antibiotics were used as measurement units (WHO ATC/DDD classification). Consumption figures obtained with the two methods for different registration intervals were compared by use of intraclass correlation analysis and Bland-Altman statistics. Results Broad-spectrum antibiotics accounted for a quarter to one-fifth of all systemic antibiotics (ATC group J01) used in the hospital and varied between wards, from 12.8 DDDs per 100 bed days in a urological ward to 24.5 DDDs in a pulmonary diseases ward. For the entire study period of 26 weeks, the pharmacy and ward defined daily doses figures for all broad-spectrum antibiotics differed only by 0.2%; however, for single wards deviations varied from -4.3% to 6.9%. The intraclass correlation coefficient, pharmacy versus ward data, increased from 0.78 to 0.94 for parenteral broad-spectrum antibiotics with increasing registration periods (1-4 weeks), whereas the corresponding figures for oral broad-spectrum antibiotics (ciprofloxacin) were from 0.46 to 0.74. For all broad-spectrum antibiotics and for parenteral antibiotics, limits of agreement between the two methods showed, according to Bland-Altman statistics, a deviation of ± 5% or less from average mean DDDs at 3- and 4-weeks registration intervals. Corresponding deviation for oral antibiotics was ± 21% at a 4-weeks interval. Conclusions There is a need for caution in interpreting pharmacy sales data aggregated over short registration intervals, especially so for oral formulations. Even a one-month registration period may be too short. PMID:22166018

Pharmacy sales data versus ward stock accounting for the surveillance of broad-spectrum antibiotic use in hospitals.

PubMed

Haug, Jon B; Myhr, Randi; Reikvam, Asmund

2011-12-13

Antibiotic consumption in hospitals is commonly measured using the accumulated amount of drugs delivered from the pharmacy to ward held stocks. The reliability of this method, particularly the impact of the length of the registration periods, has not been evaluated and such evaluation was aim of the study. During 26 weeks, we performed a weekly ward stock count of use of broad-spectrum antibiotics--that is second- and third-generation cephalosporins, carbapenems, and quinolones--in five hospital wards and compared the data with corresponding pharmacy sales figures during the same period. Defined daily doses (DDDs) for antibiotics were used as measurement units (WHO ATC/DDD classification). Consumption figures obtained with the two methods for different registration intervals were compared by use of intraclass correlation analysis and Bland-Altman statistics. Broad-spectrum antibiotics accounted for a quarter to one-fifth of all systemic antibiotics (ATC group J01) used in the hospital and varied between wards, from 12.8 DDDs per 100 bed days in a urological ward to 24.5 DDDs in a pulmonary diseases ward. For the entire study period of 26 weeks, the pharmacy and ward defined daily doses figures for all broad-spectrum antibiotics differed only by 0.2%; however, for single wards deviations varied from -4.3% to 6.9%. The intraclass correlation coefficient, pharmacy versus ward data, increased from 0.78 to 0.94 for parenteral broad-spectrum antibiotics with increasing registration periods (1-4 weeks), whereas the corresponding figures for oral broad-spectrum antibiotics (ciprofloxacin) were from 0.46 to 0.74. For all broad-spectrum antibiotics and for parenteral antibiotics, limits of agreement between the two methods showed, according to Bland-Altman statistics, a deviation of ± 5% or less from average mean DDDs at 3- and 4-weeks registration intervals. Corresponding deviation for oral antibiotics was ± 21% at a 4-weeks interval. There is a need for caution in interpreting pharmacy sales data aggregated over short registration intervals, especially so for oral formulations. Even a one-month registration period may be too short.

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

Lindsay, P. E., E-mail: Patricia.Lindsay@rmp.uhn.on.ca; Granton, P. V.; Hoof, S. van

Purpose: To compare the dosimetric and geometric properties of a commercial x-ray based image-guided small animal irradiation system, installed at three institutions and to establish a complete and broadly accessible commissioning procedure. Methods: The system consists of a 225 kVp x-ray tube with fixed field size collimators ranging from 1 to 44 mm equivalent diameter. The x-ray tube is mounted opposite a flat-panel imaging detector, on a C-arm gantry with 360° coplanar rotation. Each institution performed a full commissioning of their system, including half-value layer, absolute dosimetry, relative dosimetry (profiles, percent depth dose, and relative output factors), and characterization ofmore » the system geometry and mechanical flex of the x-ray tube and detector. Dosimetric measurements were made using Farmer-type ionization chambers, small volume air and liquid ionization chambers, and radiochromic film. The results between the three institutions were compared. Results: At 225 kVp, with 0.3 mm Cu added filtration, the first half value layer ranged from 0.9 to 1.0 mm Cu. The dose-rate in-air for a 40 × 40 mm{sup 2} field size, at a source-to-axis distance of 30 cm, ranged from 3.5 to 3.9 Gy/min between the three institutions. For field sizes between 2.5 mm diameter and 40 × 40 mm{sup 2}, the differences between percent depth dose curves up to depths of 3.5 cm were between 1% and 4% on average, with the maximum difference being 7%. The profiles agreed very well for fields >5 mm diameter. The relative output factors differed by up to 6% for fields larger than 10 mm diameter, but differed by up to 49% for fields ≤5 mm diameter. The mechanical characteristics of the system (source-to-axis and source-to-detector distances) were consistent between all three institutions. There were substantial differences in the flex of each system. Conclusions: With the exception of the half-value layer, and mechanical properties, there were significant differences between the dosimetric and geometric properties of the three systems. This underscores the need for careful commissioning of each individual system for use in radiobiological experiments.« less

Reduction of the unnecessary dose from the over-range area with a spiral dynamic z-collimator: comparison of beam pitch and detector coverage with 128-detector row CT.

PubMed

Shirasaka, Takashi; Funama, Yoshinori; Hayashi, Mutsukazu; Awamoto, Shinichi; Kondo, Masatoshi; Nakamura, Yasuhiko; Hatakenaka, Masamitsu; Honda, Hiroshi

2012-01-01

Our purpose in this study was to assess the radiation dose reduction and the actual exposed scan length of over-range areas using a spiral dynamic z-collimator at different beam pitches and detector coverage. Using glass rod dosimeters, we measured the unilateral over-range scan dose between the beginning of the planned scan range and the beginning of the actual exposed scan range. Scanning was performed at detector coverage of 80.0 and 40.0 mm, with and without the spiral dynamic z-collimator. The dose-saving ratio was calculated as the ratio of the unnecessary over-range dose, with and without the spiral dynamic z-collimator. In 80.0 mm detector coverage without the spiral dynamic z-collimator, the actual exposed scan length for the over-range area was 108, 120, and 126 mm, corresponding to a beam pitch of 0.60, 0.80, and 0.99, respectively. With the spiral dynamic z-collimator, the actual exposed scan length for the over-range area was 48, 66, and 84 mm with a beam pitch of 0.60, 0.80, and 0.99, respectively. The dose-saving ratios with and without the spiral dynamic z-collimator for a beam pitch of 0.60, 0.80, and 0.99 were 35.07, 24.76, and 13.51%, respectively. With 40.0 mm detector coverage, the dose-saving ratios with and without the spiral dynamic z-collimator had the highest value of 27.23% with a low beam pitch of 0.60. The spiral dynamic z-collimator is important for a reduction in the unnecessary over-range dose and makes it possible to reduce the unnecessary dose by means of a lower beam pitch.

Dose conversion coefficients for electron exposure of the human eye lens: calculations including a whole body phantom.

PubMed

Behrens, R

2013-07-01

In this work, conversion coefficients from electron fluence to absorbed dose to the eye lens were calculated using Monte Carlo simulations based on a detailed stylised eye model and a very simple but whole body phantom. These data supersede and complement data published earlier based on the simulation of only a single stylised eye. The new data differ from the old ones by not more than 3, 4, 7 and 16 % for angles of radiation incidence of α=0°, 15°, 30° and 45°, respectively, due to the inclusion of the whole body phantom. The data presented in the present work also complement those of a recent report of the International Commission on Radiological Protection (ICRP) (ICRP Publication 116), where conversion coefficients from electron fluence to absorbed dose to the lens of the eye are shown for solely 0°, 180° and isotropic radiation incidence (but for a much broader range of energies). In this article, values are provided for angles of incidence of 0° up to 180° in steps of 15° and for rotational geometry; no systematic deviation was observed from the values given in ICRP Publication 116 for 0° (based on the application of a bare eye) and 180° (based on the application of a voxel whole body phantom). Data are given for monoenergetic electrons from 0.1 up to 10 MeV and for a broad parallel beam geometry in vacuum.

Toxic effects of low doses of Bisphenol-A on human placental cells

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

Benachour, Nora; Aris, Aziz, E-mail: aziz.aris@usherbrooke.c; Department of Obstetrics-Gynecology, University of Sherbrooke Hospital Centre, Quebec

Humans are exposed daily to a great number of xenobiotics and their metabolites present as pollutants. Bisphenol-A (BPA) is extensively used in a broad range of products including baby bottles, food-storage containers, medical equipment, and consumer electronics. Thus, BPA is the most common monomer for polycarbonates intended for food contact. Levels of this industrial product are found in maternal blood, amniotic fluid, follicular fluid, placental tissue, umbilical cord blood, and maternal urine. In this study, we investigated toxic effects of BPA concentrations close to levels found in serum of pregnant women on human cytotrophoblasts (CTB). These cells were isolated frommore » fresh placentas and exposed to BPA for 24 h. Our results showed that very low doses of BPA induce apoptosis (2 to 3 times) as assessed using M30 antibody immunofluorescent detection, and necrosis (1.3 to 1.7 times) as assessed through the cytosolic Adenylate Kinase (AK) activity after cell membrane damage. We also showed that BPA increased significantly the tumor-necrosis factor alpha (TNF-alpha) gene expression and protein excretion as measured by real-time RT-PCR and ELISA luminescent test, respectively. Moreover, we observed that induction of AK activation and TNF-alpha gene expression require lower levels of BPA than apoptosis or TNF-alpha protein excretion. Our findings suggest that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss.« less

Toxic effects of low doses of Bisphenol-A on human placental cells.

PubMed

Benachour, Nora; Aris, Aziz

2009-12-15

Humans are exposed daily to a great number of xenobiotics and their metabolites present as pollutants. Bisphenol-A (BPA) is extensively used in a broad range of products including baby bottles, food-storage containers, medical equipment, and consumer electronics. Thus, BPA is the most common monomer for polycarbonates intended for food contact. Levels of this industrial product are found in maternal blood, amniotic fluid, follicular fluid, placental tissue, umbilical cord blood, and maternal urine. In this study, we investigated toxic effects of BPA concentrations close to levels found in serum of pregnant women on human cytotrophoblasts (CTB). These cells were isolated from fresh placentas and exposed to BPA for 24 h. Our results showed that very low doses of BPA induce apoptosis (2 to 3 times) as assessed using M30 antibody immunofluorescent detection, and necrosis (1.3 to 1.7 times) as assessed through the cytosolic Adenylate Kinase (AK) activity after cell membrane damage. We also showed that BPA increased significantly the tumor-necrosis factor alpha (TNF-alpha) gene expression and protein excretion as measured by real-time RT-PCR and ELISA luminescent test, respectively. Moreover, we observed that induction of AK activation and TNF-alpha gene expression require lower levels of BPA than apoptosis or TNF-alpha protein excretion. Our findings suggest that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss.

[Pharmacokinetics and clinical efficacy of flomoxef in neonates].

PubMed

Azagami, S; Isohata, E; Takeda, S; Kin, Y; Oikawa, T; Osano, M; Shiro, H

1991-11-01

Clinical pharmacology and efficacy of flomoxef (FMOX) in neonates were investigated. And the following results were obtained. 1. Mean serum concentrations of FMOX at 30 minutes after administration were 24.3 micrograms/ml, 47.6 micrograms/ml, and 85.8 micrograms/ml at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg administered, respectively. 2. Mean serum half-lives of FMOX were 3.4 hours in 0-3 day-old neonates, and 2.6 hours in 4 day-old or older subjects. 3. A dose response was evident among different dose groups given 10 mg/kg, 20 mg/kg, and 40 mg/kg. 4. Urinary recovery rates of FMOX in the first 6 hours after administration ranged between 12.8 and 51.1%. 5. FMOX was effective in 7 out of 8 cases in which causative pathogens were identified. 6. Diarrhea was observed in 1 case as a side effect of the drug, but the symptom was relieved soon after the completion of the treatment. There was no case in which any abnormal laboratory results were observed. 7. FMOX has a broad spectrum of activities against Gram-positive and Gram-negative aerobes and anaerobes. It is stable against most of beta-lactamases. It was demonstrated to be highly effective in our study, and yet without any serious side effects. FMOX is therefore considered to be one of the useful agents of the first choice for the treatment of bacterial infections such as sepsis and urinary tract infections in neonates and infants.

Structure and optical properties of ZnO with silver nanoparticles

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

Lyadov, N. M., E-mail: nik061287@mail.ru; Gumarov, A. I.; Kashapov, R. N.

Textured nanocrystalline ZnO thin films are synthesized by ion beam assisted deposition. According to X-ray diffraction data, the crystallite size is ∼25 nm. Thin (∼15 nm) ZnO layers containing Ag nanoparticles are formed in a thin surface region of the films by the implantation of Ag ions with an energy of 30 keV and a dose in the range (0.25–1) × 10{sup 17} ion/cm{sup 2}. The structure and optical properties of the layers are studied. Histograms of the size distribution of Ag nanoparticles are obtained. The average size of the Ag nanoparticles varies from 0.5 to 1.5–2 nm depending onmore » the Ag-ion implantation dose. The optical transmittance of the samples in the visible and ultraviolet regions increases, as the implantation dose is increased. The spectra of the absorption coefficient of the implanted films are calculated in the context of the (absorbing film)/(transparent substrate) model. It is found that the main changes in the optical-density spectra occur in the region of ∼380 nm, in which the major contribution to absorption is made by Ag nanoparticles smaller than 0.75 nm in diameter. In this spectral region, absorption gradually decreases, as the Ag-ion irradiation dose is increased. This is attributed to an increase in the average size of the Ag nanoparticles. It is established that the broad surface-plasmon-resonance absorption bands typical of nanocomposite ZnO films with Ag nanoparticles synthesized by ion implantation are defined by the fact that the size of the nanoparticles formed does not exceed 1.5–2 nm.« less

Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats

PubMed Central

Kapetanovic, Izet M.; Huang, Zhihua; Thompson, Thomas N.; McCormick, David L.

2011-01-01

Purpose Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring polyphenol with a broad range of possible health benefits, including anti-cancer activity. However, the biological activity of resveratrol may be limited by poor absorption and first-pass metabolism: only low plasma concentrations of resveratrol are seen following oral administration, and metabolism to glucuronide and sulfate conjugates is rapid. Methylated polyphenol analogs (such as pterostilbene [3,5-dimethoxy-4′-hydroxy-trans-stilbene], the dimethylether analog of resveratrol) may overcome these limitations to pharmacologic efficacy. The present study was designed to compare the bioavailability, pharmacokinetics, and metabolism of resveratrol and pterostilbene following equimolar oral dosing in rats. Methods The agents were administered orally via gavage for 14 consecutive days at 50 or 150 mg/kg/day for resveratrol and 56 or 168 mg/kg/day for pterostilbene. Two additional groups were dosed once intravenously with 10 and 11.2 mg/kg for resveratrol and pterostilbene, respectively. Plasma concentrations of agents and metabolites were measured using a high-pressure liquid chromatograph-tandem mass spectrometer system. Noncompartmental analysis was used to derive pharmacokinetic parameters. Results Resveratrol and pterostilbene were approximately 20 and 80% bioavailable, respectively. Following oral dosing, plasma levels of pterostilbene and pterostilbene sulfate were markedly greater than were plasma levels of resveratrol and resveratrol sulfate. Although plasma levels of resveratrol glucuronide exceeded those of pterostilbene glucuronide, those differences were smaller than those of the parent drugs and sulfate metabolites. Conclusions When administered orally, pterostilbene demonstrates greater bioavailability and total plasma levels of both the parent compound and metabolites than does resveratrol. These differences in agent pharmacokinetics suggest that the in vivo biological activity of equimolar doses of pterostilbene may be greater than that of resveratrol. PMID:21116625

Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

PubMed

Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J

2016-01-01

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study

PubMed Central

Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J.

2016-01-01

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773. PMID:27768695

Safety and Pharmacokinetic Profiles of Repeated-Dose Micafungin in Children and Adolescents Treated for Invasive Candidiasis

PubMed Central

Benjamin, Daniel K.; Deville, Jaime G.; Azie, Nkechi; Kovanda, Laura; Roy, Mike; Wu, Chunzhang; Arrieta, Antonio

2013-01-01

Background Micafungin is an echinocandin with proven efficacy against a broad range of fungal infections, including those caused by Candida species. Objective To evaluate the safety and pharmacokinetics of once-daily 3 mg/kg and 4.5 mg/kg micafungin in children with proven, probable, or suspected invasive candidiasis. Methods Micafungin safety and pharmacokinetics were assessed in two Phase I, open-label, repeat-dose trials. In Study 2101, children aged 2–16 years were grouped by weight to receive 3 mg/kg (≥25 kg) or 4.5 mg/kg (<25 kg) intravenous micafungin for 10–14 days. In Study 2102, children aged 4 months to <2 years received 4.5 mg/kg micafungin. Study protocols were otherwise identical. Results Safety was analyzed in seventy-eight and nine children in Studies 2101 and 2102, respectively. Although adverse events were experienced by most children (2101: n = 62; 2102: n = 9), micafungin-related adverse events were less common (2101: n = 28; 2102: n = 1), and the number of patients discontinuing due to adverse events was low (2101: n = 4; 2102: n = 1). The most common micafungin-related adverse events were infusion-associated symptoms, pyrexia, and hypomagnesemia (Study 2101), and liver function abnormalities (Study 2102). The micafungin pharmacokinetic profile was similar to that seen in other studies conducted in children, but different than that observed in adults. Conclusions In this small cohort of children, once-daily doses of 3 mg/kg and 4.5 mg/kg micafungin were well tolerated. Pharmacokinetic data will be combined in a population pharmacokinetic analysis to support U.S. dosing recommendations in children. PMID:23958810

Accelerator-based validation of shielding codes

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

Zeitlin, Cary; Heilbronn, Lawrence; Miller, Jack

2002-08-12

The space radiation environment poses risks to astronaut health from a diverse set of sources, ranging from low-energy protons and electrons to highly-charged, high-energy atomic nuclei and their associated fragmentation products, including neutrons. The low-energy protons and electrons are the source of most of the radiation dose to Shuttle and ISS crews, while the more energetic particles that comprise the Galactic Cosmic Radiation (protons, He, and heavier nuclei up to Fe) will be the dominant source for crews on long-duration missions outside the earth's magnetic field. Because of this diversity of sources, a broad ground-based experimental effort is required tomore » validate the transport and shielding calculations used to predict doses and dose-equivalents under various mission scenarios. The experimental program of the LBNL group, described here, focuses principally on measurements of charged particle and neutron production in high-energy heavy-ion fragmentation. Other aspects of the program include measurements of the shielding provided by candidate spacesuit materials against low-energy protons (particularly relevant to extra-vehicular activities in low-earth orbit), and the depth-dose relations in tissue for higher-energy protons. The heavy-ion experiments are performed at the Brookhaven National Laboratory's Alternating Gradient Synchrotron and the Heavy-Ion Medical Accelerator in Chiba in Japan. Proton experiments are performed at the Lawrence Berkeley National Laboratory's 88'' Cyclotron with a 55 MeV beam, and at the Loma Linda University Proton Facility with 100 to 250 MeV beam energies. The experimental results are an important component of the overall shielding program, as they allow for simple, well-controlled tests of the models developed to handle the more complex radiation environment in space.« less

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013

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

Taylor, Carolyn W., E-mail: carolyn.taylor@ctsu.ox.ac.uk; Wang, Zhe; Macaulay, Elizabeth

Purpose: Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Methods and Materials: Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this “mean heart dose.” Results: In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28more » countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Conclusions: Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose.« less

Dose rate mapping of VMAT treatments

NASA Astrophysics Data System (ADS)

Podesta, Mark; Antoniu Popescu, I.; Verhaegen, Frank

2016-06-01

Human tissues exhibit a varying response to radiation dose depending on the dose rate and fractionation scheme used. Dose rate effects have been reported for different radiations, and tissue types. The literature indicates that there is not a significant difference in response for low-LET radiation when using dose rates between 1 Gy min-1 and 12 Gy min-1 but lower dose rates have an observable sparing effect on tissues and a differential effect between tissues. In intensity-modulated radiotherapy such as volumetric modulated arc therapy (VMAT) the dose can be delivered with a wide range of dose rates. In this work we developed a method based on time-resolved Monte Carlo simulations to quantify the dose rate frequency distribution for clinical VMAT treatments for three cancer sites, head and neck, lung, and pelvis within both planning target volumes (PTV) and normal tissues. The results show a wide range of dose rates are used to deliver dose in VMAT and up to 75% of the PTV can have its dose delivered with dose rates  <1 Gy min-1. Pelvic plans on average have a lower mean dose rate within the PTV than lung or head and neck plans but a comparable mean dose rate within the organs at risk. Two VMAT plans that fulfil the same dose objectives and constraints may be delivered with different dose rate distributions, particularly when comparing single arcs to multiple arc plans. It is concluded that for dynamic plans, the dose rate range used varies to a larger degree than previously assumed. The effect of the dose rate range in VMAT on clinical outcome is unknown.

Atmospheric simulator and calibration system for remote sensing radiometers

NASA Technical Reports Server (NTRS)

Holland, J. A.

1983-01-01

A system for calibrating the MAPS (measurement of air pollution from satellites) instruments was developed. The design of the system provides a capability for simulating a broad range of radiant energy source temperatures and a broad range of atmospheric pressures, temperatures, and pollutant concentrations for a single slab atmosphere. The system design and the system operation are described.

Quantifying the effect of air gap, depth, and range shifter thickness on TPS dosimetric accuracy in superficial PBS proton therapy.

PubMed

Shirey, Robert J; Wu, Hsinshun Terry

2018-01-01

This study quantifies the dosimetric accuracy of a commercial treatment planning system as functions of treatment depth, air gap, and range shifter thickness for superficial pencil beam scanning proton therapy treatments. The RayStation 6 pencil beam and Monte Carlo dose engines were each used to calculate the dose distributions for a single treatment plan with varying range shifter air gaps. Central axis dose values extracted from each of the calculated plans were compared to dose values measured with a calibrated PTW Markus chamber at various depths in RW3 solid water. Dose was measured at 12 depths, ranging from the surface to 5 cm, for each of the 18 different air gaps, which ranged from 0.5 to 28 cm. TPS dosimetric accuracy, defined as the ratio of calculated dose relative to the measured dose, was plotted as functions of depth and air gap for the pencil beam and Monte Carlo dose algorithms. The accuracy of the TPS pencil beam dose algorithm was found to be clinically unacceptable at depths shallower than 3 cm with air gaps wider than 10 cm, and increased range shifter thickness only added to the dosimetric inaccuracy of the pencil beam algorithm. Each configuration calculated with Monte Carlo was determined to be clinically acceptable. Further comparisons of the Monte Carlo dose algorithm to the measured spread-out Bragg Peaks of multiple fields used during machine commissioning verified the dosimetric accuracy of Monte Carlo in a variety of beam energies and field sizes. Discrepancies between measured and TPS calculated dose values can mainly be attributed to the ability (or lack thereof) of the TPS pencil beam dose algorithm to properly model secondary proton scatter generated in the range shifter. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

A study of dose-proportionality in the pharmacokinetics of the oral direct renin inhibitor aliskiren in healthy subjects.

PubMed

Limoges, D; Dieterich, H A; Yeh, C-M; Vaidyanathan, S; Howard, D; Dole, W P

2008-05-01

To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension. This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 - 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and C(max) were analyzed to determine dose-proportionality using the power model, parameter = A*(Dose)(beta), where A = intercept and beta = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 â 600 mg were 90% confidence intervals (CI) for beta contained within the range 0.89 - 1.11. AUC and Cmax values increased with increasing doses of aliskiren. Both AUC and C(max) were associated with high variability (coefficient of variation 55 - 64% for AUC and 59 - 117% for C(max)). The estimated proportionality coefficients (beta) for AUC(0-infiniti), AUC(0-t) and C(max) were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 â 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and C(max), respectively. All doses of aliskiren were well tolerated. Exposure to aliskiren was greater than proportional over the dose range of 75 - 600 mg. Over the therapeutic dose range of 150 â 300 mg approved for the treatment of hypertension, AUC and Cmax increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.

Impact of changing the measles vaccine vial size on Niger's vaccine supply chain: a computational model

PubMed Central

2011-01-01

Background Many countries, such as Niger, are considering changing their vaccine vial size presentation and may want to evaluate the subsequent impact on their supply chains, the series of steps required to get vaccines from their manufacturers to patients. The measles vaccine is particularly important in Niger, a country prone to measles outbreaks. Methods We developed a detailed discrete event simulation model of the vaccine supply chain representing every vaccine, storage location, refrigerator, freezer, and transport device (e.g., cold trucks, 4 × 4 trucks, and vaccine carriers) in the Niger Expanded Programme on Immunization (EPI). Experiments simulated the impact of replacing the 10-dose measles vial size with 5-dose, 2-dose and 1-dose vial sizes. Results Switching from the 10-dose to the 5-dose, 2-dose and 1-dose vial sizes decreased the average availability of EPI vaccines for arriving patients from 83% to 82%, 81% and 78%, respectively for a 100% target population size. The switches also changed transport vehicle's utilization from a mean of 58% (range: 4-164%) to means of 59% (range: 4-164%), 62% (range: 4-175%), and 67% (range: 5-192%), respectively, between the regional and district stores, and from a mean of 160% (range: 83-300%) to means of 161% (range: 82-322%), 175% (range: 78-344%), and 198% (range: 88-402%), respectively, between the district to integrated health centres (IHC). The switch also changed district level storage utilization from a mean of 65% to means of 64%, 66% and 68% (range for all scenarios: 3-100%). Finally, accounting for vaccine administration, wastage, and disposal, replacing the 10-dose vial with the 5 or 1-dose vials would increase the cost per immunized patient from $0.47US to $0.71US and $1.26US, respectively. Conclusions The switch from the 10-dose measles vaccines to smaller vial sizes could overwhelm the capacities of many storage facilities and transport vehicles as well as increase the cost per vaccinated child. PMID:21635774

Reference dosimetry of proton pencil beams based on dose-area product: a proof of concept.

PubMed

Gomà, Carles; Safai, Sairos; Vörös, Sándor

2017-06-21

This paper describes a novel approach to the reference dosimetry of proton pencil beams based on dose-area product ([Formula: see text]). It depicts the calibration of a large-diameter plane-parallel ionization chamber in terms of dose-area product in a 60 Co beam, the Monte Carlo calculation of beam quality correction factors-in terms of dose-area product-in proton beams, the Monte Carlo calculation of nuclear halo correction factors, and the experimental determination of [Formula: see text] of a single proton pencil beam. This new approach to reference dosimetry proves to be feasible, as it yields [Formula: see text] values in agreement with the standard and well-established approach of determining the absorbed dose to water at the centre of a broad homogeneous field generated by the superposition of regularly-spaced proton pencil beams.

The S-layer Protein DR_2577 Binds Deinoxanthin and under Desiccation Conditions Protects against UV-Radiation in Deinococcus radiodurans

PubMed Central

Farci, Domenica; Slavov, Chavdar; Tramontano, Enzo; Piano, Dario

2016-01-01

Deinococcus radiodurans has the puzzling ability to withstand over a broad range of extreme conditions including high doses of ultraviolet radiation and deep desiccation. This bacterium is surrounded by a surface layer (S-layer) built of a regular repetition of several proteins, assembled to form a paracrystalline structure. Here we report that the deletion of a main constituent of this S-layer, the gene DR_2577, causes a decrease in the UVC resistance, especially in desiccated cells. Moreover, we show that the DR_2577 protein binds the carotenoid deinoxanthin, a strong protective antioxidant specific of this bacterium. A further spectroscopical characterization of the deinoxanthin-DR_2577 complex revealed features which could suggest a protective role of DR_2577. We propose that, especially under desiccation, the S-layer shields the bacterium from incident ultraviolet light and could behave as a first lane of defense against UV radiation. PMID:26909071

The S-layer Protein DR_2577 Binds Deinoxanthin and under Desiccation Conditions Protects against UV-Radiation in Deinococcus radiodurans.

PubMed

Farci, Domenica; Slavov, Chavdar; Tramontano, Enzo; Piano, Dario

2016-01-01

Deinococcus radiodurans has the puzzling ability to withstand over a broad range of extreme conditions including high doses of ultraviolet radiation and deep desiccation. This bacterium is surrounded by a surface layer (S-layer) built of a regular repetition of several proteins, assembled to form a paracrystalline structure. Here we report that the deletion of a main constituent of this S-layer, the gene DR_2577, causes a decrease in the UVC resistance, especially in desiccated cells. Moreover, we show that the DR_2577 protein binds the carotenoid deinoxanthin, a strong protective antioxidant specific of this bacterium. A further spectroscopical characterization of the deinoxanthin-DR_2577 complex revealed features which could suggest a protective role of DR_2577. We propose that, especially under desiccation, the S-layer shields the bacterium from incident ultraviolet light and could behave as a first lane of defense against UV radiation.

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

PubMed

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

2017-04-15

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

A question about the potential cardiac toxicity of escitalopram.

PubMed

Howland, Robert H

2012-04-01

Previous reviews have focused on the potential cardiac toxicity of the racemic drug citalopram (Celexa(®)). Evaluating the safety of escitalopram (Lexapro(®)) is an important issue to consider, since it is the S-enantiomer of citalopram. Escitalopram has a small effect on the QTc interval. A prolonged QTc was seen in 2% to 14% of escitalopram overdose cases, without serious cardiac sequelae. The QTc prolongation effect of citalopram in beagle dogs has been attributed to the minor metabolite racemic didemethylcitalopram (DDCT). Whether the escitalopram minor metabolite S-DDCT has this effect is not known. Concentrations of S-DDCT are lower than DDCT, but for a broad range of doses of escitalopram and citalopram, the S-DDCT and DDCT concentrations are well below the QTc prolonging concentrations reported in dogs. There is no strong evidence from human and animal studies that the cardiac safety of escitalopram is significantly superior to that of citalopram. Copyright 2012, SLACK Incorporated.

Immunomodulatory activity of a protein isolated from garlic extract on delayed type hypersensitivity.

PubMed

Ghazanfari, Tooba; Hassan, Zuhair M; Ebrahimi, Marzieh

2002-10-01

Garlic is known as a potent spice and a medicine with broad therapeutic properties ranging from antibacterial to anticancer, and anticoagulant. One major protein has been isolated and purified; it is the 14-kDa glycoprotein. This protein has shown to have immunomodulatory effects. In this study, two sources of garlic (freshly prepared and commercial tablet) were used. Both sources of garlic were augmented delayed type hypersensitivity (DTH) response, the optimum enhancement were detected at 20 mg/kg. Histological studies indicate that 20 mg/kg caused a hyperplasia and hypertrophy of periarteriolar lymphoid sheath of spleen and paracortical zone of lymph nodes. Partial purified fraction could increase the DTH response comparing to garlic extract, and purified protein could highly increase the DTH response comparing to both garlic extract and partial purified fraction. Garlic at all doses employed did not exhibit any effect on enhancement of antibody titer to SRBC.

Low Dose Irradiation of Fresh and Fresh-Cut Produce

USDA-ARS?s Scientific Manuscript database

Foodborne illness (FBI) outbreaks in the United States associated with contaminated fruits, vegetables, salads, and juices have prompted redoubled efforts to improve agricultural, post-harvest and supply-chain controls that reduce risk. However, the lack of a broadly applicable antimicrobial process...

The effects of stressful stimuli and hypothalamic-pituitary-adrenal axis activation are reversed by the melanin-concentrating hormone 1 receptor antagonist SNAP 94847 in rodents.

PubMed

Smith, Daniel G; Hegde, Laxminarayan G; Wolinsky, Toni D; Miller, Silke; Papp, Mariusz; Ping, Xiaoli; Edwards, Tanya; Gerald, Christophe P; Craig, Douglas A

2009-02-11

Melanin-concentrating hormone (MCH) is an orexigenic and dipsogenic neuropeptide that has been reported to mediate acute behavioral and neuroendocrine stress-related responses via MCH(1) receptor activation in rodents. The purpose of the present investigation was to use the MCH(1) receptor antagonist SNAP 94847 (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperidin-4-yl}-4-methyl-phenyl)-isobutyramide) to determine the effects of MCH(1) receptor blockade on MCH-evoked adrenocorticotropic hormone (ACTH) release, chronic mild stress-induced anhedonia, stress-induced hyperthermia and forced swim stress-induced immobility. The appropriate dose range for testing SNAP 94847 was determined by measuring MCH-evoked water drinking. The corresponding occupancy of MCH(1) receptors in rat striatum was also measured across a broad dose range. Orally administered (p.o.) SNAP 94847 (1-10 mg/kg) corresponds to 30-60% occupancy at MCH(1) receptors and significantly blocks water drinking induced by the intracerebroventricular (i.c.v.) injection of MCH. MCH (i.c.v.) significantly elevates plasma levels of ACTH in rats, and SNAP 94847 (2.5 mg/kg, p.o.) blocks MCH-evoked ACTH release. Using the chronic mild stress paradigm, we show that repeated daily exposure to environmental stressors for 5 weeks significantly suppresses sucrose intake in rats, and that SNAP 94847 (1 mg/kg, BID) for 1-5 weeks restores baseline sucrose intake. Moreover, a single administration of SNAP 94847 attenuates stress-induced hyperthermia and the behavioral effects of forced swim stress with minimal effective doses of 2.5 and 30 mg/kg (p.o.), respectively. The regulation of ACTH release and reversal of the effects of chronic and acute stress by SNAP 94847 are suggestive of a role for MCH(1) receptor blockade in the treatment of disorders characterized by high allostatic load.

Contribution of sonicate-fluid cultures and broad-range PCR to microbiological diagnosis in vascular graft infections.

PubMed

Kokosar Ulcar, Barbara; Lakic, Nikola; Jeverica, Samo; Pecavar, Blaz; Logar, Mateja; Cerar, Tjasa Kisek; Lejko-Zupanc, Tatjana

2018-06-01

Vascular graft infections (VGI) are associated with considerable morbidity and mortality, and antimicrobial treatment is an important adjunct to surgical treatment. While microbial aetiology of VGI is often difficult to determine, other techniques such as sonication of implanted material may be used to enhance the recovery of biofilm-associated organisms. We performed a retrospective analysis of 22 consecutive patients treated for VGI at University Medical Centre Ljubljana from May 2011 through January 2015. Explanted vascular grafts were flooded with sterile Ringer solution, sonicated for 1 min at a frequency of 40 kHz and inoculated on solid and liquid culture media. Aerobic and anaerobic cultures were performed, incubated for 14 days and any significant bacterial growth was quantitatively evaluated. Additionally, broad-range PCR from sonicate fluid was performed. Microbiological results were compared with the results of preoperatively taken blood cultures and the results of intraoperative tissue cultures (material from peri-graft collection). Identification of the causative organism (irrespective of the method) was achieved in 95.8%. Preoperative blood cultures were positive in 35.3%, intraoperative tissue cultures in 31.8%, sonicate fluid culture in 79.2%, while broad-range PCR from sonicate fluid was positive in 66.7%. In 37.5% the pathogen detected in sonicate fluid culture or broad-range PCR was the only positive microbiological result. Sonicate fluid culture and broad-range PCR from explanted vascular grafts may contribute to optimization of antimicrobial treatment. Optimal timing of antibiotic therapy before explantation should be further assessed to improve diagnostic yield.

