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Sample records for dosimetry animal model

  1. Specific issues in small animal dosimetry and irradiator calibration

    PubMed Central

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

    2013-01-01

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

  2. Dosimetry of ozone and nitrogen dioxide in man and animals

    SciTech Connect

    Overton, J.H. Jr.; Miller, F.J.

    1984-01-01

    The health effects of ozone (O/sub 3/) and nitrogen dioxide (NO/sub 2/) are assessed from animal toxicological, controlled human, and epidemiological studies. These assessments will be strengthened when results of animal studies can be quantitatively extrapolated to man. To achieve quantitative extrapolation, improvements are needed in the areas of dosimetry and species sensitivity. And, of course, an adequate health effect data base must exist on which to make extrapolations. The focus of this paper is to review the regional dosimetry of O/sub 3/ and NO/sub 2/ in the respiratory tract of man and animals. Dosimetry relates to estimating the amount of pollutant reaching a specific target region of the respiratory tract as a function of exposure concentration. At present, there are two approaches to dosimetry, experimental and mathematical modeling, which are discussed.

  3. Significance of DNA adduct studies in animal models for cancer molecular dosimetry and risk assessment.

    PubMed Central

    Beland, F A; Poirier, M C

    1993-01-01

    To elucidate the relationship between DNA adduct formation and tumorigenesis, a number of experiments have been conducted to measure DNA adducts in target tissues from experimental animals during continuous exposure to carcinogens. With aflatoxins, aromatic amines, and polycyclic aromatic hydrocarbons, tumor induction appears to be associated with the major DNA adduct detected, whereas with N-nitrosamines the response is normally correlated with minor forms of DNA damage. During continuous carcinogen administration, steady-state adduct concentrations are generally obtained in the target tissues, and there is often a linear correlation between the carcinogen concentration and the steady-state DNA adduct level. Exceptions exist when the mechanism of activation changes or with the onset of significant toxicity. Steady-state DNA adduct levels are often linearly related to the tumorigenic response. Carcinogen-induced cell proliferation occurs when significant deviations from linearity are observed. Because DNA adducts detected in humans are chemically identical to those found in experimental animals, DNA adduct data in animals may contribute to our understanding of human cancer risk. PMID:8319658

  4. Development and dosimetry of a small animal lung irradiation platform

    PubMed Central

    McGurk, Ross; Hadley, Caroline; Jackson, Isabel L.; Vujaskovic, Zeljko

    2015-01-01

    Advances in large scale screening of medical counter measures for radiation-induced normal tissue toxicity are currently hampered by animal irradiation paradigms that are both inefficient and highly variable among institutions. Here, we introduce a novel high-throughput small animal irradiation platform for use in orthovoltage small animal irradiators. We used radiochromic film and metal oxide semiconductor field effect transistor detectors to examine several parameters, including 2D field uniformity, dose rate consistency, and shielding transmission. We posit that this setup will improve efficiency of drug screens by allowing for simultaneous, targeted irradiation of multiple animals, improving efficiency within a single institution. Additionally, we suggest that measurement of the described parameters in all centers conducting counter measure studies will improve the translatability of findings among institutions. We also investigated the use of tissue equivalent phantoms in performing dosimetry measurements for small animal irradiation experiments. Though these phantoms are commonly used in dosimetry, we recorded a significant difference in both the entrance and target tissue dose rates between euthanized rats and mice with implanted detectors and the corresponding phantom measurement. This suggests that measurements using these phantoms may not provide accurate dosimetry for in vivo experiments. Based on these measurements, we propose that this small animal irradiation platform can increase the capacity of animal studies by allowing for more efficient animal irradiation. We also suggest that researchers fully characterize the parameters of whatever radiation setup is in use in order to facilitate better comparison among institutions. PMID:23091878

  5. Uranium Dispersion & Dosimetry Model.

    SciTech Connect

    MICHAEL,; MOMENI, H.

    2002-03-22

    The Uranium Dispersion and Dosimetry (UDAD) program provides estimates of potential radiation exposure to individuals and to the general population in the vicinity of a uranium processing facility such as a uranium mine or mill. Only transport through the air is considered. Exposure results from inhalation, external irradiation from airborne and ground-deposited activity, and ingestion of foodstuffs. Individual dose commitments, population dose commitments, and environmental dose commitments are computed. The program was developed for application to uranium mining and milling; however, it may be applied to dispersion of any other pollutant.