A paralogue of the phosphomutase-like gene family in Candida glabrata, CgPmu2, gained broad-range phosphatase activity due to a small number of clustered substitutions.

PubMed

Orlando, Kelly A; Iosue, Christine L; Leone, Sarah G; Davies, Danielle L; Wykoff, Dennis D

2015-10-15

Inorganic phosphate is required for a range of cellular processes, such as DNA/RNA synthesis and intracellular signalling. The phosphate starvation-inducible phosphatase activity of Candida glabrata is encoded by the gene CgPMU2 (C. glabrata phosphomutase-like protein). CgPMU2 is part of a three-gene family (∼75% identical) created through gene duplication in the C. glabrata clade; only CgPmu2 is a PHO-regulated broad range acid phosphatase. We identified amino acids that confer broad range phosphatase activity on CgPmu2 by creating fusions of sections of CgPMU2 with CgPMU1, a paralogue with little broad range phosphatase activity. We used site-directed mutagenesis on various fusions to sequentially convert CgPmu1 to CgPmu2. Based on molecular modelling of the Pmu proteins on to a histidine phosphatase crystal structure, clusters of amino acids were found in two distinct regions that were able to confer phosphatase activity. Substitutions in these two regions together conferred broad phosphatase activity on CgPmu1. Interestingly, one change is a histidine adjacent to the active site histidine of CgPmu2 and it exhibits a novel ability to partially replace the conserved active site histidine in CgPmu2. Additionally, a second amino acid change was able to confer nt phosphatase activity to CgPmu1, suggesting single amino acid changes neofunctionalize CgPmu2. © 2015 Authors; published by Portland Press Limited.

Characterization of polycyclic aromatic hydrocarbons (PAHs) in vegetables near industrial areas of Shanghai, China: Sources, exposure, and cancer risk.

PubMed

Jia, Jinpu; Bi, Chunjuan; Zhang, Junfeng; Jin, Xiaopei; Chen, Zhenlou

2018-06-13

Dietary consumption of contaminated vegetables may contribute to polycyclic aromatic hydrocarbon (PAH) exposure in humans; however, this exposure pathway has not been examined thoroughly. This study aims to characterize the concentrations of PAHs in six types of vegetables grown near industrial facilities in Shanghai, China. We analyzed 16 individual PAHs on the US EPA priority list, and the total concentration in vegetables ranged from 65.7 to 458.0 ng g -1 in the following order: leafy vegetables (romaine lettuce, Chinese cabbage and Shanghai green cabbage) > stem vegetables (lettuce) > seed and pod vegetables (broad bean) > rhizome vegetables (daikon). Vegetable species, wind direction, and local anthropogenic emissions were determinants of PAH concentrations in the edible part of the vegetable. Using isomer ratios and principal component analysis, PAHs in the vegetables were determined to be mainly from coal and wood combustion. The sources of PAHs in the six types of vegetables varied. Daily ingestion of PAHs due to dietary consumption of these vegetables ranged from 0.71 to 14.06 ng d -1 kg -1 , with contributions from Chinese cabbage > broad bean > romaine > Shanghai green cabbage > lettuce > daikon. The daily intake doses adjusted by body weight in children were higher than those in teenagers and adults. Moreover, in adults, higher concentrations of PAHs were found in females than in males. For individuals of different age and gender, the incremental lifetime cancer risks (ILCRs) from consuming these six vegetables ranged from 4.47 × 10 -7 to 6.39 × 10 -5 . Most were higher than the acceptable risk level of 1 × 10 -6 . Our findings demonstrate that planting vegetables near industrial facilities may pose potential cancer risks to those who consume the vegetables. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

Lucconi, G; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA; Bentefour, E

Purpose: The clinical commissioning of a workflow for pre-treatment range verification/adjustment for the head treatment of pediatric medulloblastoma patients, including dose monitoring during treatment. Methods: An array of Si-diodes (DIODES Incorporated) is placed on the patient skin on the opposite side to the beam entrance. A “scout” SOBP beam, with a longer beam range to cover the diodes in its plateau, is delivered; the measured signal is analyzed and the extracted water equivalent path lengths (WEPL) are compared to the expected values, revealing if a range correction is needed. Diodes stay in place during treatment to measure dose. The workflowmore » was tested in solid water and head phantoms and validated against independent WEPL measurements. Both measured WEPL and skin doses were compared to computed values from the TPS (XiO); a Markus chamber was used for reference dose measurements. Results: The WEPL accuracy of the method was verified by comparing it with the dose extinction method. It resulted, for both solid water and head phantom, in the sub-millimeter range, with a deviation less than 1% to the value extracted from the TPS. The accuracy of dose measurements in the fall-off part of the dose profile was validated against the Markus chamber. The entire range verification workflow was successfully tested for the mock-treatment of head phantom with the standard delivery of 90 cGy per field per fraction. The WEPL measurement revealed no need for range correction. The dose measurements agreed to better than 4% with the prescription dose. The robustness of the method and workflow, including detector array, hardware set and software functions, was successfully stress-tested with multiple repetitions. Conclusion: The performance of the in-vivo range verification system and related workflow meet the clinical requirements in terms of the needed WEPL accuracy for pretreatment range verification with acceptable dose to the patient.« less

A comparative assessment of the duration of action of amlodipine and nifedipine GITS in normotensive subjects.

PubMed

Ueda, S; Meredith, P A; Howie, C A; Elliott, H L

1993-12-01

1 This study in normotensive subjects compared the duration and consistency of action of amlodipine (5 mg) and nifedipine GITS (60 mg) by assessment of the attenuation of pressor responses to noradrenaline and angiotensin II. 2 Both drugs significantly attenuated pressor responses to both vasoconstrictors at 6 and 24 h post-dose with rightward shifts of up to 2.3-fold in the dose-response curves. 3 There was significantly less pharmacokinetic variability with amlodipine: for example, intra-subject variability was 33% with amlodipine and 59% with nifedipine GITS. 4 There were no significant differences in the pressor dose ratios up to 48 h post-dose with amlodipine whereas there was a significant and progressive reduction in the pressor dose ratios with nifedipine. 5 These results suggest that both drugs are broadly comparable as once daily treatments but amlodipine displayed less intra- and inter-subject variability and provided a significantly more sustained effect with a reserve of pharmacological activity up to 48 h post-dose.

Broad-band UHF dipole array

NASA Technical Reports Server (NTRS)

Bailey, M. C.

1985-01-01

A 6X6 array of fan-dipoles was designed to operate in the 510 to 660 MHz frequency range for aircraft flight test and evaluation of a UHF radiometer system. A broad-band dipole design operating near the first resonance is detailed. Measured VSWR and radiation patterns for the dipole array demonstrate achievable bandwidths in the 35 percent to 40 percent range.

Regulation of Cortical Dynamic Range by Background Synaptic Noise and Feedforward Inhibition.

PubMed

Khubieh, Ayah; Ratté, Stéphanie; Lankarany, Milad; Prescott, Steven A

2016-08-01

The cortex encodes a broad range of inputs. This breadth of operation requires sensitivity to weak inputs yet non-saturating responses to strong inputs. If individual pyramidal neurons were to have a narrow dynamic range, as previously claimed, then staggered all-or-none recruitment of those neurons would be necessary for the population to achieve a broad dynamic range. Contrary to this explanation, we show here through dynamic clamp experiments in vitro and computer simulations that pyramidal neurons have a broad dynamic range under the noisy conditions that exist in the intact brain due to background synaptic input. Feedforward inhibition capitalizes on those noise effects to control neuronal gain and thereby regulates the population dynamic range. Importantly, noise allows neurons to be recruited gradually and occludes the staggered recruitment previously attributed to heterogeneous excitation. Feedforward inhibition protects spike timing against the disruptive effects of noise, meaning noise can enable the gain control required for rate coding without compromising the precise spike timing required for temporal coding. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effect of Antimicrobial Peptide KSL-W on Human Gingival Tissue and C. albicans Growth, Transition and Secreted Aspartyl Proteinase (SAPS) 2, 4, 5 and 6 Expressions

DTIC Science & Technology

2016-07-01

broad range of antibacterial activity and could play a role in preventing microbial infections(Decanis et al., 2009), (Zaslof, 2002). These antimicrobial...range of antibacterial activity and could play a role in preventing microbial infections(Decanis et al., 2009),(Zaslof, 2002). These antimicrobial...KSL- W (KKVVFWVKFK)(Na et al., 2007), which possess a broad range of antibacterial activity . It killed selected strains of non-oral and oral

Melting and its relationship to impact crater morphology

NASA Technical Reports Server (NTRS)

Okeefe, John D.; Ahrens, Thomas J.

1992-01-01

Shock-melting features occur on planets at scales that range from micrometers to megameters. It is the objective of this study to determine the extent of thickness, volume geometry of the melt, and relationship with crater morphology. The variation in impact crater morphology on planets is influenced by a broad range of parameters: e.g., planetary density, thermal state, strength, impact velocity, gravitational acceleration. We modeled the normal impact of spherical projectiles on a semi-infinite planet over a broad range of conditions using numerical techniques.

(⁹⁹m)Tc-MAA overestimates the absorbed dose to the lungs in radioembolization: a quantitative evaluation in patients treated with ¹⁶⁶Ho-microspheres.

PubMed

Elschot, Mattijs; Nijsen, Johannes F W; Lam, Marnix G E H; Smits, Maarten L J; Prince, Jip F; Viergever, Max A; van den Bosch, Maurice A A J; Zonnenberg, Bernard A; de Jong, Hugo W A M

2014-10-01

Radiation pneumonitis is a rare but serious complication of radioembolic therapy of liver tumours. Estimation of the mean absorbed dose to the lungs based on pretreatment diagnostic (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) imaging should prevent this, with administered activities adjusted accordingly. The accuracy of (99m)Tc-MAA-based lung absorbed dose estimates was evaluated and compared to absorbed dose estimates based on pretreatment diagnostic (166)Ho-microsphere imaging and to the actual lung absorbed doses after (166)Ho radioembolization. This prospective clinical study included 14 patients with chemorefractory, unresectable liver metastases treated with (166)Ho radioembolization. (99m)Tc-MAA-based and (166)Ho-microsphere-based estimation of lung absorbed doses was performed on pretreatment diagnostic planar scintigraphic and SPECT/CT images. The clinical analysis was preceded by an anthropomorphic torso phantom study with simulated lung shunt fractions of 0 to 30 % to determine the accuracy of the image-based lung absorbed dose estimates after (166)Ho radioembolization. In the phantom study, (166)Ho SPECT/CT-based lung absorbed dose estimates were more accurate (absolute error range 0.1 to -4.4 Gy) than (166)Ho planar scintigraphy-based lung absorbed dose estimates (absolute error range 9.5 to 12.1 Gy). Clinically, the actual median lung absorbed dose was 0.02 Gy (range 0.0 to 0.7 Gy) based on posttreatment (166)Ho-microsphere SPECT/CT imaging. Lung absorbed doses estimated on the basis of pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging (median 0.02 Gy, range 0.0 to 0.4 Gy) were significantly better predictors of the actual lung absorbed doses than doses estimated on the basis of (166)Ho-microsphere planar scintigraphy (median 10.4 Gy, range 4.0 to 17.3 Gy; p < 0.001), (99m)Tc-MAA SPECT/CT imaging (median 2.5 Gy, range 1.2 to 12.3 Gy; p < 0.001), and (99m)Tc-MAA planar scintigraphy (median 5.5 Gy, range 2.3 to 18.2 Gy; p < 0.001). In clinical practice, lung absorbed doses are significantly overestimated by pretreatment diagnostic (99m)Tc-MAA imaging. Pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging accurately predicts lung absorbed doses after (166)Ho radioembolization.

Dose control in electron beam processing: Comparison of results from a graphite charge collector, routine dosimeters and the ISS alanine-based dosimeter

NASA Astrophysics Data System (ADS)

Fuochi, P. G.; Onori, S.; Casali, F.; Chirco, P.

1993-10-01

A 12 MeV linear accelerator is currently used for electron beam processing of power semiconductor devices for lifetime control and, on an experimental basis, for food irradiation, sludge treatment etc. In order to control the irradiation process a simple, quick and reliable method for a direct evaluation of dose and fluence in a broad electron beam has been developed. This paper presents the results obtained using a "charge collector" which measures the charge absorbed in a graphite target exposed in air. Calibration of the system with super-Fricke dosimeter and comparison of absorbed dose results obtained with plastic dosimeters and alanine pellets are discussed.

Which Clinician Questions Elicit Accurate Disclosure of Antiretroviral Non-adherence When Talking to Patients?

PubMed

Callon, Wynne; Saha, Somnath; Korthuis, P Todd; Wilson, Ira B; Moore, Richard D; Cohn, Jonathan; Beach, Mary Catherine

2016-05-01

This study evaluated how clinicians assess antiretroviral (ARV) adherence in clinical encounters, and which questions elicit accurate responses. We conducted conversation analysis of audio-recorded encounters between 34 providers and 58 patients reporting ARV non-adherence in post-encounter interviews. Among 42 visits where adherence status was unknown by providers, 4 providers did not discuss ARVs (10 %), 6 discussed ARVs but did not elicit non-adherence disclosure (14 %), and 32 discussed ARVs which prompted disclosure (76 %). Questions were classified as: (1) clarification of medication ("Are you still taking the Combivir?"); (2) broad ("How's it going with your meds?"); (3) positively-framed ("Are you taking your medications regularly?"); (4) negatively-framed ("Have you missed any doses?"). Clinicians asked 75 ARV-related questions: 23 clarification, 12 broad, 17 positively-framed, and 23 negatively-framed. Negatively-framed questions were 3.8 times more likely to elicit accurate disclosure than all other question types (p < 0.0001). Providers can improve disclosure probability by asking directly about missed doses.

Evolving paradigms for desensitization in managing broadly HLA sensitized transplant candidates.

PubMed

Reinsmoen, Nancy L; Lai, Chi-Hung; Vo, Ashley; Jordan, Stanley C

2012-04-01

The broadly human leukocyte antigen (HLA) sensitized patient awaiting organ transplantation remains a persistent and significant problem for transplant medicine. Sensitization occurs as a consequence of exposure to HLA antigens through pregnancy, blood and platelet transfusions, and previous transplants. Early experience with desensitization protocols coupled with improved diagnostics for donor-specific antibodies (DSAs) and renal pathology have greatly improved transplant rates and outcomes for patients once considered un-transplantable or at high risk for poor outcomes. More recent advances have occurred through implementation of a national allocation system requiring the entering of unacceptable antigens that reduces the rate of crossmatch positivity. Current desensitization therapies include high-dose intravenous immunoglobulin (IVIG), plasma exchange (PLEX) with low-dose IVIG, and IVIG combined with rituximab. Developing therapies include proteasome inhibitors aimed at plasma cells and modifiers of complement-mediated injury. Here we discuss the important advancements in desensitization including defining the risk for antibody-mediated rejection prior to transplantation and the evolution of therapies aimed at reducing the impact of antibody injury on allografts.

Efficacy and safety of aprepitant for the prevention of chemotherapy-induced nausea and vomiting during the first cycle of moderately emetogenic chemotherapy in Korean patients with a broad range of tumor types.

PubMed

Kim, Jeong Eun; Jang, Joung-Soon; Kim, Jae-Weon; Sung, Yong Lee; Cho, Chi-Heum; Lee, Myung-Ah; Kim, Do-Jin; Ahn, Myung-Ju; Lee, Kil Yeon; Sym, Sun Jin; Lim, Myong Choel; Jung, Hun; Cho, Eun Kim; Min, Kyung Wan

2017-03-01

This study evaluated the efficacy and safety of a 3-day aprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) during the first cycle of non-anthracycline plus cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) based on government guidelines in Korean patients. This multicenter, randomized, double-blind, phase IV trial (NCT01636947) enrolled adult South Korean patients with a broad range of tumor types who were scheduled to receive a single dose of ≥1 MEC agent. Patients were randomized to a 3-day regimen of aprepitant (aprepitant regimen) or placebo (control regimen) on top of ondansetron plus dexamethasone. The primary and key secondary efficacy endpoints were the proportions of subjects who achieved no vomiting and complete response (CR) during the overall phase. Of the 494 randomized subjects, 480 were included in the modified intent-to-treat population. Response rates for no vomiting and CR in the overall phase were numerically higher for the aprepitant regimen compared with the control regimen groups, but failed to reach statistical significance (no vomiting 77.2 vs 72.0%; p = 0.191; CR 73.4 vs 70.4%; p = 0.458). Both the aprepitant and control regimens were generally well tolerated. A 3-day aprepitant regimen was numerically better but not statistically superior to a control regimen with respect to the achievement of no vomiting or CR during the overall phase in a non-AC MEC Korean population based on government reimbursement guidelines. ClinicalTrials.gov NCT01636947 ( https://clinicaltrials.Gov/ct2/show/NCT01636947 ).

Heavy-ion conformal irradiation in the shallow-seated tumor therapy terminal at HIRFL.

PubMed

Li, Qiang; Dai, Zhongying; Yan, Zheng; Jin, Xiaodong; Liu, Xinguo; Xiao, Guoqing

2007-11-01

Basic research related to heavy-ion cancer therapy has been done at the Institute of Modern Physics (IMP), Chinese Academy of Sciences since 1995. Now a plan of clinical trial with heavy ions has been launched at IMP. First, superficially placed tumor treatment with heavy ions is expected in the therapy terminal at the Heavy Ion Research Facility in Lanzhou (HIRFL), where carbon ion beams with energy up to 100 MeV/u can be supplied. The shallow-seated tumor therapy terminal at HIRFL is equipped with a passive beam delivery system including two orthogonal dipole magnets, which continuously scan pencil beams laterally and generate a broad and uniform irradiation field, a motor-driven energy degrader and a multi-leaf collimator. Two different types of range modulator, ripple filter and ridge filter with which Guassian-shaped physical dose and uniform biological effective dose Bragg peaks can be shaped for therapeutic ion beams respectively, have been designed and manufactured. Therefore, two-dimensional and three-dimensional conformal irradiations to tumors can be performed with the passive beam delivery system at the earlier therapy terminal. Both the conformal irradiation methods have been verified experimentally and carbon-ion conformal irradiations to patients with superficially placed tumors have been carried out at HIRFL since November 2006.

Modelling of Radiological Health Risks from Gold Mine Tailings in Wonderfonteinspruit Catchment Area, South Africa.

PubMed

Mathuthu, Manny; Kamunda, Caspah; Madhuku, Morgan

2016-06-07

Mining is one of the major causes of elevation of naturally-occurring radionuclide material (NORM) concentrations on the Earth's surface. The aim of this study was to evaluate the human risk associated with exposure to NORMs in soils from mine tailings around a gold mine. A broad-energy germanium detector was used to measure activity concentrations of these NORMs in 66 soil samples (56 from five mine tailings and 10 from the control area). The RESidual RADioactivity (RESRAD) OFFSITE modeling program (version 3.1) was then used to estimate the radiation doses and the cancer morbidity risk of uranium-238 ((238)U), thorium-232 ((232)Th), and potassium-40 ((40)K) for a hypothetical resident scenario. According to RESRAD prediction, the maximum total effective dose equivalent (TEDE) during 100 years was found to be 0.0315 mSv/year at year 30, while the maximum total excess cancer morbidity risk for all the pathways was 3.04 × 10(-5) at year 15. The US Environmental Protection Agency considers acceptable for regulatory purposes a cancer risk in the range of 10(-6) to 10(-4). Therefore, results obtained from RESRAD OFFSITE code has shown that the health risk from gold mine tailings is within acceptable levels according to international standards.

A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa.

PubMed

Lu, Genmin; DeGuzman, Francis R; Hollenbach, Stanley J; Karbarz, Mark J; Abe, Keith; Lee, Gail; Luan, Peng; Hutchaleelaha, Athiwat; Inagaki, Mayuko; Conley, Pamela B; Phillips, David R; Sinha, Uma

2013-04-01

Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

Modelling of Radiological Health Risks from Gold Mine Tailings in Wonderfonteinspruit Catchment Area, South Africa

PubMed Central

Mathuthu, Manny; Kamunda, Caspah; Madhuku, Morgan

2016-01-01

Mining is one of the major causes of elevation of naturally-occurring radionuclide material (NORM) concentrations on the Earth’s surface. The aim of this study was to evaluate the human risk associated with exposure to NORMs in soils from mine tailings around a gold mine. A broad-energy germanium detector was used to measure activity concentrations of these NORMs in 66 soil samples (56 from five mine tailings and 10 from the control area). The RESidual RADioactivity (RESRAD) OFFSITE modeling program (version 3.1) was then used to estimate the radiation doses and the cancer morbidity risk of uranium-238 (238U), thorium-232 (232Th), and potassium-40 (40K) for a hypothetical resident scenario. According to RESRAD prediction, the maximum total effective dose equivalent (TEDE) during 100 years was found to be 0.0315 mSv/year at year 30, while the maximum total excess cancer morbidity risk for all the pathways was 3.04 × 10−5 at year 15. The US Environmental Protection Agency considers acceptable for regulatory purposes a cancer risk in the range of 10−6 to 10−4. Therefore, results obtained from RESRAD OFFSITE code has shown that the health risk from gold mine tailings is within acceptable levels according to international standards. PMID:27338424

Understanding the impact of visual arts interventions for people living with dementia: a realist review protocol.

PubMed

Windle, Gill; Gregory, Samantha; Newman, Andrew; Goulding, Anna; O'Brien, Dave; Parkinson, Clive

2014-08-15

Arts-based activities are being increasingly suggested as a valuable activity for people living with dementia in terms of countering the negative aspects of their condition. The potential for such programmes to improve a broad range of psychosocial outcomes is suggested in some studies. However, there is largely an absence of rigorous methodology to demonstrate the benefits, and research results are mixed. Practice variability in terms of the content, contexts and implementation of such interventions raises challenges in terms of identifying an optimal arts programme model that could be adopted by other service providers. Understanding how interventions may have the best chance at broad implementation success and uptake is limited. A realist review will be undertaken. This aims to understand how visual arts interventions influence outcomes in people living with dementia. The review will explore how the context, that is the circumstances which enable or constrain, affect outcomes through the activation of mechanisms. An early scoping search and a stakeholder survey formulated the preliminary programme theory. A systematic literature search across a broad range of disciplines (arts, humanities, social sciences, health) will be undertaken to identify journal articles and grey literature. Data will be extracted in relation to the programme theory, contextual factors, mechanisms and outcomes and their configurations, background information about the study design and participant characteristics, detail about the quantity ('dose') of an intervention, theoretical perspectives proposed by the authors of the paper and further theorising by the reviewer. Thematic connections/patterns will be sought across the extracted data, identifying patterns amongst contextual factors, the mechanisms they trigger and the associated outcomes. Along with stakeholder engagement and validation, this review will help inform the development of an optimal, replicable arts intervention for people with dementia as part of our broader research programme, titled 'Dementia and Imagination' (funded by the Arts and Humanities Research Council). Forthcoming work under this programme of research will test this theoretically informed intervention in three different geographical areas of the UK. The production of freely available practice guidance is a key aspect of dissemination. PROSPERO registration number CRD42014008702.

Engineering of the PapMV vaccine platform with a shortened M2e peptide leads to an effective one dose influenza vaccine.

PubMed

Carignan, Damien; Thérien, Ariane; Rioux, Gervais; Paquet, Geneviève; Gagné, Marie-Ève Laliberté; Bolduc, Marilène; Savard, Pierre; Leclerc, Denis

2015-12-16

The emergence of highly virulent influenza strains and the risks of pandemics as well as the limited efficiency of the current seasonal vaccines are important public health concerns. There is a major need for new influenza vaccines that would be broadly cross-protective. The ectodomain of matrix protein 2 (M2e) is highly conserved amongst different influenza strains and could be used as a broad spectrum antigen. To overcome its low immunogenicity we have fused a short peptide epitope derived from the human consensus sequence of M2e (amino acids 6-14, EVETPIRNE) to the N-terminus of papaya mosaic virus coat protein. The fusion harboring coat proteins were assembled around a single stranded RNA into virus-like particles (PapMV-sM2e). The resulting PapMV-sM2e rod-shaped particle was stable and indistinguishable from regular PapMV particles. A single intramuscular immunization with PapMV-sM2e was sufficient to mount appreciable levels of CD4 dependent M2e specific total IgG and IgG2a antibody in mice sera. PapMV-sM2e proved to be self-adjuvanting since the addition of PapMV as an exogenous adjuvant did not result in significantly improved antibody titers. In addition, we confirmed the adjuvant property of PapMV-sM2e using the trivalent inactivated flu vaccine as antigen and demonstrated that the newly engineered nanoparticles areas efficacious as an adjuvant than the original PapMV nanoparticles. Upon infection with a sub-lethal dose of influenza, PapMV-sM2e vaccinated animals were completely protected from virus induced morbidity and mortality. Mice immunized with decreasing amounts of PapMV-sM2e and challenged with a more stringent dose of influenza virus displayed dose-dependent levels of protection. Seventy percent of the mice immunized once with the highest dose of PapMV-sM2e survived the challenged. The survival of the mice correlated mainly with the levels of anti-M2e IgG2a antibodies obtained before the infection. These results demonstrate that PapMV-sM2e can be an important component of a broadly cross-reactive influenza vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.

An MCNPX2.7.0 study of Bragg peak degradation owing to density heterogeneity patterns for a CGMH therapeutic proton beam

NASA Astrophysics Data System (ADS)

Chao, Tsi-Chian; Tsai, Yi-Chun; Chen, Shih-Kuan; Wu, Shu-Wei; Tung, Chuan-Jong; Hong, Ji-Hong; Wang, Chun-Chieh; Lee, Chung-Chi

2017-08-01

The purpose of this study was to investigate the density heterogeneity pattern as a factor affecting Bragg peak degradation, including shifts in Bragg peak depth (ZBP), distal range (R80 and R20), and distal fall-off (R80-R20) using Monte Carlo N-Particles, eXtension (MCNPX). Density heterogeneities of different patterns with increasing complexity were placed downstream of commissioned proton beams at the Proton and Radiation Therapy Centre of Chang Gung Memorial Hospital, including one 150 MeV wobbling broad beam (10×10 cm2) and one 150 MeV proton pencil beam (FWHM of cross-plane=2.449 cm, FWHM of in-plane=2.256 cm). MCNPX 2.7.0 was used to model the transport and interactions of protons and secondary particles in density heterogeneity patterns and water using its repeated structure geometry. Different heterogeneity patterns were inserted into a 21×21×20 cm3 phantom. Mesh tally was used to track the dose distribution when the proton beam passed through the different density heterogeneity patterns. The results show that different heterogeneity patterns do cause different Bragg peak degradations owing to multiple Coulomb scattering (MCS) occurring in the density heterogeneities. A trend of increasing R20 and R80-R20 with increasing geometry complexity was observed. This means that Bragg peak degradation is mainly caused by the changes to the proton spectrum owing to MCS in the density heterogeneities. In contrast, R80 did not change considerably with different heterogeneity patterns, which indicated that the energy spectrum has only minimum effects on R80. Bragg peak degradation can occur both for a broad proton beam and a pencil beam, but is less significant for the broad beam.

Effective doses and organ doses in the MIRD-5 phantom exposed to monoenergetic 0.1 MeV to 200 MeV electrons in the LAT direction.

PubMed

Katagiri, M; Hikoji, M; Kitaichi, M; Aoki, Y; Sawamura, S

2001-01-01

Organ doses and effective doses were calculated using the EGS-4 Monte Carlo simulation code and a MIRD-5 mathematical human phantom placed in a vacuum. For broad right and left lateral beams of monoenergetic (0.1-200 MeV) electrons, conversion coefficients from the incident fluence to organ dose, to effective dose, and to effective dose equivalent were obtained. There were no clear differences between the conversion coefficients in the case of left-lateral (LLAT) and right-lateral (RLAT) irradiation. Therefore, when investigating lateral geometries for electron exposure, it is not necessary to evaluate both directions independently. In general, conversion coefficients for lateral irradiation (LAT) were smaller than those for AP and PA. The difference between the AP and PA conversion coefficients and LAT became smaller with increasing incident energy; at 200 MeV the conversion coefficients were almost independent of the irradiation geometry. The agreement between the results of the present study and those of other studies was acceptable within the statistical uncertainties.

Development, validation, and implementation of a patient-specific Monte Carlo 3D internal dosimetry platform

NASA Astrophysics Data System (ADS)

Besemer, Abigail E.

Targeted radionuclide therapy is emerging as an attractive treatment option for a broad spectrum of tumor types because it has the potential to simultaneously eradicate both the primary tumor site as well as the metastatic disease throughout the body. Patient-specific absorbed dose calculations for radionuclide therapies are important for reducing the risk of normal tissue complications and optimizing tumor response. However, the only FDA approved software for internal dosimetry calculates doses based on the MIRD methodology which estimates mean organ doses using activity-to-dose scaling factors tabulated from standard phantom geometries. Despite the improved dosimetric accuracy afforded by direct Monte Carlo dosimetry methods these methods are not widely used in routine clinical practice because of the complexity of implementation, lack of relevant standard protocols, and longer dose calculation times. The main goal of this work was to develop a Monte Carlo internal dosimetry platform in order to (1) calculate patient-specific voxelized dose distributions in a clinically feasible time frame, (2) examine and quantify the dosimetric impact of various parameters and methodologies used in 3D internal dosimetry methods, and (3) develop a multi-criteria treatment planning optimization framework for multi-radiopharmaceutical combination therapies. This platform utilizes serial PET/CT or SPECT/CT images to calculate voxelized 3D internal dose distributions with the Monte Carlo code Geant4. Dosimetry can be computed for any diagnostic or therapeutic radiopharmaceutical and for both pre-clinical and clinical applications. In this work, the platform's dosimetry calculations were successfully validated against previously published reference doses values calculated in standard phantoms for a variety of radionuclides, over a wide range of photon and electron energies, and for many different organs and tumor sizes. Retrospective dosimetry was also calculated for various pre-clinical and clinical patients and large dosimetric differences resulted when using conventional organ-level methods and the patient-specific voxelized methods described in this work. The dosimetric impact of various steps in the 3D voxelized dosimetry process were evaluated including quantitative imaging acquisition, image coregistration, voxel resampling, ROI contouring, CT-based material segmentation, and pharmacokinetic fitting. Finally, a multi-objective treatment planning optimization framework was developed for multi-radiopharmaceutical combination therapies.

Time-resolved dosimetry using a pinpoint ionization chamber as quality assurance for IMRT and VMAT

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

Louwe, Robert J. W., E-mail: rob.louwe@ccdbh.org.nz; Satherley, Thomas; Day, Rebecca A.

Purpose: To develop a method to verify the dose delivery in relation to the individual control points of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) using an ionization chamber. In addition to more effective problem solving during patient-specific quality assurance (QA), the aim is to eventually map out the limitations in the treatment chain and enable a targeted improvement of the treatment technique in an efficient way. Methods: Pretreatment verification was carried out for 255 treatment plans that included a broad range of treatment indications in two departments using the equipment of different vendors. In-house developed softwaremore » was used to enable calculation of the dose delivery for the individual beamlets in the treatment planning system (TPS), for data acquisition, and for analysis of the data. The observed deviations were related to various delivery and measurement parameters such as gantry angle, field size, and the position of the detector with respect to the field edge to distinguish between error sources. Results: The average deviation of the integral fraction dose during pretreatment verification of the planning target volume dose was −2.1% ± 2.2% (1 SD), −1.7% ± 1.7% (1 SD), and 0.0% ± 1.3% (1 SD) for IMRT at the Radboud University Medical Center (RUMC), VMAT (RUMC), and VMAT at the Wellington Blood and Cancer Centre, respectively. Verification of the dose to organs at risk gave very similar results but was generally subject to a larger measurement uncertainty due to the position of the detector at a high dose gradient. The observed deviations could be related to limitations of the TPS beam models, attenuation of the treatment couch, as well as measurement errors. The apparent systematic error of about −2% in the average deviation of the integral fraction dose in the RUMC results could be explained by the limitations of the TPS beam model in the calculation of the beam penumbra. Conclusions: This study showed that time-resolved dosimetry using an ionization chamber is feasible and can be largely automated which limits the required additional time compared to integrated dose measurements. It provides a unique QA method which enables identification and quantification of the contribution of various error sources during IMRT and VMAT delivery.« less

Monte Carlo patient study on the comparison of prompt gamma and PET imaging for range verification in proton therapy

NASA Astrophysics Data System (ADS)

Moteabbed, M.; España, S.; Paganetti, H.

2011-02-01

The purpose of this work was to compare the clinical adaptation of prompt gamma (PG) imaging and positron emission tomography (PET) as independent tools for non-invasive proton beam range verification and treatment validation. The PG range correlation and its differences with PET have been modeled for the first time in a highly heterogeneous tissue environment, using different field sizes and configurations. Four patients with different tumor locations (head and neck, prostate, spine and abdomen) were chosen to compare the site-specific behaviors of the PG and PET images, using both passive scattered and pencil beam fields. Accurate reconstruction of dose, PG and PET distributions was achieved by using the planning computed tomography (CT) image in a validated GEANT4-based Monte Carlo code capable of modeling the treatment nozzle and patient anatomy in detail. The physical and biological washout phenomenon and decay half-lives for PET activity for the most abundant isotopes such as 11C, 15O, 13N, 30P and 38K were taken into account in the data analysis. The attenuation of the gamma signal after traversing the patient geometry and respective detection efficiencies were estimated for both methods to ensure proper comparison. The projected dose, PG and PET profiles along many lines in the beam direction were analyzed to investigate the correlation consistency across the beam width. For all subjects, the PG method showed on average approximately 10 times higher gamma production rates than the PET method before, and 60 to 80 times higher production after including the washout correction and acquisition time delay. This rate strongly depended on tissue density and elemental composition. For broad passive scattered fields, it was demonstrated that large differences exist between PG and PET signal falloff positions and the correlation with the dose distribution for different lines in the beam direction. These variations also depended on the treatment site and the particular subject. Thus, similar to PET, direct range verification with PG in passive scattering is not easily viable. However, upon development of an optimized 3D PG detector, indirect range verification by comparing measured and simulated PG distributions (currently being explored for the PET method) would be more beneficial because it can avoid the inherent biological challenges of the PET imaging. The improved correlation of PG and PET with dose when using pencil beams was evident. PG imaging was found to be potentially advantageous especially for small tumors in the presence of high tissue heterogeneities. Including the effects of detector acceptance and efficiency may hold PET superior in terms of the amplitude of the detected signal (depending on the future development of PG detection technology), but the ability to perform online measurements and avoid signal disintegration (due to washout) with PG are important factors that can outweigh the benefits of higher detection sensitivity.

Monte Carlo patient study on the comparison of prompt gamma and PET imaging for range verification in proton therapy.