  6. Uranium Dispersion & Dosimetry Model.

    Energy Science and Technology Software Center (ESTSC)

    2002-03-22

    The Uranium Dispersion and Dosimetry (UDAD) program provides estimates of potential radiation exposure to individuals and to the general population in the vicinity of a uranium processing facility such as a uranium mine or mill. Only transport through the air is considered. Exposure results from inhalation, external irradiation from airborne and ground-deposited activity, and ingestion of foodstuffs. Individual dose commitments, population dose commitments, and environmental dose commitments are computed. The program was developed for applicationmore » to uranium mining and milling; however, it may be applied to dispersion of any other pollutant.« less

  7. Dosimetry for animals and plants: contending with biota diversity.

    PubMed

    Ulanovsky, A

    2016-06-01

    Diversity of living organisms and their environmental radiation exposure conditions represents a special challenge for non-human dosimetry. In order to contend with such diversity, the International Commission on Radiological Protection (ICRP) has: (a) set up points of reference by providing dose conversion coefficients (DCCs) for reference entities known as 'Reference Animals and Plants' (RAPs); and (b) used dosimetric models that pragmatically assume simple body shapes with uniform composition and density, homogeneous internal contamination, a limited set of idealised external radiation sources, and truncation of the radioactive decay chains. This pragmatic methodology has been further developed and extended systematically. Significant methodological changes include: a new extended approach for assessing doses of external exposure for terrestrial animals, transition to the contemporary ICRP radionuclide database, assessment-specific consideration of the contribution of radioactive progeny to dose coefficients of parent nuclides, and the use of generalised allometric relationships in the estimation of biokinetic or metabolic parameters. The new methodological developments resulted in a revision of the DCCs for RAPs. Tables of the dose coefficients have now been complemented by a web-based software tool, which can be used to calculate a user-specific DCC for an organism of arbitrary mass and shape, located at user-defined height above the ground, and for an arbitrary radionuclide and its radioactive progeny. PMID:26984904

  8. Dosimetry modeling of inhaled toxic reactive gases

    SciTech Connect

    Overton, J.H.; Miller, F.J.

    1986-07-01

    This report focuses on the physical, chemical, and biological processes and factors involved in the absorption of reactive gases. Emphasis is placed on the importance of these factors in developing dosimetry models, special consideration being given to the role of lung fluids and tissues. Several dosimetry models are discussed and illustrations of predicted results presented to demonstrate the application of the models to the uptake of NO/sub 2/ and O/sub 3/, and to demonstrate the use of models in determining the effects of physical, chemical and biological parameters on dosimetry predictions. Gaps in our knowledge and understanding of the processes of dosimetry are pointed out, and research recommendations are made to increase our understanding of the processes and to enhance the development of dosimetry models.

  9. INTERSPECIES DOSIMETRY MODELS FOR PULMONARY PHARMACOLOGY

    EPA Science Inventory

    Interspecies Dosimetry Models for Pulmonary Pharmacology

    Ted B. Martonen, Jeffry D. Schroeter, and John S. Fleming

    Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangl...

  10. Dosimetry for spectral molecular imaging of small animals with MARS-CT

    NASA Astrophysics Data System (ADS)

    Ganet, Noémie; Anderson, Nigel; Bell, Stephen; Butler, Anthony; Butler, Phil; Carbonez, Pierre; Cook, Nicholas; Cotterill, Tony; Marsh, Steven; Panta, Raj Kumar; Laban, John; Walker, Sophie; Yeabsley, Adam; Damet, Jérôme

    2015-03-01

    The Medipix All Resolution Scanner (MARS) spectral CT is intended for small animal, pre-clinical imaging and uses an x-ray detector (Medipix) operating in single photon counting mode. The MARS system provides spectrometric information to facilitate differentiation of tissue types and bio-markers. For longitudinal studies of disease models, it is desirable to characterise the system's dosimetry. This dosimetry study is performed using three phantoms each consisting of a 30 mm diameter homogeneous PMMA cylinder simulating a mouse. The imaging parameters used for this study are derived from those used for gold nanoparticle identification in mouse kidneys. Dosimetry measurement are obtained with thermo-luminescent Lithium Fluoride (LiF:CuMgP) detectors, calibrated in terms of air kerma and placed at different depths and orientations in the phantoms. Central axis TLD air kerma rates of 17.2 (± 0.71) mGy/min and 18.2 (± 0.75) mGy/min were obtained for different phantoms and TLD orientations. Validation measurements were acquired with a pencil ionization chamber, giving an air-kerma rate of 20.3 (±1) mGy/min and an estimated total air kerma of 81.2 (± 4) mGy for a 720 projection acquisition. It is anticipated that scanner design improvements will significantly decrease future dose requirements. The procedures developed in this work will be used for further dosimetry calculations when optimizing image acquisition for the MARS system as it undergoes development towards human clinical applications.