PubMed

Moteabbed, M; España, S; Paganetti, H

2011-02-21

The purpose of this work was to compare the clinical adaptation of prompt gamma (PG) imaging and positron emission tomography (PET) as independent tools for non-invasive proton beam range verification and treatment validation. The PG range correlation and its differences with PET have been modeled for the first time in a highly heterogeneous tissue environment, using different field sizes and configurations. Four patients with different tumor locations (head and neck, prostate, spine and abdomen) were chosen to compare the site-specific behaviors of the PG and PET images, using both passive scattered and pencil beam fields. Accurate reconstruction of dose, PG and PET distributions was achieved by using the planning computed tomography (CT) image in a validated GEANT4-based Monte Carlo code capable of modeling the treatment nozzle and patient anatomy in detail. The physical and biological washout phenomenon and decay half-lives for PET activity for the most abundant isotopes such as (11)C, (15)O, (13)N, (30)P and (38)K were taken into account in the data analysis. The attenuation of the gamma signal after traversing the patient geometry and respective detection efficiencies were estimated for both methods to ensure proper comparison. The projected dose, PG and PET profiles along many lines in the beam direction were analyzed to investigate the correlation consistency across the beam width. For all subjects, the PG method showed on average approximately 10 times higher gamma production rates than the PET method before, and 60 to 80 times higher production after including the washout correction and acquisition time delay. This rate strongly depended on tissue density and elemental composition. For broad passive scattered fields, it was demonstrated that large differences exist between PG and PET signal falloff positions and the correlation with the dose distribution for different lines in the beam direction. These variations also depended on the treatment site and the particular subject. Thus, similar to PET, direct range verification with PG in passive scattering is not easily viable. However, upon development of an optimized 3D PG detector, indirect range verification by comparing measured and simulated PG distributions (currently being explored for the PET method) would be more beneficial because it can avoid the inherent biological challenges of the PET imaging. The improved correlation of PG and PET with dose when using pencil beams was evident. PG imaging was found to be potentially advantageous especially for small tumors in the presence of high tissue heterogeneities. Including the effects of detector acceptance and efficiency may hold PET superior in terms of the amplitude of the detected signal (depending on the future development of PG detection technology), but the ability to perform online measurements and avoid signal disintegration (due to washout) with PG are important factors that can outweigh the benefits of higher detection sensitivity.

A Review of Current and Emerging Approaches to Pain Management in the Emergency Department.

PubMed

Todd, Knox H

2017-12-01

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

Estimation and correction of produced light from prompt gamma photons on luminescence imaging of water for proton therapy dosimetry

NASA Astrophysics Data System (ADS)

Yabe, Takuya; Komori, Masataka; Toshito, Toshiyuki; Yamaguchi, Mitsutaka; Kawachi, Naoki; Yamamoto, Seiichi

2018-02-01

Although the luminescence images of water during proton-beam irradiation using a cooled charge-coupled device camera showed almost the same ranges of proton beams as those measured by an ionization chamber, the depth profiles showed lower Bragg peak intensities than those measured by an ionization chamber. In addition, a broad optical baseline signal was observed in depths that exceed the depth of the Bragg peak. We hypothesize that this broad baseline signal originates from the interaction of proton-induced prompt gamma photons with water. These prompt gamma photons interact with water to form high-energy Compton electrons, which may cause luminescence or Cherenkov emission from depths exceeding the location of the Bragg peak. To clarify this idea, we measured the luminescence images of water during the irradiations of protons in water with minimized parallax errors, and also simulated the produced light by the interactions of prompt gamma photons with water. We corrected the measured depth profiles of the luminescence images by subtracting the simulated distributions of the produced light by the interactions of prompt gamma photons in water. Corrections were also conducted using the estimated depth profiles of the light of the prompt gamma photons, as obtained from the off-beam areas of the luminescence images of water. With these corrections, we successfully obtained depth profiles that have almost identical distributions as the simulated dose distributions for protons. The percentage relative height of the Bragg peak with corrections to that of the simulation data increased to 94% from 80% without correction. Also, the percentage relative offset heights of the deeper part of the Bragg peak with corrections decreased to 0.2%-0.4% from 4% without correction. These results indicate that the luminescence imaging of water has potential for the dose distribution measurements for proton therapy dosimetry.

Synthesis of polycyclic spiroindolines by highly diastereoselective interrupted Ugi cascade reactions of 3-(2-isocyanoethyl)indoles.

PubMed

Saya, Jordy M; Oppelaar, Barry; Cioc, Răzvan C; van der Heijden, Gydo; Vande Velde, Christophe M L; Orru, Romano V A; Ruijter, Eelco

2016-10-13

We report a highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochemically complex spiroindolines from tryptamine-derived isocyanides. The reaction is facilitated by using fluorinated alcohols (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.

Promoting Equitable Biology Lab Instruction by Engaging All Students in a Broad Range of Science Practices: An Exploratory Study

ERIC Educational Resources Information Center

Strimaitis, Anna M.; Southerland, Sherry A.; Sampson, Victor; Enderle, Patrick; Grooms, Jonathon

2017-01-01

This study examines what students enrolled in the honors and general sections of a high school biology course offered at the same school learn when they have an opportunity to participate in a broad or narrow range of science practices during their laboratory experiences. The results of our analysis suggest that the students enrolled in the…

Ocular toxicity of fludarabine

PubMed Central

Ding, Xiaoyan; Herzlich, Alexandra A; Bishop, Rachel; Tuo, Jingsheng; Chan, Chi-Chao

2008-01-01

The purine analogs, fludarabine and cladribine represent an important class of chemotherapy agents used to treat a broad spectrum of lymphoid malignancies. Their toxicity profiles include dose-limiting myelosuppression, immunosuppression, opportunistic infection and severe neurotoxicity. This review summarizes the neurotoxicity of high- and standard-dose fludarabine, focusing on the clinical and pathological manifestations in the eye. The mechanisms of ocular toxicity are probably multifactorial. With increasing clinical use, an awareness of the neurological and ocular vulnerability, particularly to fludarabine, is important owing to the potential for life- and sight-threatening consequences. PMID:18461151

A silicon strip detector array for energy verification and quality assurance in heavy ion therapy.

PubMed

Debrot, Emily; Newall, Matthew; Guatelli, Susanna; Petasecca, Marco; Matsufuji, Naruhiro; Rosenfeld, Anatoly B

2018-02-01

The measurement of depth dose profiles for range and energy verification of heavy ion beams is an important aspect of quality assurance procedures for heavy ion therapy facilities. The steep dose gradients in the Bragg peak region of these profiles require the use of detectors with high spatial resolution. The aim of this work is to characterize a one dimensional monolithic silicon detector array called the "serial Dose Magnifying Glass" (sDMG) as an independent ion beam energy and range verification system used for quality assurance conducted for ion beams used in heavy ion therapy. The sDMG detector consists of two linear arrays of 128 silicon sensitive volumes each with an effective size of 2mm × 50μm × 100μm fabricated on a p-type substrate at a pitch of 200 μm along a single axis of detection. The detector was characterized for beam energy and range verification by measuring the response of the detector when irradiated with a 290 MeV/u 12 C ion broad beam incident along the single axis of the detector embedded in a PMMA phantom. The energy of the 12 C ion beam incident on the detector and the residual energy of an ion beam incident on the phantom was determined from the measured Bragg peak position in the sDMG. Ad hoc Monte Carlo simulations of the experimental setup were also performed to give further insight into the detector response. The relative response profiles along the single axis measured with the sDMG detector were found to have good agreement between experiment and simulation with the position of the Bragg peak determined to fall within 0.2 mm or 1.1% of the range in the detector for the two cases. The energy of the beam incident on the detector was found to vary less than 1% between experiment and simulation. The beam energy incident on the phantom was determined to be (280.9 ± 0.8) MeV/u from the experimental and (280.9 ± 0.2) MeV/u from the simulated profiles. These values coincide with the expected energy of 281 MeV/u. The sDMG detector response was studied experimentally and characterized using a Monte Carlo simulation. The sDMG detector was found to accurately determine the 12 C beam energy and is suited for fast energy and range verification quality assurance. It is proposed that the sDMG is also applicable for verification of treatment planning systems that rely on particle range. © 2017 American Association of Physicists in Medicine.

Femtosecond soliton source with fast and broad spectral tunability.

PubMed

Masip, Martin E; Rieznik, A A; König, Pablo G; Grosz, Diego F; Bragas, Andrea V; Martinez, Oscar E

2009-03-15

We present a complete set of measurements and numerical simulations of a femtosecond soliton source with fast and broad spectral tunability and nearly constant pulse width and average power. Solitons generated in a photonic crystal fiber, at the low-power coupling regime, can be tuned in a broad range of wavelengths, from 850 to 1200 nm using the input power as the control parameter. These solitons keep almost constant time duration (approximately 40 fs) and spectral widths (approximately 20 nm) over the entire measured spectra regardless of input power. Our numerical simulations agree well with measurements and predict a wide working wavelength range and robustness to input parameters.

THE HUBBLE WIDE FIELD CAMERA 3 TEST OF SURFACES IN THE OUTER SOLAR SYSTEM: SPECTRAL VARIATION ON KUIPER BELT OBJECTS

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

Fraser, Wesley C.; Brown, Michael E.; Glass, Florian, E-mail: wesley.fraser@nrc.ca

2015-05-01

Here, we present additional photometry of targets observed as part of the Hubble Wide Field Camera 3 (WFC3) Test of Surfaces in the Outer Solar System. Twelve targets were re-observed with the WFC3 in the optical and NIR wavebands designed to complement those used during the first visit. Additionally, all of the observations originally presented by Fraser and Brown were reanalyzed through the same updated photometry pipeline. A re-analysis of the optical and NIR color distribution reveals a bifurcated optical color distribution and only two identifiable spectral classes, each of which occupies a broad range of colors and has correlatedmore » optical and NIR colors, in agreement with our previous findings. We report the detection of significant spectral variations on five targets which cannot be attributed to photometry errors, cosmic rays, point-spread function or sensitivity variations, or other image artifacts capable of explaining the magnitude of the variation. The spectrally variable objects are found to have a broad range of dynamical classes and absolute magnitudes, exhibit a broad range of apparent magnitude variations, and are found in both compositional classes. The spectrally variable objects with sufficiently accurate colors for spectral classification maintain their membership, belonging to the same class at both epochs. 2005 TV189 exhibits a sufficiently broad difference in color at the two epochs that span the full range of colors of the neutral class. This strongly argues that the neutral class is one single class with a broad range of colors, rather than the combination of multiple overlapping classes.« less

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

Poplawski, L; Li, T; Chino, J

Purpose: In brachytherapy, structures surrounding the target have the potential to move between treatments and receive unknown dose. Deformable image registration could overcome challenges through dose accumulation. This study uses two possible deformable dose summation techniques and compares the results to point dose summation currently performed in clinic. Methods: Data for ten patients treated with a Syed template was imported into the MIM software (Cleveland, OH). The deformable registration was applied to structures by masking other image data to a single intensity. The registration flow consisted of the following steps: 1) mask CTs so that each of the structures-of-interest hadmore » one unique intensity; 2) perform applicator — based rigid registration; 3) Perform deformable registration; 4) Refine registration by changing local alignments manually; 5) Repeat steps 1 to 3 until desired structure adequately deformed; 5) Transfer each deformed contours to the first CT. The deformed structure accuracy was determined by a dice similarity coefficient (DSC) comparison with the first fraction. Two dose summation techniques were investigated: a deformation and recalculation on the structure; and a dose deformation and accumulation method. Point doses were used as a comparison value. Results: The Syed deformations have DSC ranging from 0.53 to 0.97 and 0.75 and 0.95 for the bladder and rectum, respectively. For the bladder, contour deformation addition ranged from −34.8% to 0.98% and dose deformation accumulation ranged from −35% to 29.3% difference from clinical calculations. For the rectum, contour deformation addition ranged from −5.2% to 16.9% and the dose deformation accumulation ranged from −29.1% to 15.3% change. Conclusion: Deforming dose for summation leads to different volumetric doses than when dose is recalculated on deformed structures, raising concerns about the accuracy of the deformed dose. DSC alone cannot be used to establish the accuracy of a deformation for brachy dose summation purpose.« less

TH-A-19A-06: Site-Specific Comparison of Analytical and Monte Carlo Based Dose Calculations

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

Schuemann, J; Grassberger, C; Paganetti, H

2014-06-15

Purpose: To investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict dose distributions and to verify currently used uncertainty margins in proton therapy. Methods: Dose distributions predicted by an analytical pencilbeam algorithm were compared with Monte Carlo simulations (MCS) using TOPAS. 79 complete patient treatment plans were investigated for 7 disease sites (liver, prostate, breast, medulloblastoma spine and whole brain, lung and head and neck). A total of 508 individual passively scattered treatment fields were analyzed for field specific properties. Comparisons based on target coverage indices (EUD, D95, D90 and D50)more » were performed. Range differences were estimated for the distal position of the 90% dose level (R90) and the 50% dose level (R50). Two-dimensional distal dose surfaces were calculated and the root mean square differences (RMSD), average range difference (ARD) and average distal dose degradation (ADD), the distance between the distal position of the 80% and 20% dose levels (R80- R20), were analyzed. Results: We found target coverage indices calculated by TOPAS to generally be around 1–2% lower than predicted by the analytical algorithm. Differences in R90 predicted by TOPAS and the planning system can be larger than currently applied range margins in proton therapy for small regions distal to the target volume. We estimate new site-specific range margins (R90) for analytical dose calculations considering total range uncertainties and uncertainties from dose calculation alone based on the RMSD. Our results demonstrate that a reduction of currently used uncertainty margins is feasible for liver, prostate and whole brain fields even without introducing MC dose calculations. Conclusion: Analytical dose calculation algorithms predict dose distributions within clinical limits for more homogeneous patients sites (liver, prostate, whole brain). However, we recommend treatment plan verification using Monte Carlo simulations for patients with complex geometries.« less

SU-F-BRD-05: Robustness of Dose Painting by Numbers in Proton Therapy

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

Montero, A Barragan; Sterpin, E; Lee, J

Purpose: Proton range uncertainties may cause important dose perturbations within the target volume, especially when steep dose gradients are present as in dose painting. The aim of this study is to assess the robustness against setup and range errors for high heterogeneous dose prescriptions (i.e., dose painting by numbers), delivered by proton pencil beam scanning. Methods: An automatic workflow, based on MATLAB functions, was implemented through scripting in RayStation (RaySearch Laboratories). It performs a gradient-based segmentation of the dose painting volume from 18FDG-PET images (GTVPET), and calculates the dose prescription as a linear function of the FDG-uptake value on eachmore » voxel. The workflow was applied to two patients with head and neck cancer. Robustness against setup and range errors of the conventional PTV margin strategy (prescription dilated by 2.5 mm) versus CTV-based (minimax) robust optimization (2.5 mm setup, 3% range error) was assessed by comparing the prescription with the planned dose for a set of error scenarios. Results: In order to ensure dose coverage above 95% of the prescribed dose in more than 95% of the GTVPET voxels while compensating for the uncertainties, the plans with a PTV generated a high overdose. For the nominal case, up to 35% of the GTVPET received doses 5% beyond prescription. For the worst of the evaluated error scenarios, the volume with 5% overdose increased to 50%. In contrast, for CTV-based plans this 5% overdose was present only in a small fraction of the GTVPET, which ranged from 7% in the nominal case to 15% in the worst of the evaluated scenarios. Conclusion: The use of a PTV leads to non-robust dose distributions with excessive overdose in the painted volume. In contrast, robust optimization yields robust dose distributions with limited overdose. RaySearch Laboratories is sincerely acknowledged for providing us with RayStation treatment planning system and for the support provided.« less

Broad Resistance to ACCase Inhibiting Herbicides in a Ryegrass Population Is Due Only to a Cysteine to Arginine Mutation in the Target Enzyme

PubMed Central

Kaundun, Shiv Shankhar; Hutchings, Sarah-Jane; Dale, Richard Paul; McIndoe, Eddie

2012-01-01

Background The design of sustainable weed management strategies requires a good understanding of the mechanisms by which weeds evolve resistance to herbicides. Here we have conducted a study on the mechanism of resistance to ACCase inhibiting herbicides in a Lolium multiflorum population (RG3) from the UK. Methodology/Principal Findings Analysis of plant phenotypes and genotypes showed that all the RG3 plants (72%) that contained the cysteine to arginine mutation at ACCase codon position 2088 were resistant to ACCase inhibiting herbicides. Whole plant dose response tests on predetermined wild and mutant 2088 genotypes from RG3 and a standard sensitive population indicated that the C2088R mutation is the only factor conferring resistance to all ten ACCase herbicides tested. The associated resistance indices ranged from 13 for clethodim to over 358 for diclofop-methyl. Clethodim, the most potent herbicide was significantly affected even when applied on small mutant plants at the peri-emergence and one leaf stages. Conclusion/Significance This study establishes the clear and unambiguous importance of the C2088R target site mutation in conferring broad resistance to ten commonly used ACCase inhibiting herbicides. It also demonstrates that low levels “creeping”, multigenic, non target site resistance, is not always selected before single gene target site resistance appears in grass weed populations subjected to herbicide selection pressure. PMID:22768118

Assessment of Impact of Monoenergetic Photon Sources on Prioritized Nonproliferation Applications: Simulation Study Report

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

Geddes, Cameron; Ludewigt, Bernhard; Valentine, John

Near-monoenergetic photon sources (MPSs) have the potential to improve sensitivity at greatly reduced dose in existing applications and enable new capabilities in other applications. MPS advantages include the ability to select energy, energy spread, flux, and pulse structures to deliver only the photons needed for the application, while suppressing extraneous dose and background. Some MPSs also offer narrow divergence photon beams which can target dose and/or mitigate scattering contributions to image contrast degradation. Current broad-band, bremsstrahlung photon sources (e.g., linacs and betatrons) deliver unnecessary dose that in some cases also interferes with the signature to be detected and/or restricts operations,more » and must be collimated (reducing flux) to generate narrow divergence beams. While MPSs can in principle resolve these issues, they are technically challenging to produce. Candidate MPS technologies for nonproliferation applications are now being developed, each of which have different properties (e.g. broad divergence vs. narrow). Within each technology, source parameters trade off against one another (e.g. flux vs. energy spread), representing a large operation space. To guide development, requirements for each application of interest must be defined and simulations conducted to define MPS parameters that deliver benefit relative to current systems. The present project conducted a broad assessment of potential nonproliferation applications where MPSs may provide new capabilities or significant performance enhancement (reported separately), which led to prioritization of several applications for detailed analysis. The applications prioritized were: cargo screening and interdiction of Special Nuclear Materials (SNM), detection of hidden SNM, treaty/dismantlement verification, and spent fuel dry storage cask content verification. High resolution imaging for stockpile stewardship was considered as a sub-area of the treaty topic, as it is also of interest for future treaty use. This report presents higher-fidelity calculations and modeling results to quantitatively evaluate the prioritized applications, and to derive the key MPS properties that drive application benefit. Simulations focused on the conventional signatures of radiography, photofission, and NRF to enable comparison to present methods and evaluation of benefit.« less

Discovery and clinical introduction of first-in-class imipridone ONC201.

PubMed

Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L; Pottorf, Richard S; Nallaganchu, B Rao; Olson, Gary L; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T; Talekar, Mala K; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S

2016-11-08

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Discovery and clinical introduction of first-in-class imipridone ONC201

PubMed Central

Allen, Joshua E.; Kline, C. Leah B.; Prabhu, Varun V.; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L.; Pottorf, Richard S.; Nallaganchu, B. Rao; Olson, Gary L.; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T.; Talekar, Mala K.; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L.; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S.

2016-01-01

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials. PMID:27602582

Effects of field-realistic doses of glyphosate on honeybee appetitive behaviour.

PubMed

Herbert, Lucila T; Vázquez, Diego E; Arenas, Andrés; Farina, Walter M

2014-10-01

Glyphosate (GLY) is a broad-spectrum herbicide used for weed control. The sub-lethal impact of GLY on non-target organisms such as insect pollinators has not yet been evaluated. Apis mellifera is the main pollinator in agricultural environments and is a well-known model for behavioural research. Honeybees are also accurate biosensors of environmental pollutants and their appetitive behavioural response is a suitable tool with which to test sub-lethal effects of agrochemicals. We studied the effects of field-realistic doses of GLY on honeybees exposed chronically or acutely to the herbicide. We focused on sucrose sensitivity, elemental and non-elemental associative olfactory conditioning of the proboscis extension response (PER), and foraging-related behaviour. We found a reduced sensitivity to sucrose and learning performance for the groups chronically exposed to GLY concentrations within the range of recommended doses. When olfactory PER conditioning was performed with sucrose reward with the same GLY concentrations (acute exposure), elemental learning and short-term memory retention decreased significantly compared with controls. Non-elemental associative learning was also impaired by an acute exposure to GLY traces. Altogether, these results imply that GLY at concentrations found in agro-ecosystems as a result of standard spraying can reduce sensitivity to nectar reward and impair associative learning in honeybees. However, no effect on foraging-related behaviour was found. Therefore, we speculate that successful forager bees could become a source of constant inflow of nectar with GLY traces that could then be distributed among nestmates, stored in the hive and have long-term negative consequences on colony performance. © 2014. Published by The Company of Biologists Ltd.

Assessment of herb-drug synergy to combat doxorubicin induced cardiotoxicity.

PubMed

Jain, Aditi; Rani, Vibha

2018-07-15

Aim Doxorubicin (Dox) is one of the most cardiotoxic anti-cancerous drug that is widely used for broad-range of cancers. There is an urgent need for developing cardio-oncological therapeutic interventions. Natural products having both anti-cancerous potential as well as cardioprotective effects may hold a great potential in this regard. Curcuma longa (an Indian herb) polyphenols including curcumin, and well known for its anti-oxidative and anti-cancerous potential was used in the present study for its synergistic effect on cancer cells and cardiomyocytes. Preliminary dose dependent analysis for cell viability was conducted by MTT and trypan blue assays where the effects of curcumin and Dox on cancer cell progression and cardiotoxicity were studied. Microscopic studies were done to analyse the morphological alterations of cells followed by intracellular ROS production studies by NBT and DCFH-DA assays. Apoptotic cellular death was studied by caspase activity and Annexin/PI FACS analysis. TUNEL assay was done followed by expression analysis of different cellular death biomarkers by quantitative real-time PCR. We observed that dose dependent cardiotoxicity of Dox can be significantly minimized by supplementing it with curcumin. Curcumin supplementation exaggerates oxidative stress and apoptosis leading to cancer cell death by modulating pro- and anti-apoptotic biomarkers. The combination treatment with curcumin results in achieving the desired anti-cancerous effect of Dox without compromising its activity and hence, reduces the possibility of its dose mediated cardiotoxic effects. Hence, curcumin holds a great potential for cardio-oncological therapeutic interventions. Copyright © 2018 Elsevier Inc. All rights reserved.

Transmutation approximations for the application of hybrid Monte Carlo/deterministic neutron transport to shutdown dose rate analysis

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

Biondo, Elliott D.; Wilson, Paul P. H.

In fusion energy systems (FES) neutrons born from burning plasma activate system components. The photon dose rate after shutdown from resulting radionuclides must be quantified. This shutdown dose rate (SDR) is calculated by coupling neutron transport, activation analysis, and photon transport. The size, complexity, and attenuating configuration of FES motivate the use of hybrid Monte Carlo (MC)/deterministic neutron transport. The Multi-Step Consistent Adjoint Driven Importance Sampling (MS-CADIS) method can be used to optimize MC neutron transport for coupled multiphysics problems, including SDR analysis, using deterministic estimates of adjoint flux distributions. When used for SDR analysis, MS-CADIS requires the formulation ofmore » an adjoint neutron source that approximates the transmutation process. In this work, transmutation approximations are used to derive a solution for this adjoint neutron source. It is shown that these approximations are reasonably met for typical FES neutron spectra and materials over a range of irradiation scenarios. When these approximations are met, the Groupwise Transmutation (GT)-CADIS method, proposed here, can be used effectively. GT-CADIS is an implementation of the MS-CADIS method for SDR analysis that uses a series of single-energy-group irradiations to calculate the adjoint neutron source. For a simple SDR problem, GT-CADIS provides speedups of 200 100 relative to global variance reduction with the Forward-Weighted (FW)-CADIS method and 9 ± 5 • 104 relative to analog. As a result, this work shows that GT-CADIS is broadly applicable to FES problems and will significantly reduce the computational resources necessary for SDR analysis.« less

Transmutation approximations for the application of hybrid Monte Carlo/deterministic neutron transport to shutdown dose rate analysis

DOE PAGES

Biondo, Elliott D.; Wilson, Paul P. H.

2017-05-08

In fusion energy systems (FES) neutrons born from burning plasma activate system components. The photon dose rate after shutdown from resulting radionuclides must be quantified. This shutdown dose rate (SDR) is calculated by coupling neutron transport, activation analysis, and photon transport. The size, complexity, and attenuating configuration of FES motivate the use of hybrid Monte Carlo (MC)/deterministic neutron transport. The Multi-Step Consistent Adjoint Driven Importance Sampling (MS-CADIS) method can be used to optimize MC neutron transport for coupled multiphysics problems, including SDR analysis, using deterministic estimates of adjoint flux distributions. When used for SDR analysis, MS-CADIS requires the formulation ofmore » an adjoint neutron source that approximates the transmutation process. In this work, transmutation approximations are used to derive a solution for this adjoint neutron source. It is shown that these approximations are reasonably met for typical FES neutron spectra and materials over a range of irradiation scenarios. When these approximations are met, the Groupwise Transmutation (GT)-CADIS method, proposed here, can be used effectively. GT-CADIS is an implementation of the MS-CADIS method for SDR analysis that uses a series of single-energy-group irradiations to calculate the adjoint neutron source. For a simple SDR problem, GT-CADIS provides speedups of 200 100 relative to global variance reduction with the Forward-Weighted (FW)-CADIS method and 9 ± 5 • 104 relative to analog. As a result, this work shows that GT-CADIS is broadly applicable to FES problems and will significantly reduce the computational resources necessary for SDR analysis.« less

The need for non- or minimally-invasive biomonitoring strategies and the development of pharmacokinetic/pharmacodynamic models for quantification

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

Timchalk, Charles; Weber, Thomas J.; Smith, Jordan N.

Advancements in Exposure Science involving the development and deployment of biomarkers of exposure and biological response are anticipated to significantly (and positively) influence health outcomes associated with occupational, environmental and clinical exposure to chemicals/drugs. To achieve this vision, innovative strategies are needed to develop multiplex sensor platforms capable of quantifying individual and mixed exposures (i.e. systemic dose) by measuring biomarkers of dose and biological response in readily obtainable (non-invasive) biofluids. Secondly, the use of saliva (alternative to blood) for biomonitoring coupled with the ability to rapidly analyze multiple samples in real-time offers an innovative opportunity to revolutionize biomonitoring assessments. Inmore » this regard, the timing and number of samples taken for biomonitoring will not be limited as is currently the case. In addition, real-time analysis will facilitate identification of work practices or conditions that are contributing to increased exposures and will make possible a more rapid and successful intervention strategy. The initial development and application of computational models for evaluation of saliva/blood analyte concentration at anticipated exposure levels represents an important opportunity to establish the limits of quantification and robustness of multiplex sensor systems by exploiting a unique computational modeling framework. The use of these pharmacokinetic models will also enable prediction of an exposure dose based on the saliva/blood measurement. This novel strategy will result in a more accurate prediction of exposures and, once validated, can be employed to assess dosimetry to a broad range of chemicals in support of biomonitoring and epidemiology studies.« less

Thermoluminescence dating of Hawaiian basalt

USGS Publications Warehouse

May, Rodd James

1979-01-01

The thermoluminescence (TL) properties of plagioclase separates from 11 independently dated alkalic basalts 4,500 years to 3.3 million years old and 17 tholeiitic basalts 16 years to 450,000 years old from the Hawaiian Islands were investigated for the purpose of developing a TL dating method for young volcanic rocks. Ratios of natural to artificial TL intensity, when normalized for natural radiation dose rates, were used to quantify the thermoluminescence response of individual samples for age-determination purposes. The TL ratios for the alkalic basalt plagioclase were found to increase with age at a predictable exponential rate that permits the use of the equation for the best-fit line through a plot of the TL ratios relative to known age as a TL age equation. The equation is applicable to rocks ranging in composition from basaltic andesite to trachyte over the age range from about 2,000 to at least 250,000 years before present (B.P.). The TL ages for samples older than 50,000 years have a calculated precision of less than :t 10 percent and a potential estimated accuracy relative to potassium-argon ages of approximately :t 10 percent. An attempt to develop a similar dating curve for the tholeiitic basalts was not as successful, primarily because the dose rates are on the average lower than those for the alkalic basalts by a factor of 6, resulting in lower TL intensities in the tholeiitic basalts for samples of equivalent age, and also because the age distribution of dated material is inadequate. The basic TL properties of the plagioclase from the two rock types are similar, however, and TL dating of tholeiitic basalts should eventually be feasible over the age range 10,000 to at least 200,000 years B.P. The average composition of the plagioclase separates from the alkalic basalts ranges from oligoclase to andesine; compositional variations within this range have no apparent effect on the TL ratios. The average composition of the plagioclase from the tholeiitic basalts is labradorite. The natural radiogenic dose rates for the alkalic basalts calculated on the basis of assumed secular equilibrium range from 0.228 to 0.462 rad per year and average 0.335 rad per year exclusive of the cosmic-ray energy dose and with the alpha-particle component equal to one-tenth of the total alpha decay energy. The TL measurements were made using material of a 37 to 44-micrometer size range; the crushing required during sample preparation was found to have a negligible effect on natural TL. Both natural and artificial TL were filtered to the bandwidth 3,500 A to 5,000 A to restrict the light detected to that from the plagioclase emission peak centered at about 4,500 A and associated with structural defects. Within this bandwidth, the natural TL from both the alkalic and tholeiitic basalt plagioclase consists of a single peak with a maximum amplitude at about 350?C; the artificial TL glow curves produced by an exposure of the drained samples to a standard dose of X-radiation consist of four broad, variably overlapping peaks with maxima at about 110?C, 150?C, 225?C, and 300?C. The maximum amplitude of the 350?C natural and 300?C artificial TL peaks, both produced by the same general activation energy distribution of trapping centers, were used for TL dating. The high-temperature artificial TL peak occurs at a lower temperature than the corresponding natural TL peak owing to the presence of a large number of electrons retained in traps near the lower end of the trap-depth energy range in samples whose TL is measured a short time after intense artificial irradiation. These traps remain essentially empty in the natural environment owing to spontaneous decay and do not produce measurable low-temperature natural TL peaks. With prolonged storage after irradiation, the 300?C artificial TL peak migrates to higher temperatures and decreases in amplitude.

Augmentin (amoxicillin/clavulanate) in the treatment of community-acquired respiratory tract infection: a review of the continuing development of an innovative antimicrobial agent.

PubMed

White, Anthony R; Kaye, Clive; Poupard, James; Pypstra, Rienk; Woodnutt, Gary; Wynne, Brian

2004-01-01

Amoxicillin/clavulanate (Augmentin) is a broad-spectrum antibacterial that has been available for clinical use in a wide range of indications for over 20 years and is now used primarily in the treatment of community-acquired respiratory tract infections. Amoxicillin/clavulanate was developed to provide a potent broad spectrum of antibacterial activity, coverage of beta-lactamase-producing pathogens and a favourable pharmacokinetic/pharmacodynamic (PK/PD) profile. These factors have contributed to the high bacteriological and clinical efficacy of amoxicillin/clavulanate in respiratory tract infection over more than 20 years. This is against a background of increasing prevalence of antimicrobial resistance, notably the continued spread of beta-lactamase-mediated resistance in Haemophilus influenzae and Moraxella catarrhalis, and penicillin, macrolide and quinolone resistance in Streptococcus pneumoniae. The low propensity of amoxicillin/clavulanate to select resistance mutations as well as a favourable PK/PD profile predictive of high bacteriological efficacy may account for the longevity of this combination in clinical use. However, in certain defined geographical areas, the emergence of S. pneumoniae strains with elevated penicillin MICs has been observed. In order to meet the need to treat drug-resistant S. pneumoniae, two new high-dose amoxicillin/clavulanate formulations have been developed. A pharmacokinetically enhanced tablet dosage form of amoxicillin/clavulanate 2000/125 mg twice daily (available as Augmentin XR in the USA), has been developed for use in adult respiratory tract infection due to drug-resistant pathogens, such as S. pneumoniae with reduced susceptibility to penicillin, as well as beta-lactamase-producing H. influenzae and M. catarrhalis. Amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses (Augmentin ES-600) is for paediatric use in persistent or recurrent acute otitis media where there are risk factors for the involvement of beta-lactamase-producing strains or S. pneumoniae with reduced penicillin susceptibility. In addition to high efficacy, amoxicillin/clavulanate has a well known safety and tolerance profile of the two new high-dose formulations are not significantly different from those of conventional formulations. Amoxicillin/clavulanate is included in guidelines and recommendations for the treatment of bacterial sinusitis, acute otitis media, community-acquired pneumonia and acute exacerbations of chronic bronchitis. Amoxicillin/clavulanate continues to be an important agent in the treatment of community-acquired respiratory tract infections, both now and in the future.

SU-F-T-587: Quality Assurance of Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT) for Patient Specific Plans: A Comparison Between MATRIXX and Delta4 QA Devices

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

Tsai, YC; Lu, SH; Chen, LH

2016-06-15

Purpose: Patient-specific quality assurance (QA) is necessary to accurately deliver high dose radiation to the target, especially for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). Unlike previous 2 dimensional (D) array QA devices, Delta{sup 4} can verify the dose delivery in 3D. In this study, the difference between calculated and measured dose distribution was compared with two QA devices (MATRIXX and Delta{sup 4}) to evaluate the delivery accuracy. Methods: Twenty-seven SRS/SBRT plans with VMAT were verified with point-dose and dose-map analysis. We use an ion chamber (A1SL, 0.053cc) for point-dose measurement. For verification of the dose map, themore » differences between the calculated and measured doses were analyzed with a gamma index using MATRIXX and Delta{sup 4} devices. The passing criteria for gamma evaluation were set at 3 mm for distance-to-agreement (DTA) and 3% for dose-difference. A gamma index less than 1 was defined as the verification passing the criteria and satisfying at least 95% of the points. Results: The mean prescribed dose and fraction was 40 ± 14.41 Gy (range: 16–60) and 10 ± 2.35 fractions (range: 1–8), respectively. In point dose analysis, the differences between the calculated and measured doses were all less than 5% (mean: 2.12 ± 1.13%; range: −0.55% to 4.45%). In dose-map analysis, the average passing rates were 99.38 ± 0.96% (range: 95.31–100%) and 100 ± 0.12% (range: 99.5%–100%) for MATRIXX and Delta{sup 4}, respectively. Even using criteria of 2%/2 mm, the passing rate of Delta{sup 4} was still more than 95% (mean: 99 ± 1.08%; range: 95.6%–100%). Conclusion: Both MATRIXX and Delta{sup 4} offer accurate and efficient verification for SRS/SBRT plans. The results measured by MATRIXX and Delta{sup 4} dosimetry systems are similar for SRS/SBRT performed with the VMAT technique.« less

Efficacy of sericea lespedeza hay as a natural dewormer in goats: Dose titration study

USDA-ARS?s Scientific Manuscript database

Gastrointestinal nematode (GIN) parasitism is the greatest threat to economic sheep and goat production in the southern USA, and there is widespread prevalence of GIN resistance to broad-spectrum anthelmintics in this region. A natural alternative for controlling GIN in small ruminants is feeding h...

CONSTRUCTION OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC (PBPK/PD) MODEL FOR CARBOFURAN USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM)

EPA Science Inventory

Carbofuran, known as 2, 3-dihydro-2, 2-dimethyl-7-benzofuranyl-N-methylcarbamate, is a broad spectrum N-methyl carbamate pesticide. Carbofuran and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). Carbofuran is widel...

Alternative chitosan-based EPR dosimeter applicable for a relatively wide range of gamma radiation doses

NASA Astrophysics Data System (ADS)

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

2017-12-01

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

Broadband sensitive pump-probe setup for ultrafast optical switching of photonic nanostructures and semiconductors.

PubMed

Euser, Tijmen G; Harding, Philip J; Vos, Willem L

2009-07-01

We describe an ultrafast time resolved pump-probe spectroscopy setup aimed at studying the switching of nanophotonic structures. Both femtosecond pump and probe pulses can be independently tuned over broad frequency range between 3850 and 21,050 cm(-1). A broad pump scan range allows a large optical penetration depth, while a broad probe scan range is crucial to study strongly photonic crystals. A new data acquisition method allows for sensitive pump-probe measurements, and corrects for fluctuations in probe intensity and pump stray light. We observe a tenfold improvement of the precision of the setup compared to laser fluctuations, allowing a measurement accuracy of better than DeltaR=0.07% in a 1 s measurement time. Demonstrations of the improved technique are presented for a bulk Si wafer, a three-dimensional Si inverse opal photonic bandgap crystal, and z-scan measurements of the two-photon absorption coefficient of Si, GaAs, and the three-photon absorption coefficient of GaP in the infrared wavelength range.

Glial-released proteins in clonal cultures and their modulation by hydrocortisone

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

Arenander, A.T.; de Vellis, J.

Rat glial C6 cells release into the culture medium a reproducible spectrum of soluble proteins of 12 major peaks over a broad molecular weight range as determined by fractionation on SDS-gel electrophoresis. Exposing C6 monolayers to hydrocortisone (HC) results in a selective alteration in the pattern of glial-released protein (GRP). The selective HC-induced increase or decrease in GRP peaks is specific to HC in that 17 ..beta..-estradiol, dibutyryl cyclic AMP, isoproterenol, and melatonin exert either no detectable or a qualitatively different influence on the GRP pattern. The HC influence is dose dependent over a physiological range of concentrations from 10/supmore » -9/ to 10/sup -6/ M. Differences in culture age and in subclones of C6 can influence both the normal and the HC-induced pattern of GRP. The origin of the GRP is unknown, but pattern reproducibility, viability tests, surface labelling studies, and metabolic labelling studies of soluble and particulate compartment proteins and glycoproteins support the position that cell lysis is not an important source of GRP. More importantly, these studies indicate that GRP and HC-induced changes in GRP pattern are physiologically significant aspects of glial cell behavior.« less

An Overview of Literature Topics Related to Current Concepts, Methods, Tools, and Applications for Cumulative Risk Assessment (2007-2016).

PubMed

Fox, Mary A; Brewer, L Elizabeth; Martin, Lawrence

2017-04-07

Cumulative risk assessments (CRAs) address combined risks from exposures to multiple chemical and nonchemical stressors and may focus on vulnerable communities or populations. Significant contributions have been made to the development of concepts, methods, and applications for CRA over the past decade. Work in both human health and ecological cumulative risk has advanced in two different contexts. The first context is the effects of chemical mixtures that share common modes of action, or that cause common adverse outcomes. In this context two primary models are used for predicting mixture effects, dose addition or response addition. The second context is evaluating the combined effects of chemical and nonchemical (e.g., radiation, biological, nutritional, economic, psychological, habitat alteration, land-use change, global climate change, and natural disasters) stressors. CRA can be adapted to address risk in many contexts, and this adaptability is reflected in the range in disciplinary perspectives in the published literature. This article presents the results of a literature search and discusses a range of selected work with the intention to give a broad overview of relevant topics and provide a starting point for researchers interested in CRA applications.

An Overview of Literature Topics Related to Current Concepts, Methods, Tools, and Applications for Cumulative Risk Assessment (2007–2016)

PubMed Central

Fox, Mary A.; Brewer, L. Elizabeth; Martin, Lawrence

2017-01-01

Cumulative risk assessments (CRAs) address combined risks from exposures to multiple chemical and nonchemical stressors and may focus on vulnerable communities or populations. Significant contributions have been made to the development of concepts, methods, and applications for CRA over the past decade. Work in both human health and ecological cumulative risk has advanced in two different contexts. The first context is the effects of chemical mixtures that share common modes of action, or that cause common adverse outcomes. In this context two primary models are used for predicting mixture effects, dose addition or response addition. The second context is evaluating the combined effects of chemical and nonchemical (e.g., radiation, biological, nutritional, economic, psychological, habitat alteration, land-use change, global climate change, and natural disasters) stressors. CRA can be adapted to address risk in many contexts, and this adaptability is reflected in the range in disciplinary perspectives in the published literature. This article presents the results of a literature search and discusses a range of selected work with the intention to give a broad overview of relevant topics and provide a starting point for researchers interested in CRA applications. PMID:28387705

Feasibility and preliminary safety of nitric oxide releasing solution as a treatment for bovine mastitis.

PubMed

Regev, Gilly; Martins, James; Sheridan, Michael P; Leemhuis, Jonathan; Thompson, James; Miller, Christopher

2018-06-01

Nitric oxide-releasing solution (NORS) is a liquid formulation that releases nitric oxide, a broad spectrum antimicrobial, single electron nitroxide radical. This solution was investigated as a potential antimicrobial treatment for bovine mastitis (BM). Three experiments were performed: a) NORS' effect on Staphylococcus aureus and Escherichia coli in an in vitro model; b) NORS' effect on milk obtained from dairy cows showing symptoms of clinical mastitis; and c) the consequences of administering NORS to healthy milking cattle using a dose-escalating in vivo study. Metabolite concentrations were estimated in their blood for methaemoglobin and nitrite; also, milk nitrite concentration and somatic cell count (SCC) were measured to study possible mammary gland inflammation following treatment. NORS lowered the bacterial concentration in all infected samples, in a time- and milk-diluted dependant fashion. Blood methemoglobin concentrations following treatment were all within the normal range for cattle. However, blood and milk nitrite concentrations increased initially but, during the next 24 h, returned to normal range, as did SCC, without any clinical signs of mammary gland inflammation. NORS, if shown to be effective, could be an alternative treatment for mastitis with a shorter clearance time. Copyright © 2018 Elsevier Ltd. All rights reserved.

Quantitative modeling of the reaction/diffusion kinetics of two-chemistry photopolymers

NASA Astrophysics Data System (ADS)

Kowalski, Benjamin Andrew

Optically driven diffusion in photopolymers is an appealing material platform for a broad range of applications, in which the recorded refractive index patterns serve either as images (e.g. data storage, display holography) or as optical elements (e.g. custom GRIN components, integrated optical devices). A quantitative understanding of the reaction/diffusion kinetics is difficult to obtain directly, but is nevertheless necessary in order to fully exploit the wide array of design freedoms in these materials. A general strategy for characterizing these kinetics is proposed, in which key processes are decoupled and independently measured. This strategy enables prediction of a material's potential refractive index change, solely on the basis of its chemical components. The degree to which a material does not reach this potential reveals the fraction of monomer that has participated in unwanted reactions, reducing spatial resolution and dynamic range. This approach is demonstrated for a model material similar to commercial media, achieving quantitative predictions of index response over three orders of exposure dose (~1 to ~103 mJ cm-2) and three orders of feature size (0.35 to 500 microns). The resulting insights enable guided, rational design of new material formulations with demonstrated performance improvement.

Infectivity of housefly, Musca domestica (Diptera: Muscidae) to different entomopathogenic fungi.

PubMed

Farooq, Muzammil; Freed, Shoaib

The housefly Musca domestica is a worldwide insect pest that acts as a vector for many pathogenic diseases in both people and animals. The present study was conducted to evaluate the virulence of different local isolates of Beauveria bassiana, Metarhizium anisopliae and Isaria fumosorosea on M. domestica using two bioassay techniques: (1) adult immersion and (2) a bait method applied to both larvae and adults. The results showed evidence of a broad range of responses by both stages (larvae and adults) to the tested isolates of B. bassiana, M. anisopliae and I. fumosorosea. These responses were concentration-dependent, with mortality percentages ranging from 53.00% to 96.00%. Because it resulted in lower LC 50 values and a shorter lethal time, B. bassiana (Bb-01) proved to be the most virulent isolate against both housefly larvae and adults. Sublethal doses of the tested isolates were also assessed to evaluate their effect on M. domestica fecundity and longevity. The fungal infections reduced housefly survival regardless of their sex and also decreased egg production in females. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Magnetic field-controlled gene expression in encapsulated cells

PubMed Central

Ortner, Viktoria; Kaspar, Cornelius; Halter, Christian; Töllner, Lars; Mykhaylyk, Olga; Walzer, Johann; Günzburg, Walter H.; Dangerfield, John A.; Hohenadl, Christine; Czerny, Thomas

2012-01-01

Cell and gene therapies have an enormous range of potential applications, but as for most other therapies, dosing is a critical issue, which makes regulated gene expression a prerequisite for advanced strategies. Several inducible expression systems have been established, which mainly rely on small molecules as inducers, such as hormones or antibiotics. The application of these inducers is difficult to control and the effects on gene regulation are slow. Here we describe a novel system for induction of gene expression in encapsulated cells. This involves the modification of cells to express potential therapeutic genes under the control of a heat inducible promoter and the co-encapsulation of these cells with magnetic nanoparticles. These nanoparticles produce heat when subjected to an alternating magnetic field; the elevated temperatures in the capsules then induce gene expression. In the present study we define the parameters of such systems and provide proof-of-principle using reporter gene constructs. The fine-tuned heating of nanoparticles in the magnetic field allows regulation of gene expression from the outside over a broad range and within short time. Such a system has great potential for advancement of cell and gene therapy approaches. PMID:22197778

Helicobacter pylori-Negative Primary Rectal MALT Lymphoma: Complete Remission after Radiotherapy

PubMed Central

Okamura, Takuma; Suga, Tomoaki; Iwaya, Yugo; Ito, Tetsuya; Yokosawa, Shuichi; Arakura, Norikazu; Ota, Hiroyoshi; Tanaka, Eiji

2012-01-01

Rectal mucosa-associated lymphoid tissue (MALT) lymphoma is a rare condition. Although the majority of patients undergo surgical resection, a definitive treatment for rectal MALT lymphoma has not yet been established. In the present study, we report the outcome of radiotherapy in 3 patients with rectal MALT lymphoma. Our cohort ranged from 56 to 65 years of age. The male/female ratio was 1:2, and all patients were in stage I (Lugano classification) of the disease. Endoscopic findings revealed elevated lesions resembling submucosal tumors in 2 patients, and a sessile elevated lesion with a nodular surface in 1 patient. One of the 3 patients underwent magnifying endoscopy with crystal violet staining that demonstrated a type I pit pattern (Kudo's classification) lesion with a broad intervening area caused by the upthrust of the tumor from the submucosa. All patients tolerated radiotherapy at doses of 30 Gy without major complications and achieved complete remission. Follow-up ranged from 13 to 75 months (mean 51.0 months), revealing no recurrence of MALT lymphoma. As such, we propose radiotherapy to be a safe and effective means for treating rectal MALT lymphoma. PMID:22754493

Manufacturing Work Measurement System Evaluation. Reference Guide

DTIC Science & Technology

1987-04-01

discussions with users of the MTM-MEK predetermined time system. The coranents listed below are based on these discussions and, while a broad range...discussions with users of the MTM-V predeterroined time system. The coranents listed below are based on these discussions and, while a broad range of...industries were sampled, coranents should not be considered universal and therefore may not be applicable to all manufacturing environments: 0 Easy to

A broad-host range dual-fluorescence reporter system for gene expression analysis in Gram-negative bacteria.

PubMed

Hennessy, Rosanna C; Christiansen, Line; Olsson, Stefan; Stougaard, Peter

2018-01-01

Fluorescence-based reporter systems are valuable tools for studying gene expression dynamics in living cells. Here we describe a dual-fluorescence reporter system carrying the red fluorescent marker mCherry and the blue fluorescent protein EBFP2 enabling the simultaneous analysis of two promoters in broad-host range autofluorescent Gram-negative bacteria. Copyright © 2017 Elsevier B.V. All rights reserved.

The dose response relation for rat spinal cord paralysis analyzed in terms of the effective size of the functional subunit

NASA Astrophysics Data System (ADS)

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

2008-11-01

Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D50) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D50 value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the convolution process. The assumption of an effective FSU size is consistent with most of the effects seen when different portions of the rat spinal cord are irradiated to different doses. The effective FSU length from these experiments is about 8.5 ± 0.5 mm. This length could be interpreted as an effective size of the functional subunits in a rat spinal cord, where multiple myelin sheaths are connected by a single oligodendrocyte and repair is limited by the range of oligodendrocyte progenitor cell diffusion. It was even possible to suggest a more likely than uniform effective FSU sensitivity distribution from the experimental data.

SU-F-I-33: Estimating Radiation Dose in Abdominal Fat Quantitative CT

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

Li, X; Yang, K; Liu, B

Purpose: To compare size-specific dose estimate (SSDE) in abdominal fat quantitative CT with another dose estimate D{sub size,L} that also takes into account scan length. Methods: This study complied with the requirements of the Health Insurance Portability and Accountability Act. At our institution, abdominal fat CT is performed with scan length = 1 cm and CTDI{sub vol} = 4.66 mGy (referenced to body CTDI phantom). A previously developed CT simulation program was used to simulate single rotation axial scans of 6–55 cm diameter water cylinders, and dose integral of the longitudinal dose profile over the central 1 cm length wasmore » used to predict the dose at the center of one-cm scan range. SSDE and D{sub size,L} were assessed for 182 consecutive abdominal fat CT examinations with mean water-equivalent diameter (WED) of 27.8 cm ± 6.0 (range, 17.9 - 42.2 cm). Patient age ranged from 18 to 75 years, and weight ranged from 39 to 163 kg. Results: Mean SSDE was 6.37 mGy ± 1.33 (range, 3.67–8.95 mGy); mean D{sub size,L} was 2.99 mGy ± 0.85 (range, 1.48 - 4.88 mGy); and mean D{sub size,L}/SSDE ratio was 0.46 ± 0.04 (range, 0.40 - 0.55). Conclusion: The conversion factors for size-specific dose estimate in AAPM Report No. 204 were generated using 15 - 30 cm scan lengths. One needs to be cautious in applying SSDE to small length CT scans. For abdominal fat CT, SSDE was 80–150% higher than the dose of 1 cm scan length.« less

Analysis of lomustine drug content in FDA-approved and compounded lomustine capsules.

PubMed

KuKanich, Butch; Warner, Matt; Hahn, Kevin

2017-02-01

OBJECTIVE To determine the lomustine content (potency) in compounded and FDA-approved lomustine capsules. DESIGN Evaluation study. SAMPLE 2 formulations of lomustine capsules (low dose [7 to 11 mg] and high dose [40 to 48 mg]; 5 capsules/dose/source) from 3 compounders and from 1 manufacturer of FDA-approved capsules. PROCEDURES Lomustine content was measured by use of a validated high-pressure liquid chromatography method. An a priori acceptable range of 90% to 110% of the stated lomustine content was selected on the basis of US Pharmacopeia guidelines. RESULTS The measured amount of lomustine in all compounded capsules was less than the stated content (range, 59% to 95%) and was frequently outside the acceptable range (failure rate, 2/5 to 5/5). Coefficients of variation for lomustine content ranged from 4.1% to 16.7% for compounded low-dose capsules and from 1.1% to 10.8% for compounded high-dose capsules. The measured amount of lomustine in all FDA-approved capsules was slightly above the stated content (range, 104% to 110%) and consistently within the acceptable range. Coefficients of variation for lomustine content were 0.5% for low-dose and 2.3% for high-dose FDA-approved capsules. CONCLUSIONS AND CLINICAL RELEVANCE Compounded lomustine frequently did not contain the stated content of active drug and had a wider range of lomustine content variability than did the FDA-approved product. The sample size was small, and larger studies are needed to confirm these findings; however, we recommend that compounded veterinary formulations of lomustine not be used when appropriate doses can be achieved with FDA-approved capsules or combinations of FDA-approved capsules.

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.

Implementation of Structures in the CMS: Part 2, Weir

DTIC Science & Technology

2013-08-01

sharp - crested weir , it is between 0.55 and 0.58, and a broad - crested ...implementation, different weir coefficients are specified for the weir structure design, sharp - crested or broad - crested weir . The lowest value in the...coefficient range is used for the sharp - crested (0.55) and broad - crested (0.46) weir , respectively; the flux comparison between these two

Site-specific range uncertainties caused by dose calculation algorithms for proton therapy

NASA Astrophysics Data System (ADS)

Schuemann, J.; Dowdell, S.; Grassberger, C.; Min, C. H.; Paganetti, H.

2014-08-01

The purpose of this study was to assess the possibility of introducing site-specific range margins to replace current generic margins in proton therapy. Further, the goal was to study the potential of reducing margins with current analytical dose calculations methods. For this purpose we investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict the range of proton fields. Dose distributions predicted by an analytical pencil-beam algorithm were compared with those obtained using Monte Carlo (MC) simulations (TOPAS). A total of 508 passively scattered treatment fields were analyzed for seven disease sites (liver, prostate, breast, medulloblastoma-spine, medulloblastoma-whole brain, lung and head and neck). Voxel-by-voxel comparisons were performed on two-dimensional distal dose surfaces calculated by pencil-beam and MC algorithms to obtain the average range differences and root mean square deviation for each field for the distal position of the 90% dose level (R90) and the 50% dose level (R50). The average dose degradation of the distal falloff region, defined as the distance between the distal position of the 80% and 20% dose levels (R80-R20), was also analyzed. All ranges were calculated in water-equivalent distances. Considering total range uncertainties and uncertainties from dose calculation alone, we were able to deduce site-specific estimations. For liver, prostate and whole brain fields our results demonstrate that a reduction of currently used uncertainty margins is feasible even without introducing MC dose calculations. We recommend range margins of 2.8% + 1.2 mm for liver and prostate treatments and 3.1% + 1.2 mm for whole brain treatments, respectively. On the other hand, current margins seem to be insufficient for some breast, lung and head and neck patients, at least if used generically. If no case specific adjustments are applied, a generic margin of 6.3% + 1.2 mm would be needed for breast, lung and head and neck treatments. We conclude that the currently used generic range uncertainty margins in proton therapy should be redefined site specific and that complex geometries may require a field specific adjustment. Routine verifications of treatment plans using MC simulations are recommended for patients with heterogeneous geometries.

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

PubMed

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

2010-08-01

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

Dose density in adjuvant chemotherapy for breast cancer.

PubMed

Citron, Marc L

2004-01-01

Dose-dense chemotherapy increases the dose intensity of the regimen by delivering standard-dose chemotherapy with shorter intervals between the cycles. This article discusses the rationale for dose-dense therapy and reviews the results with dose-dense adjuvant regimens in recent clinical trials in breast cancer. The papers for this review covered evidence of a dose-response relation in cancer chemotherapy; the rationale for dose-intense (and specifically dose-dense) therapy; and clinical experience with dose-dense regimens in adjuvant chemotherapy for breast cancer, with particular attention to outcomes and toxicity. Evidence supports maintaining the dose intensity of adjuvant chemotherapy within the conventional dose range. Disease-free and overall survival with combination cyclophosphamide, methotrexate, and fluorouracil are significantly improved when patients receive within 85% of the planned dose. Moderate and high dose cyclophosphamide, doxorubicin, and fluorouracil within the standard range results in greater disease-free and overall survival than the low dose regimen. The sequential addition of paclitaxel after concurrent doxorubicin and cyclophosphamide also significantly improves survival. Disease-free and overall survival with dose-dense sequential or concurrent doxorubicin, cyclophosphamide, and paclitaxel with filgrastim (rhG-CSF; NEUPOGEN) support are significantly greater than with conventional schedules (q21d). The delivered dose intensity of adjuvant chemotherapy within the standard dose range is an important predictor of the clinical outcome. Prospective trials of high-dose chemotherapy have shown no improvement over standard regimens, and toxicity was greater. Dose-dense adjuvant chemotherapy improves the clinical outcomes with doxorubicin-containing regimens. Filgrastim support enables the delivery of dose-dense chemotherapy and reduces the risk of neutropenia and its complications.

Validation of an in-vivo proton beam range check method in an anthropomorphic pelvic phantom using dose measurements

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

Bentefour, El H., E-mail: hassan.bentefour@iba-group.com; Prieels, Damien; Tang, Shikui

Purpose: In-vivo dosimetry and beam range verification in proton therapy could play significant role in proton treatment validation and improvements. In-vivo beam range verification, in particular, could enable new treatment techniques one of which could be the use of anterior fields for prostate treatment instead of opposed lateral fields as in current practice. This paper reports validation study of an in-vivo range verification method which can reduce the range uncertainty to submillimeter levels and potentially allow for in-vivo dosimetry. Methods: An anthropomorphic pelvic phantom is used to validate the clinical potential of the time-resolved dose method for range verification inmore » the case of prostrate treatment using range modulated anterior proton beams. The method uses a 3 × 4 matrix of 1 mm diodes mounted in water balloon which are read by an ADC system at 100 kHz. The method is first validated against beam range measurements by dose extinction measurements. The validation is first completed in water phantom and then in pelvic phantom for both open field and treatment field configurations. Later, the beam range results are compared with the water equivalent path length (WEPL) values computed from the treatment planning system XIO. Results: Beam range measurements from both time-resolved dose method and the dose extinction method agree with submillimeter precision in water phantom. For the pelvic phantom, when discarding two of the diodes that show sign of significant range mixing, the two methods agree with ±1 mm. Only a dose of 7 mGy is sufficient to achieve this result. The comparison to the computed WEPL by the treatment planning system (XIO) shows that XIO underestimates the protons beam range. Quantifying the exact XIO range underestimation depends on the strategy used to evaluate the WEPL results. To our best evaluation, XIO underestimates the treatment beam range between a minimum of 1.7% and maximum of 4.1%. Conclusions: Time-resolved dose measurement method satisfies the two basic requirements, WEPL accuracy and minimum dose, necessary for clinical use, thus, its potential for in-vivo protons range verification. Further development is needed, namely, devising a workflow that takes into account the limits imposed by proton range mixing and the susceptibility of the comparison of measured and expected WEPLs to errors on the detector positions. The methods may also be used for in-vivo dosimetry and could benefit various proton therapy treatments.« less

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

PubMed

Lepak, Alexander J; Zhao, Miao; VanScoy, Brian; Taylor, Daniel S; Ellis-Grosse, Evelyn; Ambrose, Paul G; Andes, David R

2017-06-01

Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrum-beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli , 3 Klebsiella pneumoniae , and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC 0-∞ ) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy ( R 2 = 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli , K. , pneumoniae and P. aeruginosa , respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas . Copyright © 2017 American Society for Microbiology.

Determination of gonad doses during robotic stereotactic radiosurgery for various tumor sites

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

Zorlu, Faruk; Dugel, Gozde; Ozyigit, Gokhan

Purpose: The authors evaluated the absorbed dose received by the gonads during robotic stereotactic radiosurgery (SRS) for the treatment of different tumor localizations. Methods: The authors measured the gonad doses during the treatment of head and neck, thoracic, abdominal, or pelvic tumors in both RANDO phantom and actual patients. The computerized tomography images were transferred to the treatment planning system. The contours of tumor and critical organs were delineated on each slice, and treatment plans were generated. Measurements for gonad doses were taken from the geometric projection of the ovary onto the skin for female patients, and from the scrotalmore » skin for male patients by attaching films and Thermoluminescent dosimeters (TLDs). SRS was delivered with CyberKnife (Accuray Inc., Sunnyvale, CA). Results: The median gonadal doses with TLD and film dosimeter in actual patients were 0.19 Gy (range, 0.035-2.71 Gy) and 0.34 Gy (range, 0.066-3.18 Gy), respectively. In the RANDO phantom, the median ovarian doses with TLD and film dosimeter were 0.08 Gy (range, 0.03-0.159 Gy) and 0.05 Gy (range, 0.015-0.13 Gy), respectively. In the RANDO phantom, the median testicular doses with TLD and film dosimeter were 0.134 Gy (range 0.056-1.97 Gy) and 0.306 Gy (range, 0.065-2.25 Gy). Conclusions: Gonad doses are below sterility threshold in robotic SRS for different tumor localizations. However, particular attention should be given to gonads during robotic SRS for pelvic tumors.« less

The evolution of environmental tolerance and range size: a comparison of geographically restricted and widespread Mimulus.

PubMed

Sheth, Seema N; Angert, Amy L

2014-10-01

The geographic ranges of closely related species can vary dramatically, yet we do not fully grasp the mechanisms underlying such variation. The niche breadth hypothesis posits that species that have evolved broad environmental tolerances can achieve larger geographic ranges than species with narrow environmental tolerances. In turn, plasticity and genetic variation in ecologically important traits and adaptation to environmentally variable areas can facilitate the evolution of broad environmental tolerance. We used five pairs of western North American monkeyflowers to experimentally test these ideas by quantifying performance across eight temperature regimes. In four species pairs, species with broader thermal tolerances had larger geographic ranges, supporting the niche breadth hypothesis. As predicted, species with broader thermal tolerances also had more within-population genetic variation in thermal reaction norms and experienced greater thermal variation across their geographic ranges than species with narrow thermal tolerances. Species with narrow thermal tolerance may be particularly vulnerable to changing climatic conditions due to lack of plasticity and insufficient genetic variation to respond to novel selection pressures. Conversely, species experiencing high variation in temperature across their ranges may be buffered against extinction due to climatic changes because they have evolved tolerance to a broad range of temperatures. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Preoperative single fraction partial breast radiotherapy for early-stage breast cancer.

PubMed

Palta, Manisha; Yoo, Sua; Adamson, Justus D; Prosnitz, Leonard R; Horton, Janet K

2012-01-01

Several recent series evaluating external beam accelerated partial breast irradiation (PBI) have reported adverse cosmetic outcomes, possibly related to large volumes of normal tissue receiving near-prescription doses. We hypothesized that delivery of external beam PBI in a single fraction to the preoperative tumor volume would be feasible and result in a decreased dose to the uninvolved breast compared with institutional postoperative PBI historical controls. A total of 17 patients with unifocal Stage T1 breast cancer were identified. Contrast-enhanced subtraction magnetic resonance images were loaded into an Eclipse treatment planning system and used to define the target volumes. A "virtual plan" was created using four photon beams in a noncoplanar beam arrangement and optimized to deliver 15 Gy to the planning target volume. The median breast volume was 1,713 cm(3) (range: 1,014-2,140), and the median clinical target volume was 44 cm(3) (range: 26-73). In all cases, 100% of the prescription dose covered 95% of the clinical target volume. The median conformity index was 0.86 (range: 0.70-1.12). The median percentage of the ipsilateral breast volume receiving 100% and 50% of the prescribed dose was 3.8% (range: 2.2-6.9) and 13.3% (range: 7.5-20.8) compared with 18% (range: 3-42) and 53% (range: 24-65) in the institutional historical controls treated with postoperative external beam PBI (p = .002). The median maximum skin dose was 9 Gy. The median dose to 1 and 10 cm(3) of skin was 6.7 and 4.9 Gy. The doses to the heart and ipsilateral lung were negligible. Preoperative PBI resulted in a substantial reduction in ipsilateral breast tissue dose compared with postoperative PBI. The skin dose appeared reasonable, given the small volumes. A prospective Phase I trial evaluating this technique is ongoing. Copyright © 2012 Elsevier Inc. All rights reserved.

Intraoperative irradiation: precision medicine for quality cancer control promotion.

PubMed

Calvo, Felipe A

2017-02-02

Intraoperative irradiation was implemented 4 decades ago, pioneering the efforts to improve precision in local cancer therapy by combining real-time surgical exploration/resection with high single dose radiotherapy (Gunderson et al., Intraoperative irradiation: techniques and results, 2011). Clinical and technical developments have led to very precise radiation dose deposit. The ability to deliver a very precise dose of radiation is an essential element of contemporary multidisciplinary individualized oncology.This issue of Radiation Oncology contains a collection of expert review articles and updates with relevant data regarding intraoperative radiotherapy. Technology, physics, biology of single dose and clinical results in a variety of cancer sites and histologies are described and analyzed. The state of the art for advanced cancer care through medical innovation opens a significant opportunity for individualize cancer management across a broad spectrum of clinical practice. The advantage for tailoring diagnostic and treatment decisions in an individualized fashion will translate into precise medical treatment.

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

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated networkmore » (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.« less

Experimental analysis of a novel and low-cost pin photodiode dosimetry system for diagnostic radiology

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

Nazififard, Mohammad, E-mail: nazifi@kashanu.ac.ir; Mahmoudieh, Afshin; Suh, Kune Y.

Silicon PIN photodiode has recently found broad and exciting applications in the ionizing radiation dosimetry. In this study a compact and novel dosimetry system using a commercially available PIN photodiode (BPW34) has been experimentally tested for diagnostic radiology. The system was evaluated with clinical beams routinely used for diagnostic radiology and calibrated using a secondary reference standard. Measured dose with PIN photodiode (Air Kerma) varied from 10 to 430 μGy for tube voltages from 40 to 100 kVp and tube current from 0.4 to 40 mAs. The minimum detectable organ dose was estimated to be 10 μGy with 20% uncertainty.more » Results showed a linear correlation between the PIN photodiode readout and dose measured with standard dosimeters spanning doses received. The present dosimetry system having advantages of suitable sensitivity with immediate readout of dose values, low cost, and portability could be used as an alternative to passive dosimetry system such as thermoluminescent dosimeter for dose measurements in diagnostic radiology.« less

SU-E-T-248: An Extended Generalized Equivalent Uniform Dose Accounting for Dose-Range Dependency of Radio-Biological Parameters.

PubMed

Troeller, A; Soehn, M; Yan, D

2012-06-01

Introducing an extended, phenomenological, generalized equivalent uniform dose (eEUD) that incorporates multiple volume-effect parameters for different dose-ranges. The generalized EUD (gEUD) was introduced as an estimate of the EUD that incorporates a single, tissue-specific parameter - the volume-effect-parameter (VEP) 'a'. As a purely phenomenological concept, its radio-biological equivalency to a given inhomogeneous dose distribution is not a priori clear and mechanistic models based on radio-biological parameters are assumed to better resemble the underlying biology. However, for normal organs mechanistic models are hard to derive, since the structural organization of the tissue plays a significant role. Consequently, phenomenological approaches might be especially useful in order to describe dose-response for normal tissues. However, the single parameter used to estimate the gEUD may not suffice in accurately representing more complex biological effects that have been discussed in the literature. For instance, radio-biological parameters and hence the effects of fractionation are known to be dose-range dependent. Therefore, we propose an extended phenomenological eEUD formula that incorporates multiple VEPs accounting for dose-range dependency. The eEUD introduced is a piecewise polynomial expansion of the gEUD formula. In general, it allows for an arbitrary number of VEPs, each valid for a certain dose-range. We proved that the formula fulfills required mathematical and physical criteria such as invertibility of the underlying dose-effect and continuity in dose. Furthermore, it contains the gEUD as a special case, if all VEPs are equal to 'a' from the gEUD model. The eEUD is a concept that expands the gEUD such that it can theoretically represent dose-range dependent effects. Its practicality, however, remains to be shown. As a next step, this will be done by estimating the eEUD from patient data using maximum-likelihood based NTCP modelling in the same way it is commonly done for the gEUD. © 2012 American Association of Physicists in Medicine.

A dose-volume analysis of magnetic resonance imaging-aided high-dose-rate image-based interstitial brachytherapy for uterine cervical cancer.

PubMed

Yoshida, Ken; Yamazaki, Hideya; Takenaka, Tadashi; Kotsuma, Tadayuki; Yoshida, Mineo; Furuya, Seiichi; Tanaka, Eiichi; Uegaki, Tadaaki; Kuriyama, Keiko; Matsumoto, Hisanobu; Yamada, Shigetoshi; Ban, Chiaki

2010-07-01

To investigate the feasibility of our novel image-based high-dose-rate interstitial brachytherapy (HDR-ISBT) for uterine cervical cancer, we evaluated the dose-volume histogram (DVH) according to the recommendations of the Gynecological GEC-ESTRO Working Group for image-based intracavitary brachytherapy (ICBT). Between June 2005 and June 2007, 18 previously untreated cervical cancer patients were enrolled. We implanted magnetic resonance imaging (MRI)-available plastic applicators by our unique ambulatory technique. Total treatment doses were 30-36 Gy (6 Gy per fraction) combined with external beam radiotherapy (EBRT). Treatment plans were created based on planning computed tomography with MRI as a reference. DVHs of the high-risk clinical target volume (HR CTV), intermediate-risk CTV (IR CTV), and the bladder and rectum were calculated. Dose values were biologically normalized to equivalent doses in 2-Gy fractions (EQD(2)). The median D90 (HR CTV) and D90 (IR CTV) per fraction were 6.8 Gy (range, 5.5-7.5) and 5.4 Gy (range, 4.2-6.3), respectively. The median V100 (HR CTV) and V100 (IR CTV) were 98.4% (range, 83-100) and 81.8% (range, 64-93.8), respectively. When the dose of EBRT was added, the median D90 and D100 of HR CTV were 80.6 Gy (range, 65.5-96.6) and 62.4 Gy (range, 49-83.2). The D(2cc) of the bladder was 62 Gy (range, 51.4-89) and of the rectum was 65.9 Gy (range, 48.9-76). Although the targets were advanced and difficult to treat effectively by ICBT, MRI-aided image-based ISBT showed favorable results for CTV and organs at risk compared with previously reported image-based ICBT results. (c) 2010 Elsevier Inc. All rights reserved.

Cr-doped scandium borate laser

DOEpatents

Chai, Bruce H.; Lai, Shui T.; Long, Margaret N.

1989-01-01

A broadly wavelength-tunable laser is provided which comprises as the laser medium a single crystal of MBO.sub.3 :Cr.sup.3+, where M is selected from the group of Sc, In and Lu. The laser may be operated over a broad temperature range from cryogenic temperatures to elevated temperatures. Emission is in a spectral range from red to infrared, and the laser is useful in the fields of defense, communications, isotope separation, photochemistry, etc.

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.

Can job redesign interventions influence a broad range of employee outcomes by changing multiple job characteristics? A quasi-experimental study.

PubMed

Holman, David; Axtell, Carolyn

2016-07-01

Many job redesign interventions are based on a multiple mediator-multiple outcome model in which the job redesign intervention indirectly influences a broad range of employee outcomes by changing multiple job characteristics. As this model remains untested, the aim of this study is to test a multiple mediator-multiple outcome model of job redesign. Multilevel analysis of data from a quasi-experimental job redesign intervention in a call center confirmed the hypothesized model and showed that the job redesign intervention affected a broad range of employee outcomes (i.e., employee well-being, psychological contract fulfillment, and supervisor-rated job performance) through changes in 2 job characteristics (i.e., job control and feedback). The results provide further evidence for the efficacy and mechanisms of job redesign interventions. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study.