  11. Model selection for radiochromic film dosimetry

    NASA Astrophysics Data System (ADS)

    Méndez, I.

    2015-05-01

    The purpose of this study was to find the most accurate model for radiochromic film dosimetry by comparing different channel independent perturbation models. A model selection approach based on (algorithmic) information theory was followed, and the results were validated using gamma-index analysis on a set of benchmark test cases. Several questions were addressed: (a) whether incorporating the information of the non-irradiated film, by scanning prior to irradiation, improves the results; (b) whether lateral corrections are necessary when using multichannel models; (c) whether multichannel dosimetry produces better results than single-channel dosimetry; (d) which multichannel perturbation model provides more accurate film doses. It was found that scanning prior to irradiation and applying lateral corrections improved the accuracy of the results. For some perturbation models, increasing the number of color channels did not result in more accurate film doses. Employing Truncated Normal perturbations was found to provide better results than using Micke-Mayer perturbation models. Among the models being compared, the triple-channel model with Truncated Normal perturbations, net optical density as the response and subject to the application of lateral corrections was found to be the most accurate model. The scope of this study was circumscribed by the limits under which the models were tested. In this study, the films were irradiated with megavoltage radiotherapy beams, with doses from about 20-600 cGy, entire (8 inch  × 10 inch) films were scanned, the functional form of the sensitometric curves was a polynomial and the different lots were calibrated using the plane-based method.

  12. Animal Model of Dermatophytosis

    PubMed Central

    Shimamura, Tsuyoshi; Kubota, Nobuo; Shibuya, Kazutoshi

    2012-01-01

    Dermatophytosis is superficial fungal infection caused by dermatophytes that invade the keratinized tissue of humans and animals. Lesions from dermatophytosis exhibit an inflammatory reaction induced to eliminate the invading fungi by using the host's normal immune function. Many scientists have attempted to establish an experimental animal model to elucidate the pathogenesis of human dermatophytosis and evaluate drug efficacy. However, current animal models have several issues. In the present paper, we surveyed reports about the methodology of the dermatophytosis animal model for tinea corporis, tinea pedis, and tinea unguium and discussed future prospects. PMID:22619489

  13. Dosimetry in small-animal CT using Monte Carlo simulations

    NASA Astrophysics Data System (ADS)

    Lee, C.-L.; Park, S.-J.; Jeon, P.-H.; Jo, B.-D.; Kim, H.-J.

    2016-01-01

    Small-animal computed tomography (micro-CT) imaging devices are increasingly being used in biological research. While investigators are mainly interested in high-contrast, low-noise, and high-resolution anatomical images, relatively large radiation doses are required, and there is also growing concern over the radiological risk from preclinical experiments. This study was conducted to determine the radiation dose in a mouse model for dosimetric estimates using the GEANT4 application for tomographic emission simulations (GATE) and to extend its techniques to various small-animal CT applications. Radiation dose simulations were performed with the same parameters as those for the measured micro-CT data, using the MOBY phantom, a pencil ion chamber and an electrometer with a CT detector. For physical validation of radiation dose, absorbed dose of brain and liver in mouse were evaluated to compare simulated results with physically measured data using thermoluminescent dosimeters (TLDs). The mean difference between simulated and measured data was less than 2.9% at 50 kVp X-ray source. The absorbed doses of 37 brain tissues and major organs of the mouse were evaluated according to kVp changes. The absorbed dose over all of the measurements in the brain (37 types of tissues) consistently increased and ranged from 42.4 to 104.0 mGy. Among the brain tissues, the absorbed dose of the hypothalamus (157.8-414.30 mGy) was the highest for the beams at 50-80 kVp, and that of the corpus callosum (11.2-26.6 mGy) was the lowest. These results can be used as a dosimetric database to control mouse doses and preclinical targeted radiotherapy experiments. In addition, to accurately calculate the mouse-absorbed dose, the X-ray spectrum, detector alignment, and uncertainty in the elemental composition of the simulated materials must be accurately modeled.