PubMed

Marincek, Nicolas; Jörg, Ann-Catherine; Brunner, Philippe; Schindler, Christian; Koller, Michael T; Rochlitz, Christoph; Müller-Brand, Jan; Maecke, Helmut R; Briel, Matthias; Walter, Martin A

2013-01-15

We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211).

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

PubMed Central

2013-01-01

Background We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158) months, 34 (range: 1–118) months and 29 (range: 1–113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Conclusions Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. Trial registration ClinicalTrials.gov number:NCT00978211 PMID:23320604

Forms of organic phosphorus in wetland soils

NASA Astrophysics Data System (ADS)

Cheesman, A. W.; Turner, B. L.; Reddy, K. R.

2014-12-01

Phosphorus (P) cycling in freshwater wetlands is dominated by biological mechanisms, yet there has been no comprehensive examination of the forms of biogenic P (i.e., forms derived from biological activity) in wetland soils. We used solution 31P NMR spectroscopy to identify and quantify P forms in surface soils of 28 palustrine wetlands spanning a range of climatic, hydrogeomorphic, and vegetation types. Total P concentrations ranged between 51 and 3516 μg P g-1, of which an average of 58% was extracted in a single-step NaOH-EDTA procedure. The extracts contained a broad range of P forms, including phosphomonoesters (averaging 24% of the total soil P), phosphodiesters (averaging 10% of total P), phosphonates (up to 4% of total P), and both pyrophosphate and long-chain polyphosphates (together averaging 6% of total P). Soil P composition was found to be dependant upon two key biogeochemical properties: organic matter content and pH. For example, stereoisomers of inositol hexakisphosphate were detected exclusively in acidic soils with high mineral content, while phosphonates were detected in soils from a broad range of vegetation and hydrogeomorphic types but only under acidic conditions. Conversely inorganic polyphosphates occurred in a broad range of wetland soils, and their abundance appears to reflect more broadly that of a "substantial" and presumably active microbial community with a significant relationship between total inorganic polyphosphates and microbial biomass P. We conclude that soil P composition varies markedly among freshwater wetlands but can be predicted by fundamental soil properties.

Forms of organic phosphorus in wetland soils

NASA Astrophysics Data System (ADS)

Cheesman, A. W.; Turner, B. L.; Reddy, K. R.

2014-06-01

Phosphorus (P) cycling in freshwater wetlands is dominated by biological mechanisms, yet there has been no comprehensive examination of the forms of biogenic P (i.e. forms derived from biological activity) in wetland soils. We used solution 31P NMR spectroscopy to identify and quantify P forms in surface soils of 28 palustrine wetlands spanning a range of climatic, hydro-geomorphic and vegetation types. Total P concentrations ranged between 51 and 3516 μg P g

Estimating thyroid dose in pediatric CT exams from surface dose measurement

NASA Astrophysics Data System (ADS)

Al-Senan, Rani; Mueller, Deborah L.; Hatab, Mustapha R.

2012-07-01

The purpose of this study was to investigate the possibility of estimating pediatric thyroid doses from CT using surface neck doses. Optically stimulated luminescence dosimeters were used to measure the neck surface dose of 25 children ranging in ages between one and three years old. The neck circumference for each child was measured. The relationship between obtained surface doses and thyroid dose was studied using acrylic phantoms of various sizes and with holes of different depths. The ratios of hole-to-surface doses were used to convert patients' surface dose to thyroid dose. ImPACT software was utilized to calculate thyroid dose after applying the appropriate age correction factors. A paired t-test was performed to compare thyroid doses from our approach and ImPACT. The ratio of thyroid to surface dose was found to be 1.1. Thyroid doses ranged from 20 to 80 mGy. Comparison showed no statistical significance (p = 0.18). In addition, the average of surface dose variation along the z-axis in helical scans was studied and found to range between 5% (in 10 cm diameter phantom/24 mm collimation/pitch 1.0) and 8% (in 16 cm diameter phantom/12 mm collimation/pitch 0.7). We conclude that surface dose is an acceptable predictor for pediatric thyroid dose from CT. The uncertainty due to surface dose variability may be reduced if narrower collimation is used with a pitch factor close to 1.0. Also, the results did not show any effect of thyroid depth on the measured dose.

Approaches for characterizing threshold dose-response relationships for DNA-damage pathways involved in carcinogenicity in vivo and micronuclei formation in vitro.

PubMed

Clewell, Rebecca A; Andersen, Melvin E

2016-05-01

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

“I Just Wanted to Tell You That Loperamide WILL WORK”: A Web-Based Study of Extra-Medical Use of Loperamide

PubMed Central

Daniulaityte, Raminta; Carlson, Robert; Falck, Russel; Cameron, Delroy; Perera, Sujan; Chen, Lu; Sheth, Amit

2013-01-01

Aims Many websites provide a means for individuals to share their experiences and knowledge about different drugs. Such User-Generated Content (UGC) can be a rich data source to study emerging drug use practices and trends. This study examined UGC on extra-medical use of loperamide among illicit opioid users. Methods A website that allows for the free discussion of illicit drugs and is accessible for public viewing was selected for analysis. Web-forum posts were retrieved using web crawlers and retained in a local text database. The database was queried to extract posts with a mention of loperamide and relevant brand/slang terms. Over 1,290 posts were identified. A random sample of 258 posts was coded using NVivo to identify intent, dosage, and side-effects of loperamide use. Results There has been an increase in discussions related to loperamide’s use by non-medical opioid users, especially in 2010–2011. Loperamide was primarily discussed as a remedy to alleviate a broad range of opioid withdrawal symptoms, and was sometimes referred to as “poor man’s” methadone. Typical doses ranged 70–100 mg per day, much higher than an indicated daily dose of 16 mg. Conclusions This study suggests that loperamide is being used extra-medically to self-treat opioid withdrawal symptoms. There is a growing demand among people who are opioid dependent for drugs to control withdrawal symptoms, and loperamide appears to fit that role. The study also highlights the potential of the Web as a “leading edge” data source in identifying emerging drug use practices. PMID:23201175

"I just wanted to tell you that loperamide WILL WORK": a web-based study of extra-medical use of loperamide.

PubMed

Daniulaityte, Raminta; Carlson, Robert; Falck, Russel; Cameron, Delroy; Perera, Sujan; Chen, Lu; Sheth, Amit

2013-06-01

Many websites provide a means for individuals to share their experiences and knowledge about different drugs. Such User-Generated Content (UGC) can be a rich data source to study emerging drug use practices and trends. This study examined UGC on extra-medical use of loperamide among illicit opioid users. A website that allows for the free discussion of illicit drugs and is accessible for public viewing was selected for analysis. Web-forum posts were retrieved using web crawlers and retained in a local text database. The database was queried to extract posts with a mention of loperamide and relevant brand/slang terms. Over 1290 posts were identified. A random sample of 258 posts was coded using NVivo to identify intent, dosage, and side-effects of loperamide use. There has been an increase in discussions related to loperamide's use by non-medical opioid users, especially in 2010-2011 Loperamide was primarily discussed as a remedy to alleviate a broad range of opioid withdrawal symptoms, and was sometimes referred to as "poor man's" methadone. Typical doses ranged 70-100mg per day, much higher than an indicated daily dose of 16mg. This study suggests that loperamide is being used extra-medically to self-treat opioid withdrawal symptoms. There is a growing demand among people who are opioid dependent for drugs to control withdrawal symptoms, and loperamide appears to fit that role. The study also highlights the potential of the Web as a "leading edge" data source in identifying emerging drug use practices. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Synthesis characterization and luminescence studies of gamma irradiated nanocrystalline yttrium oxide

NASA Astrophysics Data System (ADS)

Shivaramu, N. J.; Lakshminarasappa, B. N.; Nagabhushana, K. R.; Singh, Fouran

2016-02-01

Nanocrystalline Y2O3 is synthesized by solution combustion technique using urea and glycine as fuels. X-ray diffraction (XRD) pattern of as prepared sample shows amorphous nature while annealed samples show cubic nature. The average crystallite size is calculated using Scherrer's formula and is found to be in the range 14-30 nm for samples synthesized using urea and 15-20 nm for samples synthesized using glycine respectively. Field emission scanning electron microscopy (FE-SEM) image of 1173 K annealed Y2O3 samples show well separated spherical shape particles and the average particle size is found to be in the range 28-35 nm. Fourier transformed infrared (FTIR) and Raman spectroscopy reveals a stretching of Y-O bond. Electron spin resonance (ESR) shows V- center, O2- and Y2 + defects. A broad photoluminescence (PL) emission with peak at 386 nm is observed when the sample is excited with 252 nm. Thermoluminescence (TL) properties of γ-irradiated Y2O3 nanopowder are studied at a heating rate of 5 K s- 1. The samples prepared by using urea show a prominent and well resolved peak at 383 K and a weak one at 570 K. It is also found that TL glow peak intensity (Im1) at 383 K increases with increase in γ-dose up to 6.0 kGy and then decreases with increase in dose. However, glycine used Y2O3 shows a prominent TL glow with peaks at 396 K and 590 K. Among the fuels, urea used Y2O3 shows simple and well resolved TL glows. This might be due to fuel and hence particle size effect. The kinetic parameters are calculated by Chen's glow curve peak shape method and results are discussed in detail.

Early gestational exposure to moderate concentrations of ethanol alters adult behaviour in C57BL/6J mice.

PubMed

Sanchez Vega, Michelle C; Chong, Suyinn; Burne, Thomas H J

2013-09-01

Alcohol consumption during pregnancy has deleterious effects on the developing foetus ranging from subtle physical deficits to severe behavioural abnormalities and is encompassed under a broad umbrella term, foetal alcohol spectrum disorders (FASD). High levels of exposure show distinct effects, whereas the consequences of moderate exposures have been less well studied. The aim of this study was to examine the effects of a moderate dose ethanol exposure using an ad libitum drinking procedure during the first eight days of gestation in mice on the behavioural phenotype of adult offspring. Adult female C57Bl/6J mice were mated and exposed to either 10% (v/v) ethanol or water for the first 8 days of gestation (GD 0-8), and then offered water for the rest of gestation. Early developmental milestone achievement was assessed in offspring at postnatal days (P) 7, 14 and 21. Adult offspring underwent a comprehensive battery of behavioural tests to examine a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception, as well as spatial memory in a water maze. Ethanol-exposed mice had similar postnatal developmental trajectories to water-exposed mice. However, the ethanol-exposed mice showed increased hyperlocomotion at P 14, 21 and 70 (p<0.05). Increased exploration and heightened motivation were also observed in adult mice. Furthermore, ethanol-exposed mice showed a significant improvement in memory in the water maze. The main findings were that mice had persistent and long lasting alterations in behaviour, including hyperactivity and enhanced spatial memory. These data suggest that even moderate dose ethanol exposure in early gestation has long term consequences on brain function and behaviour in mice. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Microstructural stability and mechanical behavior of FeNiMnCr high entropy alloy under ion irradiation

DOE PAGES

Leonard, Keith J.; Bei, Hongbin; Zinkle, Steven J.; ...

2016-05-13

In recent years, high entropy alloys (HEAs) have attracted significant attention due to their excellent mechanical properties and good corrosion resistance, making them potential candidates for high temperature fission and fusion structural applications. However there is very little known about their radiation resistance, particularly at elevated temperatures relevant for energy applications. In the present study, a single phase (face centered cubic) concentrated solid solution alloy of composition 27%Fe-28%Ni-27%Mn-18%Cr was irradiated with 3 or 5.8 MeV Ni ions at temperatures ranging from room temperature to 700 °C and midrange doses from 0.03 to 10 displacements per atom (dpa). Transmission electron microscopymore » (TEM), scanning transmission electron microscopy with energy dispersive x-ray spectrometry (STEM/EDS) and X-ray diffraction (XRD) were used to characterize the radiation defects and microstructural changes. Irradiation at higher temperatures showed evidence of relatively sluggish solute diffusion with limited solute depletion or enrichment at grain boundaries. The main microstructural feature at all temperatures was high-density small dislocation loops. Voids were not observed at any irradiation condition. Nano-indentation tests on specimens irradiated at room temperature showed a rapid increase in hardness ~35% and ~80% higher than the unirradiated value at 0.03 and 0.3 dpa midrange doses, respectively. The irradiation-induced hardening was less pronounced for 500 °C irradiations (<20% increase after 3 dpa). Overall, the examined HEA material exhibits superior radiation resistance compared to conventional single phase Fe-Cr-Ni austenitic alloys such as stainless steels. Furthermore, the present study provides insight on the fundamental irradiation behavior of a single phase HEA material over a broad range of irradiation temperatures.« less

Radiation sensitivity and EPR dosimetric potential of gallic acid and its esters

NASA Astrophysics Data System (ADS)

Tuner, Hasan; Oktay Bal, M.; Polat, Mustafa

2015-02-01

In the preset work the radiation sensitivities of Gallic Acid anhydrous and monohydrate, Octyl, Lauryl, and Ethyl Gallate (GA, GAm, OG, LG, and EG) were investigated in the intermediate (0.5-20 kGy) and low radiation (<10 Gy) dose range using Electron Paramagnetic Resonance (EPR) spectroscopy. While OG, LG, and EG are presented a singlet EPR spectra, their radiation sensitivity found to be very different in the intermediate dose range. At low radiation dose range (<10 Gy) only LG is found to be present a signal that easily distinguished from the noise signals. The intermediate and low dose range radiation sensitivities are compared using well known EPR dosimeter alanine. The radiation yields (G) of the interested material were found to be 1.34×10-2, 1.48×10-2, 4.14×10-2, and 6.03×10-2, 9.44×10-2 for EG, GA, GAm, OG, and LG, respectively at the intermediate dose range. It is found that the simple EPR spectra and the noticeable EPR signal of LG make it a promising dosimetric material to be used below 10 Gy of radiation dose.

Feasibility of RACT for 3D dose measurement and range verification in a water phantom.

PubMed

Alsanea, Fahed; Moskvin, Vadim; Stantz, Keith M

2015-02-01

The objective of this study is to establish the feasibility of using radiation-induced acoustics to measure the range and Bragg peak dose from a pulsed proton beam. Simulation studies implementing a prototype scanner design based on computed tomographic methods were performed to investigate the sensitivity to proton range and integral dose. Derived from thermodynamic wave equation, the pressure signals generated from the dose deposited from a pulsed proton beam with a 1 cm lateral beam width and a range of 16, 20, and 27 cm in water using Monte Carlo methods were simulated. The resulting dosimetric images were reconstructed implementing a 3D filtered backprojection algorithm and the pressure signals acquired from a 71-transducer array with a cylindrical geometry (30 × 40 cm) rotated over 2π about its central axis. Dependencies on the detector bandwidth and proton beam pulse width were performed, after which, different noise levels were added to the detector signals (using 1 μs pulse width and a 0.5 MHz cutoff frequency/hydrophone) to investigate the statistical and systematic errors in the proton range (at 20 cm) and Bragg peak dose (of 1 cGy). The reconstructed radioacoustic computed tomographic image intensity was shown to be linearly correlated to the dose within the Bragg peak. And, based on noise dependent studies, a detector sensitivity of 38 mPa was necessary to determine the proton range to within 1.0 mm (full-width at half-maximum) (systematic error < 150 μm) for a 1 cGy Bragg peak dose, where the integral dose within the Bragg peak was measured to within 2%. For existing hydrophone detector sensitivities, a Bragg peak dose of 1.6 cGy is possible. This study demonstrates that computed tomographic scanner based on ionizing radiation-induced acoustics can be used to verify dose distribution and proton range with centi-Gray sensitivity. Realizing this technology into the clinic has the potential to significantly impact beam commissioning, treatment verification during particle beam therapy and image guided techniques.

DSC studies on gamma irradiated poly(vinylidene fluoride) applied to high gamma dose dosimetry

NASA Astrophysics Data System (ADS)

Batista, Adriana S. M.; Faria, Luiz O.

2017-11-01

Poly(vinylidene fluoride) homopolymer (PVDF) was investigated for use on high gamma dose dosimetry. Samples were irradiated with gamma doses ranging from 100 kGy to 3000 kGy. Differential scanning calorimetry (DSC) was used to construct an unambiguous relationship between the melting transition latent heat (LM) and the absorbed dose (D). DSC thermograms were taken immediately, 1, 2 and 8 months after the irradiation process revealing that the LMx D relationship presented no change for doses ranging from 100 to 2750 kGy. FTIR and UV-Vis spectroscopy data revealed the radio-induction of C˭O and C˭C bonds. These radio-induced bonds were responsible by the chain stiffening and chain oxidation, respectively. SEM microscopy demonstrates that the spherulitic large crystalline structures present in pristine PVDF are destroyed with doses as low as 100 kGy. The DRX analysis revealed that the main effect of high gamma doses in the crystalline structure of PVDF is to provoke a change from the pristine PVDF α-phase to the γ-phase. Both the ability to detect gamma doses in a large dose range and the low fading features make PVDF homopolymers good candidates to be investigated as high gamma dose dosimeters.

Entrance radiation doses during paediatric cardiac catheterisations performed for diagnosis or the treatment of congenital heart disease.

PubMed

Papadopoulou, D; Yakoumakis, Em; Sandilos, P; Thanopoulos, V; Makri, Tr; Gialousis, G; Houndas, D; Yakoumakis, N; Georgiou, Ev

2005-01-01

The purpose of this study was to estimate the radiation exposure of children, during cardiac catheterisations for the diagnosis or treatment of congenital heart disease. Radiation doses were estimated for 45 children aged from 1 d to 13 y old. Thermoluminescent dosemeters (TLDs) were used to estimate the posterior entrance dose (DP), the lateral entrance dose (DLAT), the thyroid dose and the gonads dose. A dose-area product (DAP) meter was also attached externally to the tube of the angiographic system and gave a direct value in mGy cm2 for each procedure. Posterior and lateral entrance dose values during cardiac catheterisations ranged from 1 to 197 mGy and from 1.1 to 250.3 mGy, respectively. Radiation exposure to the thyroid and the gonads ranged from 0.3 to 8.4 mGy to 0.1 and 0.7 mGy, respectively. Finally, the DAP meter values ranged between 360 and 33,200 mGy cm2. Radiation doses measured in this study are comparable with those reported to previous studies. Moreover, strong correlation was found between the DAP values and the entrance radiation dose measured with TLDs.

The IFITMs Inhibit Zika Virus Replication.

PubMed

Savidis, George; Perreira, Jill M; Portmann, Jocelyn M; Meraner, Paul; Guo, Zhiru; Green, Sharone; Brass, Abraham L

2016-06-14

Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses. Copyright © 2016. Published by Elsevier Inc.

Passivation of carbon steel through mercury implantation

NASA Technical Reports Server (NTRS)

Wilbur, P. J.; Robinson, R. S.

1981-01-01

An experiment, in which carbon steel samples were implanted with mercury ions from a broad beam ion source and their corrosion characteristics in air were evaluated, is described. Mercury doses of a few mA min/square cm at energies of a few hundred electron volts are shown to effect significant improvements in the corrosion resistance of the treated surfaces. In a warm moist environment the onset of rusting was extended from 15 min. for an untreated sample to approximately 30 hrs. for one implanted at a dose of 33 mA min/square cm with 1000 eV mercury ions.

An accelerated gamma irradiation test of low dose rate for a single mode fiber

NASA Astrophysics Data System (ADS)

Chiou, Chung-An; Peng, Tz-Shiuan; Liu, Ren-Young

2017-09-01

Conventional single mode fiber (SMF), due to its electromagnetic interference immunity, light weight, physical flexibility and broad bandwidth for data transmission, has been well employed in space, such as optical communication [1], structural health monitoring of spacecraft [2], and attitude determining applications, e.g. interferometric fiber optic gyroscope (IFOG).

The effect of triclosan on the uterotrophic response to extended doses of ethinyl estradiol in the weanling rat

EPA Science Inventory

Triclosan (TCS), a broad-spectrum antimicrobial agent found in many personal care products, has been detected in humans and has been shown to interact with endocrine systems in rats. We previously reported that TCS potentiated the estrogenic effect of ethinyl estradiol (EE) on u...

Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model.

PubMed

Lubet, R A; Steele, V E; Eto, I; Juliana, M M; Kelloff, G J; Grubbs, C J

1997-07-03

The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%. Anethole trithione, a substituted dithiolthione and an analog of the relatively broad-spectrum chemopreventive oltipraz, was administered in the diet and significantly inhibited mammary cancer multiplicity but not cancer incidence. NAC, an antimucolytic agent, failed to inhibit DMBA-induced mammary tumorigenesis. Surprisingly, treatment with DMBA plus PEITC, a potent inhibitor of cytochrome P450 2E1, actually increased the multiplicity of tumors relative to that observed with DMBA alone.

Febrile neutropenic infection occurred in cancer patients undergoing autologous peripheral blood stem cell transplantation.

PubMed

Zhang, W-X; Zhao, Q-Y; Huang, H-Q

2015-03-01

The objective of this study was to investigate the incidence, risk factors, and clinical and prognostic characteristics of febrile infection that occurred during the neutropenic period in cancer patients who underwent autologous peripheral blood stem cell transplantation (APBSCT). Clinical data of all the APBSCT cases from 2007 to 2009 in Sun Yat-sen University Cancer Center were collected and retrospectively analyzed. Eighty-nine APBSCT subjects were investigated. Neutropenia usually occurred on the 4th day (range, 0-15) after transplantation and lasted 6 (range, 3-27) days. Febrile neutropenia occurred in 78.7% patients and lasted around 3 (range, 1-20) days and no infection-related deaths were observed. For febrile episodes, 12 patients (17.1%) were diagnosed as having microbiologically documented infections (MDI). Initial empirical antimicrobial therapy was given to all cases of post-APBSCT febrile neutropenia, of which 44 cases (62.9%) were effective. Febrile neutropenia occurred in 25/34 (73.5%) patients who were given antifungal drugs for prophylaxis. Neutropenic infection is still the major complication in APBSCT patients and duration of neutropenia is one of the major risk factors. Prophylactic administration of antifungal drugs seems to be invalid to reduce post-APBSCT infection. Sufficient doses of broad-spectrum antibiotics at the early stage lead to better results of initial antimicrobial treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Sizes of particles formed during municipal wastewater treatment.

PubMed

Lech, Smoczynski; Marta, Kosobucka; Michal, Smoczynski; Harsha, Ratnaweera; Krystyna, Pieczulis-Smoczynska

2017-02-01

Volumetric diameters Dv and specific surface area SpS of sludge particles formed during chemical coagulation and electrocoagulation of sewage were determined. The obtained aggregate-flocs differed substantially in both Dv and SpS values. The differences in Dv and SpS values of the analyzed particles were interpreted based on theoretical models for expanding aggregates. The most uniform particles were formed under exposure to: (a) optimal and maximal doses of PIX, (b) optimal doses of PAX, (c) maximal doses of the Al electro-coagulant. The lowest PIX dose produced the least uniform particles. Sludge aggregates-particles produced under exposure to minimal doses of PIX and the Al electro-coagulant were characterized by the lowest SpS values. Sludge particles coagulated by PAX and the particles formed at higher doses of PIX and the Al electro-coagulant had higher SpS values. The particles formed at all doses of the applied coagulants and electro-coagulants were generally classified into two size ranges: the main range and the secondary range. Most particles belonged to the main size range. An increase in the percentage of colloidal hydroxide particles in sewage sludge increased SpS.

Cost effectiveness of high-dose intravenous esomeprazole for peptic ulcer bleeding.

PubMed

Barkun, Alan N; Adam, Viviane; Sung, Joseph J Y; Kuipers, Ernst J; Mössner, Joachim; Jensen, Dennis; Stuart, Robert; Lau, James Y; Nauclér, Emma; Kilhamn, Jan; Granstedt, Helena; Liljas, Bengt; Lind, Tore

2010-01-01

Peptic ulcer bleeding (PUB) is a serious and sometimes fatal condition. The outcome of PUB strongly depends on the risk of rebleeding. A recent multinational placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT00251979) showed that high-dose intravenous (IV) esomeprazole, when administered after successful endoscopic haemostasis in patients with PUB, is effective in preventing rebleeding. From a policy perspective it is important to assess the cost efficacy of this benefit so as to enable clinicians and payers to make an informed decision regarding the management of PUB. Using a decision-tree model, we compared the cost efficacy of high-dose IV esomeprazole versus an approach of no-IV proton pump inhibitor for prevention of rebleeding in patients with PUB. The model adopted a 30-day time horizon and the perspective of third-party payers in the USA and Europe. The main efficacy variable was the number of averted rebleedings. Healthcare resource utilization costs (physician fees, hospitalizations, surgeries, pharmacotherapies) relevant for the management of PUB were also determined. Data for unit costs (prices) were primarily taken from official governmental sources, and data for other model assumptions were retrieved from the original clinical trial and the literature. After successful endoscopic haemostasis, patients received either high-dose IV esomeprazole (80 mg infusion over 30 min, then 8 mg/hour for 71.5 hours) or no-IV esomeprazole treatment, with both groups receiving oral esomeprazole 40 mg once daily from days 4 to 30. Rebleed rates at 30 days were 7.7% and 13.6%, respectively, for the high-dose IV esomeprazole and no-IV esomeprazole treatment groups (equating to a number needed to treat of 17 in order to prevent one additional patient from rebleeding). In the US setting, the average cost per patient for the high-dose IV esomeprazole strategy was $US14 290 compared with $US14 239 for the no-IV esomeprazole strategy (year 2007 values). For the European setting, Sweden and Spain were used as examples. In the Swedish setting the corresponding respective figures were Swedish kronor (SEK)67 862 ($US9220 at average 2006 interbank exchange rates) and SEK67 807 ($US9212) [year 2006 values]. Incremental cost-effectiveness ratios were $US866 and SEK938 ($US127), respectively, per averted rebleed when using IV esomeprazole. For the Spanish setting, the high-dose IV esomeprazole strategy was dominant (more effective and less costly than the no-IV esomeprazole strategy) [year 2008 values]. All results appeared robust to univariate/threshold sensitivity analysis, with high-dose IV esomeprazole becoming dominant with small variations in assumptions in the US and Swedish settings, while remaining a dominant approach in the Spanish scenario across a broad range of values. Sensitivity variables with prespecified ranges included lengths of stay and per diem assumptions, rebleeding rates and, in some cases, professional fees. In patients with PUB, high-dose IV esomeprazole after successful endoscopic haemostasis appears to improve outcomes at a modest increase in costs relative to a no-IV esomeprazole strategy from the US and Swedish third-party payer perspective. Whereas, in the Spanish setting, the high-dose IV esomeprazole strategy appeared dominant, being more effective and less costly.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

PubMed

Kampouraki, Emmanouela; Avery, Peter J; Wynne, Hilary; Biss, Tina; Hanley, John; Talks, Kate; Kamali, Farhad

2017-09-01

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients. © 2017 John Wiley & Sons Ltd.

Radon Exposure and the Definition of Low Doses-The Problem of Spatial Dose Distribution.

PubMed

Madas, Balázs G

2016-07-01

Investigating the health effects of low doses of ionizing radiation is considered to be one of the most important fields in radiological protection research. Although the definition of low dose given by a dose range seems to be clear, it leaves some open questions. For example, the time frame and the target volume in which absorbed dose is measured have to be defined. While dose rate is considered in the current system of radiological protection, the same cancer risk is associated with all exposures, resulting in a given amount of energy absorbed by a single target cell or distributed among all the target cells of a given organ. However, the biological effects and so the health consequences of these extreme exposure scenarios are unlikely to be the same. Due to the heterogeneous deposition of radon progeny within the lungs, heterogeneous radiation exposure becomes a practical issue in radiological protection. While the macroscopic dose is still within the low dose range, local tissue doses on the order of Grays can be reached in the most exposed parts of the bronchial airways. It can be concluded that progress in low dose research needs not only low dose but also high dose experiments where small parts of a biological sample receive doses on the order of Grays, while the average dose over the whole sample remains low. A narrow interpretation of low dose research might exclude investigations with high relevance to radiological protection. Therefore, studies important to radiological protection should be performed in the frame of low dose research even if the applied doses do not fit in the dose range used for the definition of low doses.

Feasibility of online IMPT adaptation using fast, automatic and robust dose restoration

NASA Astrophysics Data System (ADS)

Bernatowicz, Kinga; Geets, Xavier; Barragan, Ana; Janssens, Guillaume; Souris, Kevin; Sterpin, Edmond

2018-04-01

Intensity-modulated proton therapy (IMPT) offers excellent dose conformity and healthy tissue sparing, but it can be substantially compromised in the presence of anatomical changes. A major dosimetric effect is caused by density changes, which alter the planned proton range in the patient. Three different methods, which automatically restore an IMPT plan dose on a daily CT image were implemented and compared: (1) simple dose restoration (DR) using optimization objectives of the initial plan, (2) voxel-wise dose restoration (vDR), and (3) isodose volume dose restoration (iDR). Dose restorations were calculated for three different clinical cases, selected to test different capabilities of the restoration methods: large range adaptation, complex dose distributions and robust re-optimization. All dose restorations were obtained in less than 5 min, without manual adjustments of the optimization settings. The evaluation of initial plans on repeated CTs showed large dose distortions, which were substantially reduced after restoration. In general, all dose restoration methods improved DVH-based scores in propagated target volumes and OARs. Analysis of local dose differences showed that, although all dose restorations performed similarly in high dose regions, iDR restored the initial dose with higher precision and accuracy in the whole patient anatomy. Median dose errors decreased from 13.55 Gy in distorted plan to 9.75 Gy (vDR), 6.2 Gy (DR) and 4.3 Gy (iDR). High quality dose restoration is essential to minimize or eventually by-pass the physician approval of the restored plan, as long as dose stability can be assumed. Motion (as well as setup and range uncertainties) can be taken into account by including robust optimization in the dose restoration. Restoring clinically-approved dose distribution on repeated CTs does not require new ROI segmentation and is compatible with an online adaptive workflow.

SU-F-T-170: Patient Surface Dose Measurements Using Optically Stimulated Luminescence Dosimeters in Scanning Proton Beam Therapy for Breast Cancer

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

Yu, J; Strauss, D; Langner, U

Purpose: To establish patient surface dose dosimetry for scanning proton beam therapy (SPBT) for breast cancer using optically stimulated luminescence dosimeters (OSLD). Methods: OSLDs were calibrated with SPB under the similar conditions as the treatments for breast cancer. A range shifter (RS) of 5 cm water equivalent thickness (WET) was used. The air gap from the surface of the range shifter to the surface of the phantom was 15 cm. A uniform planar dose generated by nominal energy of 118 MeV was delivered. The range of 118 MeV proton beam after the 5cm RS is approximately 5 cm in water,more » which is the common range for breast treatments. The OSLDs were placed on the surface of high density polyethylene slabs, and a bolus of 1.06 cm WET was used for buildup. A variety of dose levels in the range of 0.5 to 8 Gy were delivered. Under the same condition, an ADCL calibrated parallel plate (PP) chamber was used to measure the reference dose. The correlation between the output signals of OSLDs and the reference doses was established. The calibration of OSLD was verified against the PP chamber measurements for two SPBT breast plans calculated for two patients. Results: the least squares fitting for the OSLD calibration curve was a polynomial function to the order of 2 in the range of 0.5 to 8 Gy (RBE). The differences between the dose measured with OSLDs and PP chamber were within 3% for the two breast proton plans. Conclusion: the calibrated OSLDs under the similar conditions as the treatments can be used for patient surface dose measurements.« less

Verification of Pharmacogenetics-Based Warfarin Dosing Algorithms in Han-Chinese Patients Undertaking Mechanic Heart Valve Replacement

PubMed Central

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

Objective To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. Methods We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. Results A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88–4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges. Conclusions All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement. PMID:24728385

Verification of pharmacogenetics-based warfarin dosing algorithms in Han-Chinese patients undertaking mechanic heart valve replacement.

PubMed

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88-4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges. All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement.

Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects.

PubMed

Krösser, S; Tillner, J; Fluck, M; Ungethüm, W; Wolna, P; Kovar, A

2007-05-01

Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.

Radiation dose and magnification in pelvic X-ray: EOS™ imaging system versus plain radiographs.

PubMed

Chiron, P; Demoulin, L; Wytrykowski, K; Cavaignac, E; Reina, N; Murgier, J

2017-12-01

In plain pelvic X-ray, magnification makes measurement unreliable. The EOS™ (EOS Imaging, Paris France) imaging system is reputed to reproduce patient anatomy exactly, with a lower radiation dose. This, however, has not been assessed according to patient weight, although both magnification and irradiation are known to vary with weight. We therefore conducted a prospective comparative study, to compare: (1) image magnification and (2) radiation dose between the EOS imaging system and plain X-ray. The EOS imaging system reproduces patient anatomy exactly, regardless of weight, unlike plain X-ray. A single-center comparative study of plain pelvic X-ray and 2D EOS radiography was performed in 183 patients: 186 arthroplasties; 104 male, 81 female; mean age 61.3±13.7years (range, 24-87years). Magnification and radiation dose (dose-area product [DAP]) were compared between the two systems in 186 hips in patients with a mean body-mass index (BMI) of 27.1±5.3kg/m 2 (range, 17.6-42.3kg/m 2 ), including 7 with morbid obesity. Mean magnification was zero using the EOS system, regardless of patient weight, compared to 1.15±0.05 (range, 1-1.32) on plain X-ray (P<10 -5 ). In patients with BMI<25, mean magnification on plain X-ray was 1.15±0.05 (range, 1-1.25) and, in patients with morbid obesity, 1.22±0.06 (range, 1.18-1.32). The mean radiation dose was 8.19±2.63dGy/cm 2 (range, 1.77-14.24) with the EOS system, versus 19.38±12.37dGy/cm 2 (range, 4.77-81.75) with plain X-ray (P<10 -4 ). For BMI >40, mean radiation dose was 9.36±2.57dGy/cm 2 (range, 7.4-14.2) with the EOS system, versus 44.76±22.21 (range, 25.2-81.7) with plain X-ray. Radiation dose increased by 0.20dGy with each extra BMI point for the EOS system, versus 0.74dGy for plain X-ray. Magnification did not vary with patient weight using the EOS system, unlike plain X-ray, and radiation dose was 2.5-fold lower. 3, prospective case-control study. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Binaural Pitch Fusion in Bilateral Cochlear Implant Users.

PubMed

Reiss, Lina A J; Fowler, Jennifer R; Hartling, Curtis L; Oh, Yonghee

Binaural pitch fusion is the fusion of stimuli that evoke different pitches between the ears into a single auditory image. Individuals who use hearing aids or bimodal cochlear implants (CIs) experience abnormally broad binaural pitch fusion, such that sounds differing in pitch by as much as 3-4 octaves are fused across ears, leading to spectral averaging and speech perception interference. The goal of this study was to determine if adult bilateral CI users also experience broad binaural pitch fusion. Stimuli were pulse trains delivered to individual electrodes. Fusion ranges were measured using simultaneous, dichotic presentation of reference and comparison stimuli in opposite ears, and varying the comparison stimulus to find the range that fused with the reference stimulus. Bilateral CI listeners had binaural pitch fusion ranges varying from 0 to 12 mm (average 6.1 ± 3.9 mm), where 12 mm indicates fusion over all electrodes in the array. No significant correlations of fusion range were observed with any subject factors related to age, hearing loss history, or hearing device history, or with any electrode factors including interaural electrode pitch mismatch, pitch match bandwidth, or within-ear electrode discrimination abilities. Bilateral CI listeners have abnormally broad fusion, similar to hearing aid and bimodal CI listeners. This broad fusion may explain the variability of binaural benefits for speech perception in quiet and in noise in bilateral CI users.

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

Moore, Bria M.; Brady, Samuel L., E-mail: samuel.brady@stjude.org; Kaufman, Robert A.

Purpose: To investigate the correlation of size-specific dose estimate (SSDE) with absorbed organ dose, and to develop a simple methodology for estimating patient organ dose in a pediatric population (5–55 kg). Methods: Four physical anthropomorphic phantoms representing a range of pediatric body habitus were scanned with metal oxide semiconductor field effect transistor (MOSFET) dosimeters placed at 23 organ locations to determine absolute organ dose. Phantom absolute organ dose was divided by phantom SSDE to determine correlation between organ dose and SSDE. Organ dose correlation factors (CF{sub SSDE}{sup organ}) were then multiplied by patient-specific SSDE to estimate patient organ dose. Themore » CF{sub SSDE}{sup organ} were used to retrospectively estimate individual organ doses from 352 chest and 241 abdominopelvic pediatric CT examinations, where mean patient weight was 22 kg ± 15 (range 5–55 kg), and mean patient age was 6 yrs ± 5 (range 4 months to 23 yrs). Patient organ dose estimates were compared to published pediatric Monte Carlo study results. Results: Phantom effective diameters were matched with patient population effective diameters to within 4 cm; thus, showing appropriate scalability of the phantoms across the entire pediatric population in this study. IndividualCF{sub SSDE}{sup organ} were determined for a total of 23 organs in the chest and abdominopelvic region across nine weight subcategories. For organs fully covered by the scan volume, correlation in the chest (average 1.1; range 0.7–1.4) and abdominopelvic region (average 0.9; range 0.7–1.3) was near unity. For organ/tissue that extended beyond the scan volume (i.e., skin, bone marrow, and bone surface), correlation was determined to be poor (average 0.3; range: 0.1–0.4) for both the chest and abdominopelvic regions, respectively. A means to estimate patient organ dose was demonstrated. Calculated patient organ dose, using patient SSDE and CF{sub SSDE}{sup organ}, was compared to previously published pediatric patient doses that accounted for patient size in their dose calculation, and was found to agree in the chest to better than an average of 5% (27.6/26.2) and in the abdominopelvic region to better than 2% (73.4/75.0). Conclusions: For organs fully covered within the scan volume, the average correlation of SSDE and organ absolute dose was found to be better than ±10%. In addition, this study provides a complete list of organ dose correlation factors (CF{sub SSDE}{sup organ}) for the chest and abdominopelvic regions, and describes a simple methodology to estimate individual pediatric patient organ dose based on patient SSDE.« less

Induction of Micronuclei in Human Fibroblasts from the Los Alamos High Energy Neutron Beam

NASA Technical Reports Server (NTRS)

Cox, Bradley

2009-01-01

The space radiation field includes a broad spectrum of high energy neutrons. Interactions between these neutrons and a spacecraft, or other material, significantly contribute to the dose equivalent for astronauts. The 15 degree beam line in the Weapons Neutron Research beam at Los Alamos Nuclear Science Center generates a neutron spectrum relatively similar to that seen in space. Human foreskin fibroblast (AG1522) samples were irradiated behind 0 to 20 cm of water equivalent shielding. The cells were exposed to either a 0.05 or 0.2 Gy entrance dose. Following irradiation, micronuclei were counted to see how the water shield affects the beam and its damage to cell nuclei. Micronuclei induction was then compared with dose equivalent data provided from a tissue equivalent proportional counter.

Thermoluminescence glow-curve characteristics of LiF phosphors at high doses of gamma radiation

NASA Astrophysics Data System (ADS)

Benny, P. G.; Khader, S. A.; Sarma, K. S. S.

2013-05-01

High doses of ionising radiation are becoming increasingly common for radiation-processing applications of various medical, agricultural and polymer products using gamma and electron beams. The objective of this work was to study thermoluminescence (TL) glow-curve characteristics of commonly used commercial LiF TL phosphors at high doses of radiation with a view to use them in dosimetry of radiation-processing applications. The TL properties of TLD 100 and 700 phosphors, procured from the Thermo-Scientific (previously Harshaw) company, have been studied in the dose range of 1-60 kGy. The shift in glow peaks was observed in this dose range. Integral TL responses of TLD 100 and TLD 700 were found to decrease as a linear function of dose in the range of 5-50 kGy. The paper describes initial results related to the glow-curve characteristics of these phosphors.

Simplified method for creating a density-absorbed dose calibration curve for the low dose range from Gafchromic EBT3 film.

PubMed

Gotanda, Tatsuhiro; Katsuda, Toshizo; Gotanda, Rumi; Kuwano, Tadao; Akagawa, Takuya; Tanki, Nobuyoshi; Tabuchi, Akihiko; Shimono, Tetsunori; Kawaji, Yasuyuki

2016-01-01

Radiochromic film dosimeters have a disadvantage in comparison with an ionization chamber in that the dosimetry process is time-consuming for creating a density-absorbed dose calibration curve. The purpose of this study was the development of a simplified method of creating a density-absorbed dose calibration curve from radiochromic film within a short time. This simplified method was performed using Gafchromic EBT3 film with a low energy dependence and step-shaped Al filter. The simplified method was compared with the standard method. The density-absorbed dose calibration curves created using the simplified and standard methods exhibited approximately similar straight lines, and the gradients of the density-absorbed dose calibration curves were -32.336 and -33.746, respectively. The simplified method can obtain calibration curves within a much shorter time compared to the standard method. It is considered that the simplified method for EBT3 film offers a more time-efficient means of determining the density-absorbed dose calibration curve within a low absorbed dose range such as the diagnostic range.

Simplified method for creating a density-absorbed dose calibration curve for the low dose range from Gafchromic EBT3 film

PubMed Central

Gotanda, Tatsuhiro; Katsuda, Toshizo; Gotanda, Rumi; Kuwano, Tadao; Akagawa, Takuya; Tanki, Nobuyoshi; Tabuchi, Akihiko; Shimono, Tetsunori; Kawaji, Yasuyuki

2016-01-01

Radiochromic film dosimeters have a disadvantage in comparison with an ionization chamber in that the dosimetry process is time-consuming for creating a density-absorbed dose calibration curve. The purpose of this study was the development of a simplified method of creating a density-absorbed dose calibration curve from radiochromic film within a short time. This simplified method was performed using Gafchromic EBT3 film with a low energy dependence and step-shaped Al filter. The simplified method was compared with the standard method. The density-absorbed dose calibration curves created using the simplified and standard methods exhibited approximately similar straight lines, and the gradients of the density-absorbed dose calibration curves were −32.336 and −33.746, respectively. The simplified method can obtain calibration curves within a much shorter time compared to the standard method. It is considered that the simplified method for EBT3 film offers a more time-efficient means of determining the density-absorbed dose calibration curve within a low absorbed dose range such as the diagnostic range. PMID:28144120

Space Radiation Transport Codes: A Comparative Study for Galactic Cosmic Rays Environment

NASA Astrophysics Data System (ADS)

Tripathi, Ram; Wilson, John W.; Townsend, Lawrence W.; Gabriel, Tony; Pinsky, Lawrence S.; Slaba, Tony

For long duration and/or deep space human missions, protection from severe space radiation exposure is a challenging design constraint and may be a potential limiting factor. The space radiation environment consists of galactic cosmic rays (GCR), solar particle events (SPE), trapped radiation, and includes ions of all the known elements over a very broad energy range. These ions penetrate spacecraft materials producing nuclear fragments and secondary particles that damage biological tissues, microelectronic devices, and materials. In deep space missions, where the Earth's magnetic field does not provide protection from space radiation, the GCR environment is significantly enhanced due to the absence of geomagnetic cut-off and is a major component of radiation exposure. Accurate risk assessments critically depend on the accuracy of the input information as well as radiation transport codes used, and so systematic verification of codes is necessary. In this study, comparisons are made between the deterministic code HZETRN2006 and the Monte Carlo codes HETC-HEDS and FLUKA for an aluminum shield followed by a water target exposed to the 1977 solar minimum GCR spectrum. Interaction and transport of high charge ions present in GCR radiation environment provide a more stringent constraint in the comparison of the codes. Dose, dose equivalent and flux spectra are compared; details of the comparisons will be discussed, and conclusions will be drawn for future directions.

Pharmacokinetics and Target Attainment of Ceftobiprole in Asian and Non-Asian Subjects.

PubMed

Muller, A E; Punt, N; Engelhardt, M; Schmitt-Hoffmann, A H; Mouton, J W

2018-05-16

Ceftobiprole is a broad-spectrum cephalosporin. The objective of this study was to test the hypothesis that the pharmacokinetics (PK) and exposure of ceftobiprole in Asian subjects are similar to those in non-Asian subjects. Three approaches were followed. The first compared the individual PK estimates between the 2 subgroups derived from a population PK model previously built. Next, it was determined whether "Asian subject" was a significant covariate. Finally, a pharmacodynamic analysis was performed by comparing measures of exposure and target attainment. No significant differences were found between PK parameter estimates for Asian and non-Asian subjects, with median values (range) for clearance of 4.82 L/h (2.12-10.47) and 4.97 L/h (0.493-20.6), respectively (P = .736). "Asian subject" was not a significant covariate in the population PK model. There were no significant differences between the measures of exposure. The geometric mean ratio for the fAUC was 1.022 (90%CI, 0.91-1.15), indicating bioequivalence. Taking a target of 60% coverage of the dose interval, more than 90% of the population in both subgroups was adequately exposed. This analysis demonstrated that there are no PK or pharmacodynamic differences between Asian and non-Asian subjects for a ceftobiprole dose of 500 mg every 8 hours as a 2-hour infusion. © 2018, The American College of Clinical Pharmacology.

Safety profile and gender specific differences of a methanol extract of Eriosema laurentii (Leguminosae) in acute and subchronic (28 days) oral toxicity studies in Wistar rats.

PubMed

Ateba, Sylvin Benjamin; Simo, Rudy Valdès; Mbanya, Jean Claude; Krenn, Liselotte; Njamen, Dieudonné

2014-03-01

Despite widespread use of Eriosema laurentii De Wild (Leguminosae) in West and Central Africa as herbal medicine and food additive the toxicity of this plant is unknown. Therefore, we performed the safety evaluation of a methanol extract (AEL). In acute toxicity, single oral administration of 2000mg/kg AEL caused neither toxicological symptoms nor mortality and the LD50 was estimated >5000mg/kg. In the subchronic oral toxicity, AEL induced no phenotypical signs of toxicity during and after treatment. Only a delayed decrease of relative spleen weight in males at the highest dose of 400mg/kg occurred. High density lipoprotein (HDL) increased significantly in females at 200 and 400mg/kg. Non-persistent increases in alanine aminotransferase activity within normal ranges were noted at 200mg/kg in males and at all doses in females. In males, AEL induced a decrease of white blood cell count at 400mg/kg, whereas lymphocytes increased at 200 and 400mg/kg and granulocytes at 400mg/kg. In females, no differences in haematological parameters occurred. Neither differences in bilirubin, creatinine and total protein levels were observed nor histological alterations in organs. The results indicate a broad safety margin for AEL. Copyright © 2013 Elsevier Ltd. All rights reserved.

Metronidazole excretion in human milk and its effect on the suckling neonate.

PubMed Central

Passmore, C M; McElnay, J C; Rainey, E A; D'Arcy, P F

1988-01-01

1. Milk and plasma metronidazole and hydroxymetronidazole concentrations were measured in 12 breast-feeding patients following multiple doses of metronidazole (400 mg three times daily). All patients received metronidazole in combination with other broad spectrum antibiotics. 2. Plasma concentrations of both parent drug and metabolite were measured in seven suckling infants. Thirty-five infants were monitored for adverse reactions to maternal metronidazole therapy and two further groups of suckling infants, those whose mothers received either ampicillin alone or no drug therapy, were recruited as controls. 3. The mean milk to plasma ratio (M/P) was 0.9 for metronidazole and 0.76 for hydroxymetronidazole while the mean milk metronidazole concentrations (around Cmax) were 15.5 micrograms ml-1. The mean milk hydroxymetronidazole concentration was 5.7 micrograms ml-1. 4. Infant plasma metronidazole concentrations ranged from 1.27 micrograms ml-1 to 2.41 micrograms ml-1, and the corresponding hydroxymetronidazole concentrations from 1.1 to 2.4 micrograms ml-1. 5. There were no significant increases in adverse effects in infants which could be attributable to maternal metronidazole therapy. 6. Metronidazole was excreted in milk at concentrations which caused no serious reactions in the infants studied. The drug may therefore be administered at doses of 400 mg three times daily to mothers wishing to breast-feed their infants. PMID:3203060

Initial Efforts in Characterizing Radiation and Plasma Effects on Space Assets: Bridging the Space Environment, Engineering and User Community

NASA Astrophysics Data System (ADS)

Zheng, Y.; Ganushkina, N. Y.; Guild, T. B.; Jiggens, P.; Jun, I.; Mazur, J. E.; Meier, M. M.; Minow, J. I.; Pitchford, D. A.; O'Brien, T. P., III; Shprits, Y.; Tobiska, W. K.; Xapsos, M.; Rastaetter, L.; Jordanova, V. K.; Kellerman, A. C.; Fok, M. C. H.

2017-12-01

The Community Coordinated Modeling Center (CCMC) has been leading the community-wide model validation projects for many years. Such effort has been broadened and extended via the newly-launched International Forum for Space Weather Modeling Capabilities Assessment (https://ccmc.gsfc.nasa.gov/assessment/), Its objective is to track space weather models' progress and performance over time, which is critically needed in space weather operations. The Radiation and Plasma Effects Working Team is working on one of the many focused evaluation topics and deals with five different subtopics: Surface Charging from 10s eV to 40 keV electrons, Internal Charging due to energetic electrons from hundreds keV to several MeVs. Single Event Effects from solar energetic particles (SEPs) and galactic cosmic rays (GCRs) (several MeV to TeVs), Total Dose due to accumulation of doses from electrons (>100 KeV) and protons (> 1 MeV) in a broad energy range, and Radiation Effects from SEPs and GCRs at aviation altitudes. A unique aspect of the Radiation and Plasma Effects focus area is that it bridges the space environments, engineering and user community. This presentation will summarize the working team's progress in metrics discussion/definition and the CCMC web interface/tools to facilitate the validation efforts. As an example, tools in the areas of surface charging/internal charging will be demoed.

A rapid method to assess a broad inventory of organic species in marine sediments using ultra-high resolution mass spectrometry.

PubMed

Radović, Jagoš R; Silva, Renzo C; Snowdon, Ryan W; Brown, Melisa; Larter, Steve; Oldenburg, Thomas B P

2016-06-15

A broad range of organic species in marine sediments is routinely used as biogeochemical proxies of Earth history. These species are typically analyzed using different analytical methods, targeting very specific components and often including time-intensive sample preparation. There is, therefore, a need for a more comprehensive, rapid and high-throughput approach to simultaneously analyze a broad range of known sedimentary polar species and also have a surveillance capability able to identify candidate new species classes. Whole solvent extracts from recently deposited Gulf of Mexico marine sediments were obtained after a simple, one-step extraction. They were analyzed by Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), using atmospheric pressure photoionization in positive ion mode (APPI-P), over a broad mass range (m/z 150-1500). From 3000 to over 5000 peaks per sample were assigned molecular formulae, and the majority of assignments (90%) showed an absolute error lower than 200 ppb. The detected species belong to the NO1-7 , N4 O2-8 , O1-9 , HC, N and OS compound classes, including known biomarker species such as pigments (e.g. tetrapyrrole macrocycles and carotenoids) and lipids (e.g. glycerol dialkyl glycerol tetraethers, GDGTs), but also compounds of still unknown detailed molecular structure, but with clear potential geochemical relevance. The reported method enables rapid (12 min FTICR-MS analysis time) and simultaneous detection of a broad range of multi-heteroatom, polar organic species in whole sediment extracts. This allows for higher sample throughput, a more comprehensive investigation of sedimentary geochemistry, and potentially the discovery of new components and derivation of novel, multi-species proxies. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults.

PubMed

Banzhoff, Angelika; Gasparini, Roberto; Laghi-Pasini, Franco; Staniscia, Tommaso; Durando, Paolo; Montomoli, Emanuele; Capecchi, Pier Leopoldo; Capecchi, Pamela; di Giovanni, Pamela; Sticchi, Laura; Gentile, Chiara; Hilbert, Anke; Brauer, Volker; Tilman, Sandrine; Podda, Audino

2009-01-01

Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed. Healthy adults aged 18-60 and > 60 years (n = 313 and n = 173, respectively) were randomized (1:1) to receive two primary and one booster injection of 7.5 microg or 15 microg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 microg and 15 microg doses were comparable. The rates for seroprotection (HI>40; SRH>25 mm(2); MN > or = 40) after the primary vaccination ranged 72-87%. Six months after primary vaccination with the 7.5 microg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 microg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations. Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs. (ClinicalTrials.gov) NCT00311480.

National survey on the natural radioactivity and 222Rn exhalation rate of building materials in The Netherlands.

PubMed

de Jong, P; van Dijk, W; van der Graaf, E R; de Groot, T J H

2006-09-01

The present study reports on results of a nation-wide survey on the natural radioactivity concentrations and Rn exhalation rates of the prevailing building materials in the Netherlands. In total 100 samples were taken and analyzed for the activity concentrations of Ra, Ra, Th, and K and for their Rn exhalation rate. The sampled materials consisted of gypsum products, aerated concrete, sand-lime and clay bricks, mortars and concrete, representing about 95% of the stony building materials used in the construction of Dutch homes. The laboratory analyses were performed according to two well-documented standard procedures, the interlaboratory reproducibility of which is found to be within 5% on average. The highest radionuclide concentrations were found in a porous inner wall brick to which fly ash was added. The second highest were clay bricks with average Ra and Ra levels around 40 Bq kg. Concrete and mortar show the highest exhalation rates with a fairly broad range of 1 to 13 microBq (kg s). Low natural radioactivity levels are associated with either natural gypsum (products) or gypsum from flue gas desulphurization units, and low exhalation rates with clay bricks. To evaluate the radiological impact the radioactivity concentrations in each sample were combined into a so-called dose factor, representing the absorbed dose rate in a room with a floor, walls and ceiling of 20 cm of the material in question. For that purpose, calculations with the computer codes MCNP, Marmer and MicroShield on the specific absorbed dose rates were incorporated in the paper. The results of these codes corresponded within 6% and average values were calculated at 0.90, 1.10, and 0.080 nGy h per Bq kg for the U series, the Th series, and K, respectively. Model calculations on the external dose rate, based on the incidence of the various building materials in 1,336 living rooms, are in accordance with measured data.

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

Šefl, Martin, E-mail: martin.sefl@gmail.com; Kyriakou, Ioanna; Emfietzoglou, Dimitris, E-mail: demfietz@cc.uoi.gr

Purpose: To study theoretically the impact on cell survival of the radionuclide uptake rate inside tumor cells for a single administration of a radiopharmaceutical. Methods: The instantaneous-uptake model of O’Donoghue [“The impact of tumor cell proliferation in radioimmunotherapy,” Cancer 73, 974–980 (1994)] for a proliferating cell population irradiated by an exponentially decreasing dose-rate is here extended to allow for the monoexponential uptake of the radiopharmaceutical by the targeted cells. The time derivative of the survival curve is studied in detail deducing an expression for the minimum of the surviving fraction and the biologically effective dose (BED). Results: Surviving fractions aremore » calculated over a parameter range that is clinically relevant and broad enough to establish general trends. Specifically, results are presented for the therapy radionuclides Y-90, I-131, and P-32, assuming uptake half-times 1–24 h, extrapolated initial dose-rates 0.5–1 Gy h{sup −1}, and a biological clearance half-life of seven days. Representative radiobiological parameters for radiosensitive and rapidly proliferating tumor cells are used, with cell doubling time equal to 2 days and α-coefficient equal to 0.3 and 0.5 Gy{sup −1}. It is shown that neglecting the uptake phase of the radiopharmaceutical (i.e., assuming instantaneous-uptake) results in a sizeable over-estimation of cell-kill (i.e., under-estimation of cell survival) even for uptake half-times of only a few hours. The differences between the exponential-uptake model and the instantaneous-uptake model become larger for high peak dose-rates, slow uptakes, and (slightly) for long-lived radionuclides. Moreover, the sensitivity of the survival curve on the uptake model was found to be higher for the tumor cells with the larger α-coefficient. Conclusions: The exponential-uptake rate of the radiopharmaceutical inside targeted cells appears to have a considerable effect on the survival of a proliferating cell population and might need to be considered in radiobiological models of tumor cell-kill in radionuclide therapy.« less

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

PubMed Central

Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

2017-01-01

Background Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Methodology/Principal findings Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38–4.13%) and 0.35% (95% CI: 0.06–1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Conclusions/Significance Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in good physical condition after withdrawing anti-neurosyphilis regimen. We did not see an exacerbation of neutropenia in patients with the readministration of benzylpenicillin. PMID:28288165

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

PubMed

Peng, Rui-Rui; Wu, Juan; Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

2017-03-01

Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in good physical condition after withdrawing anti-neurosyphilis regimen. We did not see an exacerbation of neutropenia in patients with the readministration of benzylpenicillin.

Quantitative comparison of the results obtained by the multiple-dose guinea pig maximization test and the non-radioactive murine local lymph-node assay for various biocides.

PubMed

Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

2005-07-01

We compared the results of the multiple-dose guinea pig maximization test (GPMT) and the non-radioactive murine local lymph-node assay (LLNA) for various biocides. Thirteen out of 17 positive biocides in the GPMT gave positive results in the LLNA. In the GPMT, the minimum first induction doses ranged over four orders (0.00005-0.5%), while elicitation-threshold doses, which were evaluated using an optimally sensitized group of animals in the multiple-dose studies, ranged over five orders (0.00006-2.8%). In the LLNA, minimum induction doses ranged over more than three orders (0.01-30%). With respect to 13 biocides that were positive in both the GPMT and the LLNA, results were quantitatively compared. When compared after conversion to corresponding area doses (microg/cm), the minimum doses required to elicit skin reaction in guinea pigs were always lower than that for induction in mice with all biocides. Correlation between minimum induction doses from the GPMT and the LLNA seemed poor (r=0.57), while that between minimum induction doses in the LLNA and elicitation-threshold doses in the GPMT was relatively good (r=0.73). The results suggest the possibility to estimate human elicitation-threshold doses, which are definitely lacking in the process of risk assessment for skin-sensitizers, from the data of the LLNA.

Safinamide for symptoms of Parkinson's disease.

PubMed

Müller, T

2015-11-01

Chronic and slow progression of neuronal death in Parkinson's disease is responsible for an altered neurotransmission of various biogenic amines, such as dopamine. Therefore, an individually different pronounced heterogeneity of motor and nonmotor symptoms characterizes each Parkinson's disease patient. Ideal candidates for the balance of these neurotransmitter deficits are compounds like safinamide with broad mechanisms of action such as reversible monoamine oxidase type B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release. Safinamide is administered one time daily with oral doses ranging from 50 to 100 mg. Safinamide was well tolerated and safe, ameliorated motor symptoms when combined with dopamine agonist only or additional levodopa in clinical trials. Safinamide is a novel instrument for the drug therapy of Parkinson's disease with better safety and tolerability particularly concerning diarrhea than inhibitors of catechol-O-methyltransferase, like entacapone, according to an indirect comparison within a meta-analysis with entacapone. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

The ketogenic diet as broad-spectrum treatment for super-refractory pediatric status epilepticus: challenges in implementation in the pediatric and neonatal intensive care units.

PubMed

Cobo, Nicole H; Sankar, Raman; Murata, Kristina K; Sewak, Sarika L; Kezele, Michele A; Matsumoto, Joyce H

2015-02-01

Refractory status epilepticus carries significant morbidity and mortality. Recent reports have promoted the use of the ketogenic diet as an effective treatment for refractory status epilepticus. We describe our recent experience with instituting the ketogenic diet for 4 critically ill children in refractory status epilepticus, ranging in age from 9 weeks to 13.5 years after failure of traditional treatment. The ketogenic diet allowed these patients to be weaned off continuous infusions of anesthetics without recurrence of status epilepticus, though delayed ketosis and persistently elevated glucose measurements posed special challenges to effective initiation, and none experienced complete seizure cessation. The ease of sustaining myocardial function with fatty acid energy substrates compares favorably over the myocardial toxicity posed by anesthetic doses of barbiturates and contributes to the safety profile of the ketogenic diet. The ketogenic diet can be implemented successfully and safely for the treatment of refractory status epilepticus in pediatric patients. © The Author(s) 2014.

Tombusvirus-based vector systems to permit over-expression of genes or that serve as sensors of antiviral RNA silencing in plants.

PubMed

Shamekova, Malika; Mendoza, Maria R; Hsieh, Yi-Cheng; Lindbo, John; Omarov, Rustem T; Scholthof, Herman B

2014-03-01

A next generation Tomato bushy stunt virus (TBSV) coat protein gene replacement vector system is described that can be applied by either RNA inoculation or through agroinfiltration. A vector expressing GFP rapidly yields high levels of transient gene expression in inoculated leaves of various plant species, as illustrated for Nicotiana benthamiana, cowpea, tomato, pepper, and lettuce. A start-codon mutation to down-regulate the dose of the P19 silencing suppressor reduces GFP accumulation, whereas mutations that result in undetectable levels of P19 trigger rapid silencing of GFP. Compared to existing virus vectors the TBSV system has a unique combination of a very broad host range, rapid and high levels of replication and gene expression, and the ability to regulate its suppressor. These features are attractive for quick transient assays in numerous plant species for over-expression of genes of interest, or as a sensor to monitor the efficacy of antiviral RNA silencing. Copyright © 2014. Published by Elsevier Inc.

ADVANTG An Automated Variance Reduction Parameter Generator, Rev. 1

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

Mosher, Scott W.; Johnson, Seth R.; Bevill, Aaron M.

2015-08-01

The primary objective of ADVANTG is to reduce both the user effort and the computational time required to obtain accurate and precise tally estimates across a broad range of challenging transport applications. ADVANTG has been applied to simulations of real-world radiation shielding, detection, and neutron activation problems. Examples of shielding applications include material damage and dose rate analyses of the Oak Ridge National Laboratory (ORNL) Spallation Neutron Source and High Flux Isotope Reactor (Risner and Blakeman 2013) and the ITER Tokamak (Ibrahim et al. 2011). ADVANTG has been applied to a suite of radiation detection, safeguards, and special nuclear materialmore » movement detection test problems (Shaver et al. 2011). ADVANTG has also been used in the prediction of activation rates within light water reactor facilities (Pantelias and Mosher 2013). In these projects, ADVANTG was demonstrated to significantly increase the tally figure of merit (FOM) relative to an analog MCNP simulation. The ADVANTG-generated parameters were also shown to be more effective than manually generated geometry splitting parameters.« less

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

PubMed

Jentsch, J D; Roth, R H

1999-03-01

Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.

Competitive exclusion over broad spatial extents is a slow process: Evidence and implications for species distribution modeling

USGS Publications Warehouse

Yackulic, Charles B.

2016-01-01

There is considerable debate about the role of competition in shaping species distributions over broad spatial extents. This debate has practical implications because predicting changes in species' geographic ranges in response to ongoing environmental change would be simpler if competition could be ignored. While this debate has been the subject of many reviews, recent literature has not addressed the rates of relevant processes. This omission is surprising in that ecologists hypothesized decades ago that regional competitive exclusion is a slow process. The goal of this review is to reassess the debate under the hypothesis that competitive exclusion over broad spatial extents is a slow process.Available evidence, including simulations presented for the first time here, suggests that competitive exclusion over broad spatial extents occurs slowly over temporal extents of many decades to millennia. Ecologists arguing against an important role for competition frequently study modern patterns and/or range dynamics over periods of decades, while much of the evidence for competition shaping geographic ranges at broad spatial extents comes from paleoecological studies over time scales of centuries or longer. If competition is slow, as evidence suggests, the geographic distributions of some, perhaps many species, would continue to change over time scales of decades to millennia, even if environmental conditions did not continue to change. If the distributions of competing species are at equilibrium it is possible to predict species distributions based on observed species–environment relationships. However, disequilibrium is widespread as a result of competition and many other processes. Studies whose goal is accurate predictions over intermediate time scales (decades to centuries) should focus on factors associated with range expansion (colonization) and loss (local extinction), as opposed to current patterns. In general, understanding of modern range dynamics would be enhanced by considering the rates of relevant processes.

An Efficient Strategy for Broad-Range Detection of Low Abundance Bacteria without DNA Decontamination of PCR Reagents

PubMed Central

Chang, Shy-Shin; Hsu, Hsung-Ling; Cheng, Ju-Chien; Tseng, Ching-Ping

2011-01-01

Background Bacterial DNA contamination in PCR reagents has been a long standing problem that hampers the adoption of broad-range PCR in clinical and applied microbiology, particularly in detection of low abundance bacteria. Although several DNA decontamination protocols have been reported, they all suffer from compromised PCR efficiency or detection limits. To date, no satisfactory solution has been found. Methodology/Principal Findings We herein describe a method that solves this long standing problem by employing a broad-range primer extension-PCR (PE-PCR) strategy that obviates the need for DNA decontamination. In this method, we first devise a fusion probe having a 3′-end complementary to the template bacterial sequence and a 5′-end non-bacterial tag sequence. We then hybridize the probes to template DNA, carry out primer extension and remove the excess probes using an optimized enzyme mix of Klenow DNA polymerase and exonuclease I. This strategy allows the templates to be distinguished from the PCR reagent contaminants and selectively amplified by PCR. To prove the concept, we spiked the PCR reagents with Staphylococcus aureus genomic DNA and applied PE-PCR to amplify template bacterial DNA. The spiking DNA neither interfered with template DNA amplification nor caused false positive of the reaction. Broad-range PE-PCR amplification of the 16S rRNA gene was also validated and minute quantities of template DNA (10–100 fg) were detectable without false positives. When adapting to real-time and high-resolution melting (HRM) analytical platforms, the unique melting profiles for the PE-PCR product can be used as the molecular fingerprints to further identify individual bacterial species. Conclusions/Significance Broad-range PE-PCR is simple, efficient, and completely obviates the need to decontaminate PCR reagents. When coupling with real-time and HRM analyses, it offers a new avenue for bacterial species identification with a limited source of bacterial DNA, making it suitable for use in clinical and applied microbiology laboratories. PMID:21637859

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.

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

PubMed

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

2003-02-01

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

Age- and gender-specific estimates of cumulative CT dose over 5 years using real radiation dose tracking data in children.

PubMed

Lee, Eunsol; Goo, Hyun Woo; Lee, Jae-Yeong

2015-08-01

It is necessary to develop a mechanism to estimate and analyze cumulative radiation risks from multiple CT exams in various clinical scenarios in children. To identify major contributors to high cumulative CT dose estimates using actual dose-length product values collected for 5 years in children. Between August 2006 and July 2011 we reviewed 26,937 CT exams in 13,803 children. Among them, we included 931 children (median age 3.5 years, age range 0 days-15 years; M:F = 533:398) who had 5,339 CT exams. Each child underwent at least three CT scans and had accessible radiation dose reports. Dose-length product values were automatically extracted from DICOM files and we used recently updated conversion factors for age, gender, anatomical region and tube voltage to estimate CT radiation dose. We tracked the calculated CT dose estimates to obtain a 5-year cumulative value for each child. The study population was divided into three groups according to the cumulative CT dose estimates: high, ≥30 mSv; moderate, 10-30 mSv; and low, <10 mSv. We reviewed clinical data and CT protocols to identify major contributors to high and moderate cumulative CT dose estimates. Median cumulative CT dose estimate was 5.4 mSv (range 0.5-71.1 mSv), and median number of CT scans was 4 (range 3-36). High cumulative CT dose estimates were most common in children with malignant tumors (57.9%, 11/19). High frequency of CT scans was attributed to high cumulative CT dose estimates in children with ventriculoperitoneal shunt (35 in 1 child) and malignant tumors (range 18-49). Moreover, high-dose CT protocols, such as multiphase abdomen CT (median 4.7 mSv) contributed to high cumulative CT dose estimates even in children with a low number of CT scans. Disease group, number of CT scans, and high-dose CT protocols are major contributors to higher cumulative CT dose estimates in children.

Proton Minibeam Radiation Therapy Reduces Side Effects in an In Vivo Mouse Ear Model.

PubMed

Girst, Stefanie; Greubel, Christoph; Reindl, Judith; Siebenwirth, Christian; Zlobinskaya, Olga; Walsh, Dietrich W M; Ilicic, Katarina; Aichler, Michaela; Walch, Axel; Wilkens, Jan J; Multhoff, Gabriele; Dollinger, Günther; Schmid, Thomas E

2016-05-01

Proton minibeam radiation therapy is a novel approach to minimize normal tissue damage in the entrance channel by spatial fractionation while keeping tumor control through a homogeneous tumor dose using beam widening with an increasing track length. In the present study, the dose distributions for homogeneous broad beam and minibeam irradiation sessions were simulated. Also, in an animal study, acute normal tissue side effects of proton minibeam irradiation were compared with homogeneous irradiation in a tumor-free mouse ear model to account for the complex effects on the immune system and vasculature in an in vivo normal tissue model. At the ion microprobe SNAKE, 20-MeV protons were administered to the central part (7.2 × 7.2 mm(2)) of the ear of BALB/c mice, using either a homogeneous field with a dose of 60 Gy or 16 minibeams with a nominal 6000 Gy (4 × 4 minibeams, size 0.18 × 0.18 mm(2), with a distance of 1.8 mm). The same average dose was used over the irradiated area. No ear swelling or other skin reactions were observed at any point after minibeam irradiation. In contrast, significant ear swelling (up to fourfold), erythema, and desquamation developed in homogeneously irradiated ears 3 to 4 weeks after irradiation. Hair loss and the disappearance of sebaceous glands were only detected in the homogeneously irradiated fields. These results show that proton minibeam radiation therapy results in reduced adverse effects compared with conventional homogeneous broad-beam irradiation and, therefore, might have the potential to decrease the incidence of side effects resulting from clinical proton and/or heavy ion therapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Analysis of patient CT dose data using virtualdose

NASA Astrophysics Data System (ADS)

Bennett, Richard

X-ray computer tomography has many benefits to medical and research applications. Recently, over the last decade CT has had a large increase in usage in hospitals and medical diagnosis. In pediatric care, from 2000 to 2006, abdominal CT scans increased by 49 % and chest CT by 425 % in the emergency room (Broder 2007). Enormous amounts of effort have been performed across multiple academic and government groups to determine an accurate measure of organ dose to patients who undergo a CT scan due to the inherent risks with ionizing radiation. Considering these intrinsic risks, CT dose estimating software becomes a necessary tool that health care providers and radiologist must use to determine many metrics to base the risks versus rewards of having an x-ray CT scan. This thesis models the resultant organ dose as body mass increases for patients with all other related scan parameters fixed. In addition to this,this thesis compares a modern dose estimating software, VirtualDose CT to two other programs, CT-Expo and ImPACT CT. The comparison shows how the software's theoretical basis and the phantom they use to represent the human body affect the range of results in organ dose. CT-Expo and ImPACT CT dose estimating software uses a different model for anatomical representation of the organs in the human body and the results show how that approach dramatically changes the outcome. The results categorizes four datasets as compared to the three software types where the appropriate phantom was available. Modeling was done to simulate chest abdominal pelvis scans and whole body scans. Organ dose difference versus body mass index shows as body mass index (BMI) ranges from 23.5 kg/m 2 to 45 kg/m2 the amount of organ dose also trends a percent change from -4.58 to -176.19 %. Comparing organ dose difference with increasing x-ray tube potential from 120 kVp to 140 kVp the percent change in organ dose increases from 55 % to 65 % across all phantoms. In comparing VirtualDose to CT-Expo for organ dose difference versus age, male phantoms show percent difference of -19 % to 25 % for various organs minus bone surface and breast tissues results. Finally, for organ dose difference across all software for average adult phantom the results range from -45 % to 6 % in the comparison of ImPACT CT to VirtualDose and -27 % to 66 % for the comparison of CT-Expo to VirtualDose. In the comparison for increased BMI (done only in VirtualDose), results show that with all other parameters fixed, the organ dose goes down as BMI increases, which is due to the increase in adipose tissue and bulk of the patient model. The range of results when comparing all the three softwares have a wide range, in some cases greater than 150 %, it is evident that using a different anatomical basis for the human phantom and the theoretical basis for the dose estimation will cause fluctuation in the results. Therefore, choosing the software with the most accurate human phantom will provide a closer range to the true dose to the organ.

The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

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

Liebl, Jakob, E-mail: jakob.liebl@medaustron.at; Francis H. Burr Proton Therapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Therapeutic Radiology and Oncology, Medical University of Graz, 8036 Graz

2014-09-15

Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patientmore » positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R{sup 2} < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions in the human brain as well as target and OAR dosimetry were studied. Observed range uncertainties were correlated with HIs. The clinical practice of using multiple fields with smeared compensators while avoiding distal OAR sparing is considered to be safe.« less

The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

PubMed Central

Liebl, Jakob; Paganetti, Harald; Zhu, Mingyao; Winey, Brian A.

2014-01-01

Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patient positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R2 < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions in the human brain as well as target and OAR dosimetry were studied. Observed range uncertainties were correlated with HIs. The clinical practice of using multiple fields with smeared compensators while avoiding distal OAR sparing is considered to be safe. PMID:25186386

Effective radiation dose of ProMax 3D cone-beam computerized tomography scanner with different dental protocols.

PubMed

Qu, Xing-min; Li, Gang; Ludlow, John B; Zhang, Zu-yan; Ma, Xu-chen

2010-12-01

The aim of this study was to compare effective doses resulting from different scan protocols for cone-beam computerized tomography (CBCT) using International Commission on Radiological Protection (ICRP) 1990 and 2007 calculations of dose. Average tissue-absorbed dose, equivalent dose, and effective dose for a ProMax 3D CBCT with different dental protocols were calculated using thermoluminescent dosimeter chips in a human equivalent phantom. Effective doses were derived using ICRP 1990 and the superseding 2007 recommendations. Effective doses (ICRP 2007) for default patient sizes from small to large ranged from 102 to 298 μSv. The coefficient of determination (R(2)) between tube current and effective dose (ICRP 2007) was 0.90. When scanning with lower resolution settings, the effective doses were reduced significantly (P < .05). ProMax 3D can provide a wide range of radiation dose levels. Reduction in radiation dose can be achieved when using lower settings of exposure parameters. Copyright © 2010 Mosby, Inc. All rights reserved.

Dosimetry for Small and Nonstandard Fields

NASA Astrophysics Data System (ADS)

Junell, Stephanie L.

The proposed small and non-standard field dosimetry protocol from the joint International Atomic Energy Agency (IAEA) and American Association of Physicist in Medicine working group introduces new reference field conditions for ionization chamber based reference dosimetry. Absorbed dose beam quality conversion factors (kQ factors) corresponding to this formalism were determined for three different models of ionization chambers: a Farmer-type ionization chamber, a thimble ionization chamber, and a small volume ionization chamber. Beam quality correction factor measurements were made in a specially developed cylindrical polymethyl methacrylate (PMMA) phantom and a water phantom using thermoluminescent dosimeters (TLDs) and alanine dosimeters to determine dose to water. The TLD system for absorbed dose to water determination in high energy photon and electron beams was fully characterized as part of this dissertation. The behavior of the beam quality correction factor was observed as it transfers the calibration coefficient from the University of Wisconsin Accredited Dosimetry Calibration Laboratory (UWADCL) 60Co reference beam to the small field calibration conditions of the small field formalism. TLD-determined beam quality correction factors for the calibration conditions investigated ranged from 0.97 to 1.30 and had associated standard deviations from 1% to 3%. The alanine-determined beam quality correction factors ranged from 0.996 to 1.293. Volume averaging effects were observed with the Farmer-type ionization chamber in the small static field conditions. The proposed small and non-standard field dosimetry protocols new composite-field reference condition demonstrated its potential to reduce or remove ionization chamber volume dependancies, but the measured beam quality correction factors were not equal to the standard CoP's kQ, indicating a change in beam quality in the small and non-standard field dosimetry protocols new composite-field reference condition relative to the standard broad beam reference conditions. The TLD- and alanine-determined beam quality correction factors in the composite-field reference conditions were approximately 3% greater and differed by more than one standard deviation from the published TG-51 kQ values for all three chambers.

Cost-effectiveness of gemcitabine in stage IV non-small cell lung cancer: an estimate using the Population Health Model lung cancer module.

PubMed

Evans, W K

1997-04-01

Statistics Canada (Ottawa, Ontario, Canada) is in the process of developing the Population Health Model to simulate the health and common illnesses of Canadians. The Population Health Model incorporates a lung cancer module that is based on contemporary Canadian practice. This microsimulation model can be used to estimate the total direct care costs of treating all lung cancer cases diagnosed in Canada and to evaluate the cost and cost-effectiveness of new therapeutic interventions as they are introduced into practice. Gemcitabine, a new nucleoside analogue with a broad spectrum of antitumor activity, is about to be introduced on the Canadian market. The Population Health Model has been used to estimate the cost-effectiveness of gemcitabine in the management of lung cancer over a range of drug doses per treatment cycle starting at 1,000 mg/m2 weekly x 3, as well as potential survival benefits. The survival of stage IV non-small cell lung cancer (NSCLC) patients treated on an international trial of gemcitabine (EO-18) was used to estimate the potential survival gain relative to the survival of stage IV NSCLC patients managed with best supportive care on a randomized trial conducted by the National Cancer Institute of Canada (BR 5). Sensitivity analyses were performed assuming that the survival gain was 25% or 50% less than that reported in the EO-18 trial. The perspective of the economic analysis is that of the government as payer in a universal health care system, and all costs are expressed in 1993 Canadian dollars. Based on the apparent survival advantage of the EO-18 trial in comparison to best supportive care, the cost per life-year gained ranged from $632 to $9,285, depending on the dose per treatment cycle. At the highest dose per cycle (2,000 mg/m2) and with survival reduced by 50% as compared with the EO-18 result, the cost per life-year gained was estimated to be $17,390. From these estimates of direct care costs in the Canadian health care system, gemcitabine appears to be a cost-effective intervention for advanced NSCLC.

Feasibility and acceptability of maternal choline supplementation in heavy drinking pregnant women: A randomized, double-blind, placebo-controlled clinical trial.

PubMed

Jacobson, Sandra W; Carter, R Colin; Molteno, Christopher D; Meintjes, Ernesta M; Senekal, Marjanne; Lindinger, Nadine M; Dodge, Neil C; Zeisel, Steven H; Duggan, Christopher P; Jacobson, Joseph L

2018-05-11

Choline, an essential nutrient, serves as a methyl-group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies suggest that choline supplementation during pregnancy may mitigate adverse effects of prenatal alcohol exposure on growth and neurocognitive function. We conducted a randomized, double-blind exploratory trial to examine feasibility and acceptability of a choline supplementation intervention during pregnancy. 70 heavy drinkers, recruited in mid-pregnancy, were randomly assigned to receive a daily oral dose of 2g of choline or a placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape-flavored drink. Adherence was assessed by collecting used and unused drink packets on a monthly basis and tabulating the number used. Side effects were assessed in monthly interviews. Blood samples obtained at enrollment and at 4 and 12 weeks after randomization were assayed for plasma choline concentration. Adherence was good-to-excellent (median doses taken=74.0%; interquartile range=53.9-88.7%) and was not related to a range of sociodemographic characteristics or to alcohol consumption ascertained using a timeline follow-back interview. By 4 weeks, plasma choline concentrations were significantly higher in the choline supplementation than the placebo arm, and this group difference continued to be evident at 12 weeks. The only side effect was a small increase in nausea/dyspepsia. No effects were seen for diarrhea, vomiting, muscle stiffness, blood pressure, or body odor changes. This study demonstrated that a choline supplementation program with very heavy drinkers during pregnancy is feasible even among highly disadvantaged, poorly educated women. The broad acceptability of this intervention is indicated by our finding that adherence was not related to maternal education, intellectual function, depression, nutritional status, or alcohol use. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

In vivo quality assurance of volumetric modulated arc therapy for ano-rectal cancer with thermoluminescent dosimetry and image-guidance.

PubMed

Dipasquale, Giovanna; Nouet, Philippe; Rouzaud, Michel; Dubouloz, Angèle; Miralbell, Raymond; Zilli, Thomas

2014-06-01

To assess in vivo dose distribution using cone-beam computed tomography scans (CBCTs) and thermoluminescent dosimeters (TLDs) in patients with anal or rectal cancer treated with volumetric modulated arc therapy (VMAT). Intracavitary (IC) in vivo dosimetry (IVD) was performed in 11 patients using adapted endorectal probes containing TLDs, with extra measurements at the perianal skin (PS) for anal margin tumors. Measured doses were compared to calculated ones obtained from image fusion of CBCT with CT treatments plans. A total of 55 IC and 6 PS measurements were analyzed. IC TLD median planned and measured doses were 1.81 Gy (range, 0.25-2.02 Gy) and 1.82 Gy (range, 0.19-2.12 Gy), respectively. In comparison to the planned doses all IC TLD dose measurements differed by a median dose of 0.02 Gy (range, -0.11/+0.19 Gy, p=0.102) (median difference of 1.1%, range -6.1%/+10.6%). Overall, 95% of IC measurements were within ±7.7% of the expected percentage doses and only 1 value was above +10%. For PS measurements, only one was not within ±7.7% of expected values (i.e., -8.9%). Image guidance using CBCT for IVD with TLDs is helpful to validate the delivered doses in patients treated with VMAT for ano-rectal tumors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Broad Detection Range Rhenium Diselenide Photodetector Enhanced by (3-Aminopropyl)Triethoxysilane and Triphenylphosphine Treatment.

PubMed

Jo, Seo-Hyeon; Park, Hyung-Youl; Kang, Dong-Ho; Shim, Jaewoo; Jeon, Jaeho; Choi, Seunghyuk; Kim, Minwoo; Park, Yongkook; Lee, Jaehyeong; Song, Young Jae; Lee, Sungjoo; Park, Jin-Hong

2016-08-01

The effects of triphenylphosphine and (3-aminopropyl)triethoxysilane on a rhenium diselenide (ReSe2 ) photodetector are systematically studied by comparing with conventional MoS2 devices. This study demonstrates a very high performance ReSe2 photodetector with high photoresponsivity (1.18 × 10(6) A W(-1) ), fast photoswitching speed (rising/decaying time: 58/263 ms), and broad photodetection range (possible above 1064 nm). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Estimated ultraviolet radiation doses in wetlands in six national parks

USGS Publications Warehouse

Diamond, S.A.; Trenham, P.C.; Adams, Michael J.; Hossack, B.R.; Knapp, R.A.; Stark, L.; Bradford, D.; Corn, P.S.; Czarnowski, K.; Brooks, P.D.; Fagre, D.B.; Breen, B.; Dentenbeck, N.E.; Tonnessen, K.

2005-01-01

Ultraviolet-B radiation (UV-B, 280–320-nm wavelengths) doses were estimated for 1024 wetlands in six national parks: Acadia (Acadia), Glacier (Glacier), Great Smoky Mountains (Smoky), Olympic (Olympic), Rocky Mountain (Rocky), and Sequoia/Kings Canyon (Sequoia). Estimates were made using ground-based UV-B data (Brewer spectrophotometers), solar radiation models, GIS tools, field characterization of vegetative features, and quantification of DOC concentration and spectral absorbance. UV-B dose estimates were made for the summer solstice, at a depth of 1 cm in each wetland. The mean dose across all wetlands and parks was 19.3 W-h m−2 (range of 3.4–32.1 W-h m−2). The mean dose was lowest in Acadia (13.7 W-h m−2) and highest in Rocky (24.4 W-h m−2). Doses were significantly different among all parks. These wetland doses correspond to UV-B flux of 125.0 μW cm−2 (range 21.4–194.7 μW cm−2) based on a day length, averaged among all parks, of 15.5 h. Dissolved organic carbon (DOC), a key determinant of water-column UV-B flux, ranged from 0.6 (analytical detection limit) to 36.7 mg C L−1 over all wetlands and parks, and reduced potential maximal UV-B doses at 1-cm depth by 1%–87 %. DOC concentration, as well as its effect on dose, was lowest in Sequoia and highest in Acadia (DOC was equivalent in Acadia, Glacier, and Rocky). Landscape reduction of potential maximal UV-B doses ranged from zero to 77% and was lowest in Sequoia. These regional differences in UV-B wetland dose illustrate the importance of considering all aspects of exposure in evaluating the potential impact of UV-B on aquatic organisms.

DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR ETHYLENE GLYCOL AND ITS MAJOR METABOLITE, GLYCOLIC ACID, IN RATS AND HUMANS

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

Corley, Rick A.; Bartels, M J.; Carney, E W.

2005-05-19

An extensive database on the toxicity and modes of action of the major industrial chemical, ethylene glycol (EG), has been developed over the past several decades. These studies have consistently identified the kidney as a primary target organ, with rats being more sensitive than mice and males more sensitive than females following chronic exposure. Renal toxicity has been associated with the terminal metabolite, oxalic acid which can precipitate with calcium to form crystals. EG also induces developmental toxicity, although these effects appear to require high-doses or accelerated dose-rates, and have been reported only in rats and mice. The developmental toxicitymore » of EG has been attributed to the intermediate metabolite, glycolic acid (GA). The developmental toxicity of EG has been the subject of extensive research and regulatory review in recent years. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to integrate the extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessment. Metabolic rate constants and partition coefficients for EG and GA were estimated from in vitro studies. Other biochemical constants were optimized from appropriate in vivo pharmacokinetic studies. The resulting PBPK model includes inhalation, oral, dermal, intravenous and subcutaneous routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys. Several rat and human metabolism studies were used to validate the resulting PBPK model. Consistent with these studies, simulations indicated that the metabolism of EG to GA was essentially first-order (linear) up to 2500 mg/kg/day while the metabolism of GA saturated between bolus ethylene glycol doses of 200 and 1000 mg/kg/day. This saturation results in non-linear increases in blood GA concentrations, correlating with the developmental toxicity of EG. Pregnancy had no effect on maternal EG and GA kinetics over a broad dose range. The human PBPK model was validated against a large database of human clinical case reports in a companion study (Corley and McMartin, 2004) where the impacts of treatment and a comparison of internal dose surrogates for human health risk assessments were conducted.« less

Aripiprazole Lauroxil

PubMed Central

Hard, Marjie L.; Mills, Richard J.; Sadler, Brian M.; Turncliff, Ryan Z.; Citrome, Leslie

2017-01-01

Abstract Background Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Methods Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. Findings The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441–882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. Conclusions This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice. PMID:28350572

PHARMACOKINETICS OF A SINGLE DOSE OF METRONIDAZOLE AFTER RECTAL ADMINISTRATION IN CAPTIVE ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

PubMed

Sander, Samantha J; Siegal-Willott, Jessica L; Ziegler, Jessie; Lee, Elizabeth; Tell, Lisa; Murray, Suzan

2016-03-01

Metronidazole is a nitroimidazole antibacterial and antiprotozoal drug with bacteriocidal activity against a broad range of anaerobic bacteria. It is a recognized treatment for elephants diagnosed with anaerobic bacterial infection or protozoal disease or exhibiting signs of colonic impaction, diarrhea, and colic. This study evaluated the pharmacokinetics of rectally administered metronidazole (15 mg/kg) in five adult female Asian elephants (Elephas maximus). Serum samples were collected from each animal for 96 hr after rectal administration of metronidazole. Serum concentrations of metronidazole and its primary metabolite, hydroxymetronidazole, were measured via ultraperformance liquid chromatography. Data were analyzed via a noncompartmental pharmacokinetic approach. Results indicated that serum levels of metronidazole were quantifiable at the 0.25 hr time point and absent in all elephants by the 96 hr time point. The serum peak concentration (mean ± SD, 13.15 ± 2.59 μg/ml) and area under the curve from time 0 to infinity (mean ± SD, 108.79 ± 24.77 hr × μg/ml) were higher than that reported in domestic horses after similar usage. Concurrently, the time of maximum serum concentration (mean ± SD, 1.2 ± 0.45 hr) and terminal elimination half-life (harmonic mean ± pseudo-SD, 7.85 ± 0.93 hr) were longer when compared to equine reports. Rectal administration of metronidazole was well tolerated and rapidly absorbed in all study elephants. Based on the findings in this study, metronidazole administered at a single dose of 15 mg/kg per rectum in the Asian elephant is likely to result in serum concentrations above 4 μg/ml for 8 hr and above 2 μg/ml for 24 hr after treatment is administered. Dosing recommendations should reflect the mean inhibitory concentration of metronidazole for each pathogen.

Biological Response to SPE Exposures

NASA Technical Reports Server (NTRS)

Wilson, J. W.; Cucinotta, F. A.; Kim, M.; Shinn, J. L.; Jones, T. D.; Chang, C. K.

2004-01-01

It has long been recognized that a single solar particle event (SPE) can produce, over a short period of time, exposures on the order of LD50 for humans under normal physiological conditions. It is further recognized that recovery from injury over the period of exposure would greatly increase the chances of survival (dose rate effects) although such effects were left unquantified. In the present report we use the bioresponse model derived from a broad range of animal and human exposure data for evaluation of troop readiness in tactical nuclear warfare to evaluate the biological risk posed by the solar event of 4 August 1972. The astronaut blood forming organ (BFO) exposure in deep space would have been 2.2 Sv (1.6 Gy) in a space suit, 1.8 Sv (1.3 Gy) in an aluminum pressure vessel, and 0.7 Sv (0.5 Gy) in an equipment room compared to an X-ray mortality threshold of 1.5 Gy (assuming high dose rate). We find BFO dose rate effectiveness factors for this SPE on the order of 3 to 4, greatly reducing the mortality risks for this event. There is an approximate 3 percent chance that an even larger event may occur for which exposures could be 2-4 times higher. Assured survival of the astronaut requires added shelter shielding and a warning system for this event. The required mass of the shelter shield can be greatly reduced by using hydrogenous materials such as polymers, water, food, and other biological materials in its construction. Limitations of the current bioresponse model arise from the exposures taking place in the microgravity environment wherein the immune system is already challenged and the effective mortality threshold may be reduced by a factor of two. Such microgravity effects could greatly affect astronaut risks.

Intramuscular Tranexamic Acid in Tactical and Combat Settings.

PubMed

Vu, Erik N; Wan, Wilson C Y; Yeung, Titus C; Callaway, David W

Uncontrolled hemorrhage remains a leading cause of preventable death in tactical and combat settings. Alternate routes of delivery of tranexamic acid (TXA), an adjunct in the management of hemorrhagic shock, are being studied. A working group for the Committee for Tactical Emergency Casualty Care reviewed the available evidence on the potential role for intramuscular (IM) administration of TXA in nonhospital settings as soon as possible from the point of injury. EMBASE and MEDLINE/PubMed databases were sequentially searched by medical librarians for evidence of TXA use in the following contexts and/or using the following keywords: prehospital, trauma, hemorrhagic shock, optimal timing, optimal dose, safe volume, incidence of venous thromboembolism (VTE), IM bioavailability. A total of 183 studies were reviewed. The strength of the available data was variable, generally weak in quality, and included laboratory research, case reports, retrospective observational reviews, and few prospective studies. Current volume and concentrations of available formulations of TXA make it, in theory, amenable to IM injection. Current bestpractice guidelines for large-volume injection (i.e., 5mL) support IM administration in four locations in the adult human body. One case series suggests complete bioavailability of IM TXA in healthy patients. Data are lacking on the efficacy and safety of IM TXA in hemorrhagic shock. There is currently insufficient evidence to support a strong recommendation for or against IM administration of TXA in the combat setting; however, there is an abundance of literature demonstrating efficacy and safety of TXA use in a broad range of patient populations. Balancing the available data and risk- benefit ratio, IM TXA should be considered a viable treatment option for tactical and combat applications. Additional studies should focus on the optimal dose and bioavailability of IM dosing of patients in hemorrhagic shock, with assessment of potential downstream sequelae. 2018.

Long term neurocognitive impact of low dose prenatal methylmercury exposure in Hong Kong.

PubMed

Lam, Hugh Simon; Kwok, Ka Ming; Chan, Peggy Hiu Ying; So, Hung Kwan; Li, Albert Martin; Ng, Pak Cheung; Fok, Tai Fai

2013-04-01

International studies suggest that low dose prenatal methylmercury exposure (>29 nmol/L) has long-term adverse neurocognitive effects. There is evidence that the majority of children in Hong Kong exceed this level as a result of high fish consumption of mothers during pregnancy. To study whether there are any associations between low-dose prenatal methylmercury exposure and neurocognitive outcomes in Hong Kong children. All 1057 children from the original birth cohort were eligible for entry into the study, except children with conditions that would affect neurocognitive development, but were unrelated to methylmercury exposure. Subjects were assessed by a wide panel of tests covering a broad range of neurocognitive functions: Hong Kong Wechsler Intelligence Scale for Children (HK-WISC), Hong Kong List Learning Test (HKLLT), Tests of Everyday Attention for Children (TEACH), Boston Naming Test, and Grooved Pegboard Test. 608 subjects were recruited (median age 8.2 years, IQR 7.3, 8.8; 53.9% boys). After correction by confounders including child age and sex, multivariate analysis showed that cord blood mercury concentration was significantly associated with three subtests: Picture Arrangement of HK-WISC (coefficient -0.944, P=0.049) and Short and Long Delay Recall Difference of the HKLLT (coefficient -1.087, P=0.007 and coefficient -1.161, P=0.005, respectively), i.e., performance worsened with increasing prenatal methylmercury exposure in these subtests. Small, but statistically significant adverse associations between prenatal methylmercury exposure and long-term neurocognitive effects (a visual sequencing task and retention ability of verbal memory) were found in our study. These effects are compatible with findings of studies with higher prenatal methylmercury exposure levels and suggest that safe strategies to further reduce exposure levels in Hong Kong are desirable. Copyright © 2013 Elsevier Ltd. All rights reserved.

SU-C-12A-05: Radiation Dose in High-Pitch Pediatric Cardiac CTA: Correlation Between Lung Dose and CTDIvol, DLP, and Size Specific Dose Estimates (SSDE)

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

Wang, J; Kino, A; Newman, B

2014-06-01

Purpose: To investigate the radiation dose for pediatric high pitch cardiac CTA Methods: A total of 14 cases were included in this study, with mean age of 6.2 years (ranges from 2 months to 15 years). Cardiac CTA was performed using a dual-source CT system (Definition Flash, Siemens). Tube voltage (70, 80 and 100kV) was chosen based on patient weight. All patients were scanned using a high-pitch spiral mode (pitch ranges from 2.5 to 3) with tube current modulation technique (CareDose4D, Siemens). For each case, the three dimensional dose distributions were calculated using a Monte Carlo software package (IMPACT-MC, CTmore » Image GmbH). Scanning parameters of each exam, including tube voltage, tube current, beamshaping filters, beam collimation, were defined in the Monte Carlo calculation. Tube current profile along projection angles was obtained from projection data of each tube, which included data within the over-scanning range along z direction. The volume of lungs was segmented out with CT images (3DSlicer). Lung doses of all patients were calculated and compared with CTDIvol, DLP, and SSDE. Results: The average (range) of CTDIvol, DLP and SSDE of all patients was 1.19 mGy (0.58 to 3.12mGy), 31.54 mGy*cm (12.56 to 99 mGy*cm), 2.26 mGy (1.19 to 6.24 mGy), respectively. Radiation dose to the lungs ranged from 0.83 to 4.18 mGy. Lung doses correlated with CTDIvol, DLP and SSDE with correlation coefficients(k) at 0.98, 0.93, and 0.99. However, for the cases with CTDIvol less than 1mGy, only SSDE preserved a strong correlation with lung doses (k=0.83), while much weaker correlations were found for CTDIvol (k=0.29) and DLP (k=-0.47). Conclusion: Lung doses to pediatric patients during Cardiac CTA were estimated. SSDE showed the most robust correlation with lung doses in contrast to CTDIvol and DLP.« less

Defense Threat Reduction Agency > Research > DTRIAC > Media Collection

Science.gov Websites

*Cover a broad scope of both the pre- and post-test activities of a test series or operation *Detonations FOIA Electronic Reading Room Privacy Impact Assessment DTRA No Fear Act Reporting Nuclear Test Personnel Review NTPR Fact Sheets NTPR Radiation Dose Assessment Documents US Atmospheric Nuclear Test

Use of Threshold of Toxicological Concern (TTC) with High Throughput Exposure Predictions as a Risk-Based Screening Approach of Several Thousand Commodity Chemicals (SOT Poster)

EPA Science Inventory

Although progress has been made with HTS (high throughput screening) in profiling biological activity (e.g., EPA’s ToxCast™), challenges arise interpreting HTS results in the context of adversity & converting HTS assay concentrations to equivalent human doses for the broad domain...

Analytical probabilistic proton dose calculation and range uncertainties

NASA Astrophysics Data System (ADS)

Bangert, M.; Hennig, P.; Oelfke, U.

2014-03-01

We introduce the concept of analytical probabilistic modeling (APM) to calculate the mean and the standard deviation of intensity-modulated proton dose distributions under the influence of range uncertainties in closed form. For APM, range uncertainties are modeled with a multivariate Normal distribution p(z) over the radiological depths z. A pencil beam algorithm that parameterizes the proton depth dose d(z) with a weighted superposition of ten Gaussians is used. Hence, the integrals ∫ dz p(z) d(z) and ∫ dz p(z) d(z)2 required for the calculation of the expected value and standard deviation of the dose remain analytically tractable and can be efficiently evaluated. The means μk, widths δk, and weights ωk of the Gaussian components parameterizing the depth dose curves are found with least squares fits for all available proton ranges. We observe less than 0.3% average deviation of the Gaussian parameterizations from the original proton depth dose curves. Consequently, APM yields high accuracy estimates for the expected value and standard deviation of intensity-modulated proton dose distributions for two dimensional test cases. APM can accommodate arbitrary correlation models and account for the different nature of random and systematic errors in fractionated radiation therapy. Beneficial applications of APM in robust planning are feasible.

SU-E-J-146: A Research of PET-CT SUV Range for the Online Dose Verification in Carbon Ion Radiation Therapy

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

Sun, L; Hu, W; Moyers, M

2015-06-15

Purpose: Positron-emitting isotope distributions can be used for the image fusion of the carbon ion planning CT and online target verification PETCT, after radiation in the same decay period,the relationship between the same target volume and the SUV value of different every single fraction dose can be found,then the range of SUV for the radiation target could be decided.So this online range also can provide reference for the correlation and consistency in planning target dose verification and evaluation for the clinical trial. Methods: The Rando head phantom can be used as real body,the 10cc cube volume target contouring is done,beammore » ISO Center depth is 7.6cm and the 90 degree fixed carbon ion beams should be delivered in single fraction effective dose of 2.5GyE,5GyE and 8GyE.After irradiation,390 seconds later the 30 minutes PET-CT scanning is performed,parameters are set to 50Kg virtual weight,0.05mCi activity.MIM Maestro is used for the image processing and fusion,five 16mm diameter SUV spheres have been chosen in the different direction in the target.The average SUV in target for different fraction dose can be found by software. Results: For 10cc volume target,390 seconds decay period,the Single fraction effective dose equal to 2.5Gy,Ethe SUV mean value is 3.42,the relative range is 1.72 to 6.83;Equal to 5GyE,SUV mean value is 9.946,the relative range is 7.016 to 12.54;Equal or above to 8GyE,SUV mean value is 20.496,the relative range is 11.16 to 34.73. Conclusion: Making an evaluation for accuracy of the dose distribution using the SUV range which is from the planning CT with after treatment online PET-CT fusion for the normal single fraction carbon ion treatment is available.Even to the plan which single fraction dose is above 2GyE,in the condition of other parameters all the same,the SUV range is linearly dependent with single fraction dose,so this method also can be used in the hyper-fraction treatment plan.« less

Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum.

PubMed

Colín-Lozano, Blanca; León-Rivera, Ismael; Chan-Bacab, Manuel Jesús; Ortega-Morales, Benjamín Otto; Moo-Puc, Rosa; López-Guerrero, Vanessa; Hernández-Núñez, Emanuel; Argüello-Garcia, Raúl; Scior, Thomas; Barbosa-Cabrera, Elizabeth; Navarrete-Vázquez, Gabriel

2017-08-01

We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC 50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC 50 of 0.145μM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709μg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Mead, H; St. Jude Children’s Research Hospital, Memphis, TN; Brady, S

Purpose: To discover if a previously published methodology for estimating patient-specific organ dose in a pediatric population (5–55kg) is translatable to the adult sized patient population (> 55 kg). Methods: An adult male anthropomorphic phantom was scanned with metal oxide semiconductor field effect transistor (MOSFET) dosimeters placed at 23 organ locations in the chest and abdominopelvic regions to determine absolute organ dose. Organ-dose-to-SSDE correlation factors were developed by dividing individual phantom organ doses by SSDE of the phantom; where SSDE was calculated at the center of the scan volume of the chest and abdomen/pelvis separately. Organ dose correlation factors developedmore » in phantom were multiplied by 28 chest and 22 abdominopelvic patient SSDE values to estimate organ dose. The median patient weight from the CT examinations was 68.9 kg (range 57–87 kg) and median age was 17 years (range 13–28 years). Calculated organ dose estimates were compared to published Monte Carlo simulated patient and phantom results. Results: Organ-dose-to-SSDE correlation was determined for a total of 23 organs in the chest and abdominopelvic regions. For organs fully covered by the scan volume, correlation in the chest (median 1.3; range 1.1–1.5) and abdominopelvic (median 0.9; range 0.7–1.0) was 1.0 ± 10%. For organs that extended beyond the scan volume (i.e. skin bone marrow and bone surface) correlation was determined to be a median of 0.3 (range 0.1–0.4). Calculated patient organ dose using patient SSDE agreed to better than 6% (chest) and 15% (abdominopelvic) to published values. Conclusion: This study demonstrated that our previous published methodology for calculating organ dose using patient-specific SSDE for the chest and abdominopelvic regions is translatable to adult sized patients for organs fully covered by the scan volume.« less

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

PubMed

Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

2017-02-01

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max ) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2 ) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-last ), and maximum plasma concentration (C max ) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

Dose calculation algorithm of fast fine-heterogeneity correction for heavy charged particle radiotherapy.

PubMed

Kanematsu, Nobuyuki

2011-04-01

This work addresses computing techniques for dose calculations in treatment planning with proton and ion beams, based on an efficient kernel-convolution method referred to as grid-dose spreading (GDS) and accurate heterogeneity-correction method referred to as Gaussian beam splitting. The original GDS algorithm suffered from distortion of dose distribution for beams tilted with respect to the dose-grid axes. Use of intermediate grids normal to the beam field has solved the beam-tilting distortion. Interplay of arrangement between beams and grids was found as another intrinsic source of artifact. Inclusion of rectangular-kernel convolution in beam transport, to share the beam contribution among the nearest grids in a regulatory manner, has solved the interplay problem. This algorithmic framework was applied to a tilted proton pencil beam and a broad carbon-ion beam. In these cases, while the elementary pencil beams individually split into several tens, the calculation time increased only by several times with the GDS algorithm. The GDS and beam-splitting methods will complementarily enable accurate and efficient dose calculations for radiotherapy with protons and ions. Copyright © 2010 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

PubMed Central

Kuempel, Eileen D.; Sweeney, Lisa M.; Morris, John B.; Jarabek, Annie M.

2015-01-01

The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates. PMID:26551218

Dosimetric properties of a proton beamline dedicated to the treatment of ocular disease

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

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

2014-01-15

Purpose: A commercial proton eyeline has been developed to treat ocular disease. Radiotherapy of intraocular lesions (e.g., uveal melanoma, age-related macular degeneration) requires sharp dose gradients to avoid critical structures like the macula and optic disc. A high dose rate is needed to limit patient gazing times during delivery of large fractional dose. Dose delivery needs to be accurate and predictable, not in the least because current treatment planning algorithms have limited dose modeling capabilities. The purpose of this paper is to determine the dosimetric properties of a new proton eyeline. These properties are compared to those of existing systemsmore » and evaluated in the context of the specific clinical requirements of ocular treatments. Methods: The eyeline is part of a high-energy, cyclotron-based proton therapy system. The energy at the entrance of the eyeline is 105 MeV. A range modulator (RM) wheel generates the spread-out Bragg peak, while a variable range shifter system adjusts the range and spreads the beam laterally. The range can be adjusted from 0.5 up to 3.4 g/cm{sup 2}; the modulation width can be varied in steps of 0.3 g/cm{sup 2} or less. Maximum field diameter is 2.5 cm. All fields can be delivered with a dose rate of 30 Gy/min or more. The eyeline is calibrated according to the IAEA TRS-398 protocol using a cylindrical ionization chamber. Depth dose distributions and dose/MU are measured with a parallel-plate ionization chamber; lateral profiles with radiochromic film. The dose/MU is modeled as a function of range, modulation width, and instantaneous MU rate with fit parameters determined per option (RM wheel). Results: The distal fall-off of the spread-out Bragg peak is 0.3 g/cm{sup 2}, larger than for most existing systems. The lateral penumbra varies between 0.9 and 1.4 mm, except for fully modulated fields that have a larger penumbra at skin. The source-to-axis distance is found to be 169 cm. The dose/MU shows a strong dependence on range (up to 4%/mm). A linear increase in dose/MU as a function of instantaneous MU rate is observed. The dose/MU model describes the measurements with an accuracy of ±2%. Neutron dose is found to be 146 ± 102 μSv/Gy at the contralateral eye and 19 ± 13 μSv/Gy at the chest. Conclusions: Measurements show the proton eyeline meets the requirements to effectively treat ocular disease.« less

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

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

Purpose: A commercial proton eyeline has been developed to treat ocular disease. Radiotherapy of intraocular lesions (e.g., uveal melanoma, age-related macular degeneration) requires sharp dose gradients to avoid critical structures like the macula and optic disc. A high dose rate is needed to limit patient gazing times during delivery of large fractional dose. Dose delivery needs to be accurate and predictable, not in the least because current treatment planning algorithms have limited dose modeling capabilities. The purpose of this paper is to determine the dosimetric properties of a new proton eyeline. These properties are compared to those of existing systemsmore » and evaluated in the context of the specific clinical requirements of ocular treatments. Methods: The eyeline is part of a high-energy, cyclotron-based proton therapy system. The energy at the entrance of the eyeline is 105 MeV. A range modulator (RM) wheel generates the spread-out Bragg peak, while a variable range shifter system adjusts the range and spreads the beam laterally. The range can be adjusted from 0.5 up to 3.4 g/cm{sup 2}; the modulation width can be varied in steps of 0.3 g/cm{sup 2} or less. Maximum field diameter is 2.5 cm. All fields can be delivered with a dose rate of 30 Gy/min or more. The eyeline is calibrated according to the IAEA TRS-398 protocol using a cylindrical ionization chamber. Depth dose distributions and dose/MU are measured with a parallel-plate ionization chamber; lateral profiles with radiochromic film. The dose/MU is modeled as a function of range, modulation width, and instantaneous MU rate with fit parameters determined per option (RM wheel). Results: The distal fall-off of the spread-out Bragg peak is 0.3 g/cm{sup 2}, larger than for most existing systems. The lateral penumbra varies between 0.9 and 1.4 mm, except for fully modulated fields that have a larger penumbra at skin. The source-to-axis distance is found to be 169 cm. The dose/MU shows a strong dependence on range (up to 4%/mm). A linear increase in dose/MU as a function of instantaneous MU rate is observed. The dose/MU model describes the measurements with an accuracy of ±2%. Neutron dose is found to be 146 ± 102 μSv/Gy at the contralateral eye and 19 ± 13 μSv/Gy at the chest. Conclusions: Measurements show the proton eyeline meets the requirements to effectively treat ocular disease.« less

SU-E-J-11: Measurement of Eye Lens Dose for Varian On-Board Imaging with Different CBCT Acquisition Techniques

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

Deshpande, S; Dhote, D; Kumar, R

Purpose: To measure actual patient eye lens dose for different cone beam computed tomography (CBCT) acquisition protocol of Varian’s On Board Imagining (OBI) system using Optically Stimulated Luminescence (OSL) dosimeter and study the eye lens dose with patient geometry and distance of isocenter to the eye lens Methods: OSL dosimeter was used to measure eye lens dose of patient. OSL dosimeter was placed on patient forehead center during CBCT image acquisition to measure eye lens dose. For three different cone beam acquisition protocol (standard dose head, low dose head and high quality head) of Varian On-Board Imaging, eye lens dosesmore » were measured. Measured doses were correlated with patient geometry and distance between isocenter to eye lens. Results: Measured eye lens dose for standard dose head was in the range of 1.8 mGy to 3.2 mGy, for high quality head protocol dose was in range of 4.5mGy to 9.9 mGy whereas for low dose head was in the range of 0.3mGy to 0.7mGy. Dose to eye lens is depends upon position of isocenter. For posterioraly located tumor eye lens dose is less. Conclusion: From measured doses it can be concluded that by proper selection of imagining protocol and frequency of imaging, it is possible to restrict the eye lens dose below the new limit set by ICRP. However, undoubted advantages of imaging system should be counter balanced by careful consideration of imaging protocol especially for very intense imaging sequences for Adoptive Radiotherapy or IMRT.« less

Real-Time Patient and Staff Radiation Dose Monitoring in IR Practice

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

Sailer, Anna M., E-mail: karmanna@stanford.edu; Paulis, Leonie, E-mail: leonie.paulis@mumc.nl; Vergoossen, Laura

PurposeKnowledge of medical radiation exposure permits application of radiation protection principles. In our center, the first dedicated real-time, automated patient and staff dose monitoring system (DoseWise Portal, Philips Healthcare) was installed. Aim of this study was to obtain insight in the procedural and occupational doses.Materials and MethodsAll interventional radiologists, vascular surgeons, and technicians wore personal dose meters (PDMs, DoseAware, Philips Healthcare). The dose monitoring system simultaneously registered for each procedure dose-related data as the dose area product (DAP) and effective staff dose (E) from PDMs. Use and type of shielding were recorded separately. All procedures were analyzed according to proceduremore » type; these included among others cerebral interventions (n = 112), iliac and/or caval venous recanalization procedures (n = 68), endovascular aortic repair procedures (n = 63), biliary duct interventions (n = 58), and percutaneous gastrostomy procedure (n = 28).ResultsMedian (±IQR) DAP doses ranged from 2.0 (0.8–3.1) (percutaneous gastrostomy) to 84 (53–147) Gy cm{sup 2} (aortic repair procedures). Median (±IQR) first operator doses ranged from 1.6 (1.1–5.0) μSv to 33.4 (12.1–125.0) for these procedures, respectively. The relative exposure, determined as first operator dose normalized to procedural DAP, ranged from 1.9 in biliary interventions to 0.1 μSv/Gy cm{sup 2} in cerebral interventions, indicating large variation in staff dose per unit DAP among the procedure types.ConclusionReal-time dose monitoring was able to identify the types of interventions with either an absolute or relatively high staff dose, and may allow for specific optimization of radiation protection.« less

Correlation of Radiation Dose Estimates by DIC with the METREPOL Hematological Classes of Disease Severity.

PubMed

Port, M; Pieper, B; Dörr, H D; Hübsch, A; Majewski, M; Abend, M

2018-05-01

The degree of severity of hematologic acute radiation syndrome (HARS) may vary across the range of radiation doses, such that dose alone may be a less reliable predictor of clinical course. We sought to elucidate the relationship between absorbed dose and risk of clinically relevant HARS in humans. We used the database SEARCH (System for Evaluation and Archiving of Radiation Accidents based on Case Histories), which contains the histories of radiation accident victims. From 153 cases we extracted data on dose estimates using the dicentric assay to measure individual biological dosimetry. The data were analyzed according to the corresponding hematological response categories of clinical significance (H1-4). These categories are derived from the medical treatment protocols for radiation accident victims (METREPOL) and represent the clinical outcome of HARS based on severity categories ranging from 1-4. In addition, the category H0 represents a post-exposure hematological response that is within the normal range for nonexposed individuals. Age at exposure, gender and ethnicity were considered as potential confounders in unconditional cumulative logistic regression analysis. In most cases, victims were Caucasian (82.4%) and male (92.8%), who originated from either the Chernobyl (69.3%) or Goiânia (10.5%) accident, and nearly 60% were aged 20-40 years at time of exposure. All individuals were whole-body exposed (mean 3.8 Gy, stdev ±3.1), and single exposures were predominantly reported (79%). Seventy percent of victims in category H0 were exposed to ≤1 Gy, with rapidly decreasing proportions of H0 seen at doses up to 5 Gy. There were few HARS H4 cases reported at exposed dose of 1-2 Gy, while 82% of H4 cases received doses of >5 Gy. HARS H1-3 cases varied among dose ranges from 1-5 Gy. In summary, single whole-body radiation doses <1 Gy and >5 Gy corresponded in general with H0 and H3-4, respectively, and this was consistent with medical expectations. This underlines the usefulness of dose estimates for HARS prediction. However, whole-body doses between 1-5 Gy poorly corresponded to HARS H1-3. The dose range of 1-5 Gy was of limited value for medical decision-making regarding, e.g., hospitalization for H2-3, but not H1 and treatment decisions that differ between H1-3. Also, there were some H0 cases at high doses and H2-4 cases at low doses, thereby challenging an individual recommendation based solely on dose.

An end-to-end assessment of range uncertainty in proton therapy using animal tissues.

PubMed

Zheng, Yuanshui; Kang, Yixiu; Zeidan, Omar; Schreuder, Niek

2016-11-21

Accurate assessment of range uncertainty is critical in proton therapy. However, there is a lack of data and consensus on how to evaluate the appropriate amount of uncertainty. The purpose of this study is to quantify the range uncertainty in various treatment conditions in proton therapy, using transmission measurements through various animal tissues. Animal tissues, including a pig head, beef steak, and lamb leg, were used in this study. For each tissue, an end-to-end test closely imitating patient treatments was performed. This included CT scan simulation, treatment planning, image-guided alignment, and beam delivery. Radio-chromic films were placed at various depths in the distal dose falloff region to measure depth dose. Comparisons between measured and calculated doses were used to evaluate range differences. The dose difference at the distal falloff between measurement and calculation depends on tissue type and treatment conditions. The estimated range difference was up to 5, 6 and 4 mm for the pig head, beef steak, and lamb leg irradiation, respectively. Our study shows that the TPS was able to calculate proton range within about 1.5% plus 1.5 mm. Accurate assessment of range uncertainty in treatment planning would allow better optimization of proton beam treatment, thus fully achieving proton beams' superior dose advantage over conventional photon-based radiation therapy.

BLACK HOLE MASS AND EDDINGTON RATIO DISTRIBUTION FUNCTIONS OF X-RAY-SELECTED BROAD-LINE AGNs AT z {approx} 1.4 IN THE SUBARU XMM-NEWTON DEEP FIELD

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

Nobuta, K.; Akiyama, M.; Ueda, Y.

2012-12-20

In order to investigate the growth of supermassive black holes (SMBHs), we construct the black hole mass function (BHMF) and Eddington ratio distribution function (ERDF) of X-ray-selected broad-line active galactic nuclei (AGNs) at z {approx} 1.4 in the Subaru XMM-Newton Deep Survey (SXDS) field. A significant part of the accretion growth of SMBHs is thought to take place in this redshift range. Black hole masses of X-ray-selected broad-line AGNs are estimated using the width of the broad Mg II line and 3000 A monochromatic luminosity. We supplement the Mg II FWHM values with the H{alpha} FWHM obtained from our NIRmore » spectroscopic survey. Using the black hole masses of broad-line AGNs at redshifts between 1.18 and 1.68, the binned broad-line AGN BHMFs and ERDFs are calculated using the V{sub max} method. To properly account for selection effects that impact the binned estimates, we derive the corrected broad-line AGN BHMFs and ERDFs by applying the maximum likelihood method, assuming that the ERDF is constant regardless of the black hole mass. We do not correct for the non-negligible uncertainties in virial BH mass estimates. If we compare the corrected broad-line AGN BHMF with that in the local universe, then the corrected BHMF at z = 1.4 has a higher number density above 10{sup 8} M{sub Sun} but a lower number density below that mass range. The evolution may be indicative of a downsizing trend of accretion activity among the SMBH population. The evolution of broad-line AGN ERDFs from z = 1.4 to 0 indicates that the fraction of broad-line AGNs with accretion rates close to the Eddington limit is higher at higher redshifts.« less

Methods for Probabilistic Radiological Dose Assessment at a High-Level Radioactive Waste Repository.

NASA Astrophysics Data System (ADS)

Maheras, Steven James

Methods were developed to assess and evaluate the uncertainty in offsite and onsite radiological dose at a high-level radioactive waste repository to show reasonable assurance that compliance with applicable regulatory requirements will be achieved. Uncertainty in offsite dose was assessed by employing a stochastic precode in conjunction with Monte Carlo simulation using an offsite radiological dose assessment code. Uncertainty in onsite dose was assessed by employing a discrete-event simulation model of repository operations in conjunction with an occupational radiological dose assessment model. Complementary cumulative distribution functions of offsite and onsite dose were used to illustrate reasonable assurance. Offsite dose analyses were performed for iodine -129, cesium-137, strontium-90, and plutonium-239. Complementary cumulative distribution functions of offsite dose were constructed; offsite dose was lognormally distributed with a two order of magnitude range. However, plutonium-239 results were not lognormally distributed and exhibited less than one order of magnitude range. Onsite dose analyses were performed for the preliminary inspection, receiving and handling, and the underground areas of the repository. Complementary cumulative distribution functions of onsite dose were constructed and exhibited less than one order of magnitude range. A preliminary sensitivity analysis of the receiving and handling areas was conducted using a regression metamodel. Sensitivity coefficients and partial correlation coefficients were used as measures of sensitivity. Model output was most sensitive to parameters related to cask handling operations. Model output showed little sensitivity to parameters related to cask inspections.

Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?

PubMed Central

Day, Troy; Read, Andrew F.

2016-01-01

High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients. PMID:26820986

Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?

PubMed

Day, Troy; Read, Andrew F

2016-01-01

High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients.

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

PubMed

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J

2009-01-01

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

Acid-fast Smear and Histopathology Results Provide Guidance for the Appropriate Use of Broad-Range Polymerase Chain Reaction and Sequencing for Mycobacteria.

PubMed

Miller, Kennon; Harrington, Susan M; Procop, Gary W

2015-08-01

New molecular diagnostic tests are attractive because of the potential they hold for improving diagnostics in microbiology. The value of these tests, which is often assumed, should be investigated to determine the best use of these potentially powerful tools. To investigate the usefulness of broad-range polymerase chain reaction (PCR), followed by sequencing, in mycobacterial infections. We reviewed the test performance of acid-fast bacilli (AFB) PCR and traditional diagnostic methods (histopathology, AFB smear, and culture). We assessed the diagnostic effect and cost of the unrestricted ordering of broad-range PCR for the detection and identification of mycobacteria in clinical specimens. The AFB PCR was less sensitive than culture and histopathology and was less specific than culture, AFB smear, and histopathology. During 18 months, $93 063 was spent on 183 patient specimens for broad-range PCR and DNA sequencing for mycobacteria to confirm one culture-proven Mycobacterium tuberculosis infection that was also known to be positive by AFB smear and histopathology. In this cohort, there was a false-negative AFB PCR for M tuberculosis and a false-positive AFB PCR for Mycobacterium lentiflavum . Testing of AFB smear-negative specimens from patients without an inflammatory response supportive of a mycobacterial infection is costly and has not been proven to improve patient care. Traditional diagnostics (histopathology, AFB smear, and culture) should remain the primary methods for the detection of mycobacteria in clinical specimens.

Genetics and variation

Treesearch

John R. Jones; Norbert V. DeByle

1985-01-01

The broad genotypic variability in quaking aspen (Populus tremuloides Michx.), that results in equally broad phenotypic variability among clones is important to the ecology and management of this species. This chapter considers principles of aspen genetics and variation, variation in aspen over its range, and local variation among clones. For a more...

Stability and broad-sense heritaibility of mineral content in potato: copper and sulfur

USDA-ARS?s Scientific Manuscript database

Potato breeding lines and varieties in two separate trials were evaluated for copper and sulfur content by wet ashing and Inductively Coupled Argon Plasma Emission Spectrophotometer analysis. Stability and broad-sense heritability were determined. Copper contents ranged among genotypes between 2.0...

SU-F-J-197: A Novel Intra-Beam Range Detection and Adaptation Strategy for Particle Therapy

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

Chen, M; Jiang, S; Shao, Y

2016-06-15

Purpose: In-vivo range detection/verification is crucial in particle therapy for effective and safe delivery. The state-of-art techniques are not sufficient for in-vivo on-line range verification due to conflicts among patient dose, signal statistics and imaging time. We propose a novel intra-beam range detection and adaptation strategy for particle therapy. Methods: This strategy uses the planned mid-range spots as probing beams without adding extra radiation to patients. Such choice of probing beams ensures the Bragg peaks to remain inside the tumor even with significant range variation from the plan. It offers sufficient signal statistics for in-beam positron emission tomography (PET) duemore » to high positron activity of therapeutic dose. The probing beam signal can be acquired and reconstructed using in-beam PET that allows for delineation of the Bragg peaks and detection of range shift with ease of detection enabled by single-layered spots. If the detected range shift is within a pre-defined tolerance, the remaining spots will be delivered as the original plan. Otherwise, a fast re-optimization using range-shifted beamlets and accounting for the probing beam dose is applied to consider the tradeoffs posed by the online anatomy. Simulated planning and delivery studies were used to demonstrate the effectiveness of the proposed techniques. Results: Simulations with online range variations due to shifts of various foreign objects into the beam path showed successful delineation of the Bragg peaks as a result of delivering probing beams. Without on-line delivery adaptation, dose distribution was significantly distorted. In contrast, delivery adaptation incorporating detected range shift recovered well the planned dose. Conclusion: The proposed intra-beam range detection and adaptation utilizing the planned mid-range spots as probing beams, which illuminate the beam range with strong and accurate PET signals, is a safe, practical, yet effective approach to address range uncertainty issues in particle therapy.« less

Acute behavioral and EEG effects of NW-1015 on electrically-induced afterdischarge in conscious monkeys.

PubMed

Fariello, R G; Maj, R; Marrari, P; Beard, D; Algate, C; Salvati, P

2000-03-01

NW-1015 is a novel Na+ and Ca2+ channel blocker with broad spectrum anticonvulsant activity and an excellent safety margin. As the compound also shows sigma-1 receptor ligand properties it was deemed important to determine whether it possesses anticonvulsant properties in primates without causing behavioral and EEG abnormalities. Thus, the effects of NW-1015 on limbic electrically-induced afterdischarge (AD) were evaluated in four cynomolgus monkeys, and its activity compared to a single effective dose of phenytoin (PHT). The four male cynomolgus monkeys were chronically implanted for EEG recordings, from cortex and limbic structures. AD was induced in limbic areas by electrical stimulation. The effects of NW-1015 on the duration and the behavioral component of the AD were randomly tested at doses from 25 to 75 mg/kg and compared with the effects of PHT 50 mg/kg. Similarly to PHT, 50 mg/kg of NW-1015 significantly shortened the EEG AD and almost abolished AD elicited behavioral seizure. Only the behavioral effects of AD were reduced after administration of 25 mg/kg p.o. NW-1015 did not cause EEG or interictal behavioral alterations at doses up to 75 mg/kg p.o. These data further confirm the broad-spectrum anticonvulsant activity and a good safety profile of NW-1015 even in a primate model of complex partial seizures and suggest that its affinity for sigma-1 receptors is behaviorally irrelevant.

Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose.

PubMed

Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro

2015-12-28

Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Phytosanitary Irradiation

PubMed Central

Hallman, Guy J.; Blackburn, Carl M.

2016-01-01

Phytosanitary treatments disinfest traded commodities of potential quarantine pests. Phytosanitary irradiation (PI) treatments use ionizing radiation to accomplish this, and, since their international commercial debut in 2004, the use of this technology has increased by ~10% annually. Generic PI treatments (one dose is used for a group of pests and/or commodities, although not all have been tested for efficacy) are used in virtually all commercial PI treatments, and new generic PI doses are proposed, such as 300 Gy, for all insects except pupae and adult Lepidoptera (moths). Fresh fruits and vegetables tolerate PI better than any other broadly used treatment. Advances that would help facilitate the use of PI include streamlining the approval process, making the technology more accessible to potential users, lowering doses and broadening their coverage, and solving potential issues related to factors that might affect efficacy. PMID:28231103

Variation in Prescribing Patterns and Therapeutic Drug Monitoring of Intravenous Busulfan in Pediatric Hematopoietic Cell Transplant Recipients

PubMed Central

McCune, Jeannine S.; Baker, K. Scott; Blough, David K.; Gamis, Alan; Bemer, Meagan J.; Kelton-Rehkopf, Megan C.; Winter, Laura; Barrett, Jeffrey S.

2016-01-01

Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors’ group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children. PMID:23444282

The impact of different algorithms for ideal body weight on screening for hydroxychloroquine retinopathy in women.

PubMed

Browning, David J; Lee, Chong; Rotberg, David

2014-01-01

To determine how algorithms for ideal body weight (IBW) affect hydroxychloroquine dosing in women. This was a retrospective study of 520 patients screened for hydroxychloroquine retinopathy. Charts were reviewed for sex, height, weight, and daily dose. The outcome measures were ranges of IBW across algorithms; rates of potentially toxic dosing; height thresholds below which 400 mg/d dosing is potentially toxic; and rates for which actual body weight (ABW) was less than IBW. Women made up 474 (91%) of the patients. The IBWs for a height varied from 30-34 pounds (13.6-15.5 kg) across algorithms. The threshold heights below which toxic dosing occurred varied from 62-70 inches (157.5-177.8 cm). Different algorithms placed 16%-98% of women in the toxic dosing range. The proportion for whom dosing should have been based on ABW rather than IBW ranged from 5%-31% across algorithms. Although hydroxychloroquine dosing should be based on the lesser of ABW and IBW, there is no consensus about the definition of IBW. The Michaelides algorithm is associated with the most frequent need to adjust dosing; the Metropolitan Life Insurance, large frame, mean value table with the least frequent need. No evidence indicates that one algorithm is superior to others.

A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases

NASA Astrophysics Data System (ADS)

Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Murray, Iain; Divoli, Antigoni; McCready, V. Ralph; Dearnaley, David P.; O'Sullivan, Joe M.; Johnson, Bernadette; Flux, Glenn D.

2017-04-01

Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83-105 Gy), whilst a median of 183 Gy (interquartile range: 107-247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r  =  0.98, P  <  0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden.

Food irradiation dosimetry by opti-chromic technique

NASA Astrophysics Data System (ADS)

Zhan-Jun, Liu; Radak, B. B.; McLaughlin, W. L.

The measurement of gamma-radiation quantities, e.g., absorbed dose in materials such as water, plastics, foodstuffs, is a convenient means of quality assurance in radiation processing. A new dosimetry system, called the "Opti-Chromic" dosimeter, is commercially available in large batches for use as a routine measurement system in the absorbed dose range 10 to 2x10 4 Gy. This dose range covers most food irradiation applications. A statistical evaluation was made of the reproducibility of this dosimeter for measuring doses appropriate for the disinfestation and shelf-life extension of many foods, namely 10 to 2x10 3 Gy. In addition, the small dosimeters were used to map absorbed dose distributions in boxes of foods having four different bulk densities (grapefruit, lemons, peanuts, and wheat bran). It is demonstrated that the dosimeters are rugged and stable enough to be used over a wide temperature and humidity range, and, in fact, can be placed in such environments as the inside of citrus fruits without adverse effects on their ability to give satisfactory dose assessment.

Effects of perfluorooctane sulfonate on genes controlling hepatic fatty acid metabolism in livers of chicken embryos.

PubMed

Jacobsen, Annette V; Nordén, Marcus; Engwall, Magnus; Scherbak, Nikolai

2018-06-02

Per- and polyfluoroalkyl substances (PFAS) are synthetic surfactants with a wide variety of applications; however, due to their stability, they are particularly resistant to degradation and, as such, are classed as persistent organic pollutants. Perfluorooctane sulfonate (PFOS) is one such PFAS that is still detectable in a range of different environmental settings, despite its use now being regulated in numerous countries. Elevated levels of PFOS have been detected in various avian species, and the impact of this on avian health is of interest when determining acceptable levels of PFOS in the environment. Due to its similarities to naturally occurring fatty acids, PFOS has potential to disrupt a range of biological pathways, particularly those associated with lipid metabolism, and this has been shown in various species. In this study, we have investigated how in ovo exposure to environmentally relevant levels of PFOS affects expression of genes involved in lipid metabolism of developing chicken embryos. We have found a broad suppression of transcription of genes involved in fatty acid oxidation and PPAR-mediated transcription with more significant effects apparent at lower doses of PFOS. These results highlight the need for more research investigating the biological impacts of low levels of PFAS to properly inform environmental policy governing their regulation.

A Haloalkane Dehalogenase from a Marine Microbial Consortium Possessing Exceptionally Broad Substrate Specificity.

PubMed

Buryska, Tomas; Babkova, Petra; Vavra, Ondrej; Damborsky, Jiri; Prokop, Zbynek

2018-01-15

The haloalkane dehalogenase enzyme DmmA was identified by marine metagenomic screening. Determination of its crystal structure revealed an unusually large active site compared to those of previously characterized haloalkane dehalogenases. Here we present a biochemical characterization of this interesting enzyme with emphasis on its structure-function relationships. DmmA exhibited an exceptionally broad substrate specificity and degraded several halogenated environmental pollutants that are resistant to other members of this enzyme family. In addition to having this unique substrate specificity, the enzyme was highly tolerant to organic cosolvents such as dimethyl sulfoxide, methanol, and acetone. Its broad substrate specificity, high overexpression yield (200 mg of protein per liter of cultivation medium; 50% of total protein), good tolerance to organic cosolvents, and a broad pH range make DmmA an attractive biocatalyst for various biotechnological applications. IMPORTANCE We present a thorough biochemical characterization of the haloalkane dehalogenase DmmA from a marine metagenome. This enzyme with an unusually large active site shows remarkably broad substrate specificity, high overexpression, significant tolerance to organic cosolvents, and activity under a broad range of pH conditions. DmmA is an attractive catalyst for sustainable biotechnology applications, e.g., biocatalysis, biosensing, and biodegradation of halogenated pollutants. We also report its ability to convert multiple halogenated compounds to corresponding polyalcohols. Copyright © 2018 American Society for Microbiology.

Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia.

PubMed

Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Turncliff, Ryan Z; Citrome, Leslie

2017-06-01

Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Retrospective cohort study of bronchial doses and radiation-induced atelectasis after stereotactic body radiation therapy of lung tumors located close to the bronchial tree.

PubMed

Karlsson, Kristin; Nyman, Jan; Baumann, Pia; Wersäll, Peter; Drugge, Ninni; Gagliardi, Giovanna; Johansson, Karl-Axel; Persson, Jan-Olov; Rutkowska, Eva; Tullgren, Owe; Lax, Ingmar

2013-11-01

To evaluate the dose-response relationship between radiation-induced atelectasis after stereotactic body radiation therapy (SBRT) and bronchial dose. Seventy-four patients treated with SBRT for tumors close to main, lobar, or segmental bronchi were selected. The association between incidence of atelectasis and bronchial dose parameters (maximum point-dose and minimum dose to the high-dose bronchial volume [ranging from 0.1 cm(3) up to 2.0 cm(3)]) was statistically evaluated with survival analysis models. Prescribed doses varied between 4 and 20 Gy per fraction in 2-5 fractions. Eighteen patients (24.3%) developed atelectasis considered to be radiation-induced. Statistical analysis showed a significant correlation between the incidence of radiation-induced atelectasis and minimum dose to the high-dose bronchial volumes, of which 0.1 cm(3) (D(0.1cm3)) was used for further analysis. The median value of D(0.1cm3) (α/β = 3 Gy) was EQD(2,LQ) = 147 Gy3 (range, 20-293 Gy3). For patients who developed atelectasis the median value was EQD(2,LQ) = 210 Gy3, and for patients who did not develop atelectasis, EQD(2,LQ) = 105 Gy3. Median time from treatment to development of atelectasis was 8.0 months (range, 1.1-30.1 months). In this retrospective study a significant dose-response relationship between the incidence of atelectasis and the dose to the high-dose volume of the bronchi is shown. Copyright © 2013 Elsevier Inc. All rights reserved.

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

SU-E-T-616: Comparison of Plan Dose Accuracy for Anterior Vs. Lateral Fields in Proton Therapy of Prostate Cancer

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

Moteabbed, M; Trofimov, A; Testa, M

2014-06-01

Purpose: With the anticipated introduction of in vivo range verification methods, the use of anterior fields for proton therapy of prostate cancer may become an attractive treatment option, and improve upon the dose distributions achievable with conventional lateral-opposed fields. This study aimed to evaluate and compare the planned dose accuracy for lateral versus anterior oblique field arrangements. Methods: Four patients with low/intermediate risk prostate cancer, participating in a clinical trial at our institution, were selected for this study. All patients were treated using lateral-opposed fields (LAT). The clinical target volume (CTV) received a total dose of 79.2 Gy in 44more » fractions. Anterior oblique research plans (ANT) were created using the clinical planning system, and featured beams with ±35-degree gantry angle, 1.2 cm aperture margins, 3-mm range compensator smearing and no range uncertainty margins. Monte Carlo (MC) simulations were performed for both beam arrangements using TOPAS. Dose volume histograms were analyzed and compared for planned and MC dose distributions. Differences between MC and planned DVH parameters were computed as a percentage of the total prescribed dose. Results: For all patients, CTV dose was systematically lower (∼2–2.5%) for MC than the plan. This discrepancy was slightly larger (∼0.5%) for LAT compared to ANT plans for all cases. Although the dose differences for bladder and anterior rectal wall remained within 0.7% for all LAT cases, they were slightly larger for ANT plans, especially for case 3 due to larger patient size and MC-plan range difference. The EUD difference for femoral heads was within 0.6% for both LAT and ANT cases. Conclusion: The dose calculated by the treatment planning system using pencil beam algorithm agrees with MC to within 2.5% and is comparable for lateral and anterior scenarios. The dose agreement in the anterior rectal wall is range- and hence, patient-dependent for ANT treatments.« less

IMRT and RapidArc commissioning of a TrueBeam linear accelerator using TG-119 protocol cases.

PubMed

Wen, Ning; Zhao, Bo; Kim, Jinkoo; Chin-Snyder, Karen; Bellon, Maria; Glide-Hurst, Carri; Barton, Kenneth; Chen, Daiquan; Chetty, Indrin J

2014-09-08

The purpose of this study is to evaluate the overall accuracy of intensity-modulated radiation therapy (IMRT) and RapidArc delivery using both flattening filter (FF) and flattening filter-free (FFF) modalities based on test cases developed by AAPM Task Group 119. Institutional confidence limits (CLs) were established as the baseline for patient specific treatment plan quality assurance (QA). The effects of gantry range, gantry speed, leaf speed, dose rate, as well as the capability to capture intentional errors, were evaluated by measuring a series of Picket Fence (PF) tests using the electronic portal imaging device (EPID) and EBT3 films. Both IMRT and RapidArc plans were created in a Solid Water phantom (30 × 30 × 15 cm3) for the TG-119 test cases representative of normal clinical treatment sites for all five photon energies (6X, 10X, 15X, 6X-FFF, 10X-FFF) and the Exact IGRT couch was included in the dose calculation. One high-dose point in the PTV and one low-dose point in the avoidance structure were measured with an ion chamber in each case for each energy. Similarly, two GAFCHROMIC EBT3 films were placed in the coronal planes to measure planar dose distributions in both high- and low-dose regions. The confidence limit was set to have 95% of the measured data fall within the tolerance. The mean of the absolute dose deviation for variable dose rate and gantry speed during RapidArc delivery was within 0.5% for all energies. The corresponding results for leaf speed tests were all within 0.4%. The combinations of dynamic leaf gap (DLG) and MLC transmission factor were optimized based on the ion chamber measurement results of RapidArc delivery for each energy. The average 95% CLs for the high-dose point in the PTV were 0.030 ± 0.007 (range, 0.022-0.038) for the IMRT plans and 0.029 ± 0.011 (range, 0.016-0.043) for the RapidArc plans. For low-point dose in the avoidance structures, the CLs were 0.029 ± 0.006 (range, 0.024-0.039) for the IMRT plans and 0.027 ± 0.013 (range, 0.017-0.047) for the RapidArc plans. The average 95% CLs using 3%/3 mm gamma criteria in the high-dose region were 5.9 ± 2.7 (range, 1.4-8.6) and 3.9 ± 2.9 (range, 1.5-8.8) for IMRT and RapidArc plans, respectively. The average 95% CLs in the low-dose region were 5.3 ± 2.6 (range, 1.2-7.4) and 3.7 ± 2.8 (range, 1.8-8.3) for IMRT and RapidArc plans, respectively. Based on ion chamber, as well as film measurements, we have established CLs values to ensure the high precision of IMRT and RapidArc delivery for both FF and FFF modalities.

Selection of common bean to broad environmental adaptation in Haiti

USDA-ARS?s Scientific Manuscript database

Common bean (Phaseolus vulgaris L.) cultivars in Haiti need adaptation to a broad range of environments and resistance to the most important diseases such as Bean Golden Yellow Mosaic Virus. The Legume Breeding Program (LBP), a collaborative effort of the AREA project (USAID funded through IFAS/Univ...

Using Mixed Methods to Assess Initiatives with Broad-Based Goals

ERIC Educational Resources Information Center

Inkelas, Karen Kurotsuchi

2017-01-01

This chapter describes a process for assessing programmatic initiatives with broad-ranging goals with the use of a mixed-methods design. Using an example of a day-long teaching development conference, this chapter provides practitioners step-by-step guidance on how to implement this assessment process.

A Wider Spectrum of Opportunities.

ERIC Educational Resources Information Center

Council for Industry and Higher Education (United Kingdom).

The United Kingdom must invest in a comprehensive system of post-18 education that is broadly inclusive and that offers a broad range of educational opportunities to meet the needs of both the increasing numbers of 16-year-olds choosing to pursue postsecondary education and the many older individuals needing additional education throughout their…

SU-E-T-75: A Simple Technique for Proton Beam Range Verification

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

Burgdorf, B; Kassaee, A; Garver, E

2015-06-15

Purpose: To develop a measurement-based technique to verify the range of proton beams for quality assurance (QA). Methods: We developed a simple technique to verify the proton beam range with in-house fabricated devices. Two separate devices were fabricated; a clear acrylic rectangular cuboid and a solid polyvinyl chloride (PVC) step wedge. For efficiency in our clinic, we used the rectangular cuboid for double scattering (DS) beams and the step wedge for pencil beam scanning (PBS) beams. These devices were added to our QA phantom to measure dose points along the distal fall-off region (between 80% and 20%) in addition tomore » dose at mid-SOBP (spread out Bragg peak) using a two-dimensional parallel plate chamber array (MatriXX™, IBA Dosimetry, Schwarzenbruck, Germany). This method relies on the fact that the slope of the distal fall-off is linear and does not vary with small changes in energy. Using a multi-layer ionization chamber (Zebra™, IBA Dosimetry), percent depth dose (PDD) curves were measured for our standard daily QA beams. The range (energy) for each beam was then varied (i.e. ±2mm and ±5mm) and additional PDD curves were measured. The distal fall-off of all PDD curves was fit to a linear equation. The distal fall-off measured dose for a particular beam was used in our linear equation to determine the beam range. Results: The linear fit of the fall-off region for the PDD curves, when varying the range by a few millimeters for a specific QA beam, yielded identical slopes. The calculated range based on measured point dose(s) in the fall-off region using the slope resulted in agreement of ±1mm of the expected beam range. Conclusion: We developed a simple technique for accurately verifying the beam range for proton therapy QA programs.« less

Nitrogen-rich functional groups carbon nanoparticles based fluorescent pH sensor with broad-range responding for environmental and live cells applications.

PubMed

Shi, Bingfang; Su, Yubin; Zhang, Liangliang; Liu, Rongjun; Huang, Mengjiao; Zhao, Shulin

2016-08-15

A nitrogen-rich functional groups carbon nanoparticles (N-CNs) based fluorescent pH sensor with a broad-range responding was prepared by one-pot hydrothermal treatment of melamine and triethanolamine. The as-prepared N-CNs exhibited excellent photoluminesence properties with an absolute quantum yield (QY) of 11.0%. Furthermore, the N-CNs possessed a broad-range pH response. The linear pH response range was 3.0 to 12.0, which is much wider than that of previously reported fluorescent pH sensors. The possible mechanism for the pH-sensitive response of the N-CNs was ascribed to photoinduced electron transfer (PET). Cell toxicity experiment showed that the as-prepared N-CNs exhibited low cytotoxicity and excellent biocompatibility with the cell viabilities of more than 87%. The proposed N-CNs-based pH sensor was used for pH monitoring of environmental water samples, and pH fluorescence imaging of live T24 cells. The N-CNs is promising as a convenient and general fluorescent pH sensor for environmental monitoring and bioimaging applications. Copyright © 2016 Elsevier B.V. All rights reserved.