  14. Animal models of atherosclerosis

    PubMed Central

    Kapourchali, Fatemeh Ramezani; Surendiran, Gangadaran; Chen, Li; Uitz, Elisabeth; Bahadori, Babak; Moghadasian, Mohammed H

    2014-01-01

    In this mini-review several commonly used animal models of atherosclerosis have been discussed. Among them, emphasis has been made on mice, rabbits, pigs and non-human primates. Although these animal models have played a significant role in our understanding of induction of atherosclerotic lesions, we still lack a reliable animal model for regression of the disease. Researchers have reported several genetically modified and transgenic animal models that replicate human atherosclerosis, however each of current animal models have some limitations. Among these animal models, the apolipoprotein (apo) E-knockout (KO) mice have been used extensively because they develop spontaneous atherosclerosis. Furthermore, atherosclerotic lesions developed in this model depending on experimental design may resemble humans’ stable and unstable atherosclerotic lesions. This mouse model of hypercholesterolemia and atherosclerosis has been also used to investigate the impact of oxidative stress and inflammation on atherogenesis. Low density lipoprotein (LDL)-r-KO mice are a model of human familial hypercholesterolemia. However, unlike apo E-KO mice, the LDL-r-KO mice do not develop spontaneous atherosclerosis. Both apo E-KO and LDL-r-KO mice have been employed to generate other relevant mouse models of cardiovascular disease through breeding strategies. In addition to mice, rabbits have been used extensively particularly to understand the mechanisms of cholesterol-induced atherosclerosis. The present review paper details the characteristics of animal models that are used in atherosclerosis research. PMID:24868511

  15. Modelling Farm Animal Welfare

    PubMed Central

    Collins, Lisa M.; Part, Chérie E.

    2013-01-01

    Simple Summary In this review paper we discuss the different modeling techniques that have been used in animal welfare research to date. We look at what questions they have been used to answer, the advantages and pitfalls of the methods, and how future research can best use these approaches to answer some of the most important upcoming questions in farm animal welfare. Abstract The use of models in the life sciences has greatly expanded in scope and advanced in technique in recent decades. However, the range, type and complexity of models used in farm animal welfare is comparatively poor, despite the great scope for use of modeling in this field of research. In this paper, we review the different modeling approaches used in farm animal welfare science to date, discussing the types of questions they have been used to answer, the merits and problems associated with the method, and possible future applications of each technique. We find that the most frequently published types of model used in farm animal welfare are conceptual and assessment models; two types of model that are frequently (though not exclusively) based on expert opinion. Simulation, optimization, scenario, and systems modeling approaches are rarer in animal welfare, despite being commonly used in other related fields. Finally, common issues such as a lack of quantitative data to parameterize models, and model selection and validation are discussed throughout the review, with possible solutions and alternative approaches suggested. PMID:26487411

  16. MODELING APPROACHES FOR ESTIMATING THE DOSIMETRY OF INHALED TOXICANTS IN CHILDREN

    EPA Science Inventory

    Risk assessment of inhaled toxicants has typically focused upon adults, with modeling used to extrapolate dosimetry and risks from laboratory animals to humans. However, behavioral factors such as time spent playing outdoors can lead to more exposure to inhaled toxicants in chil...

  17. Animal models for osteoporosis

    NASA Technical Reports Server (NTRS)

    Turner, R. T.; Maran, A.; Lotinun, S.; Hefferan, T.; Evans, G. L.; Zhang, M.; Sibonga, J. D.

    2001-01-01

    Animal models will continue to be important tools in the quest to understand the contribution of specific genes to establishment of peak bone mass and optimal bone architecture, as well as the genetic basis for a predisposition toward accelerated bone loss in the presence of co-morbidity factors such as estrogen deficiency. Existing animal models will continue to be useful for modeling changes in bone metabolism and architecture induced by well-defined local and systemic factors. However, there is a critical unfulfilled need to develop and validate better animal models to allow fruitful investigation of the interaction of the multitude of factors which precipitate senile osteoporosis. Well characterized and validated animal models that can be recommended for investigation of the etiology, prevention and treatment of several forms of osteoporosis have been listed in Table 1. Also listed are models which are provisionally recommended. These latter models have potential but are inadequately characterized, deviate significantly from the human response, require careful choice of strain or age, or are not practical for most investigators to adopt. It cannot be stressed strongly enough that the enormous potential of laboratory animals as models for osteoporosis can only be realized if great care is taken in the choice of an appropriate species, age, experimental design, and measurements. Poor choices will results in misinterpretation of results which ultimately can bring harm to patients who suffer from osteoporosis by delaying advancement of knowledge.

  18. Animal models for osteoporosis.

    PubMed

    Turner, R T; Maran, A; Lotinun, S; Hefferan, T; Evans, G L; Zhang, M; Sibonga, J D

    2001-01-01

    Animal models will continue to be important tools in the quest to understand the contribution of specific genes to establishment of peak bone mass and optimal bone architecture, as well as the genetic basis for a predisposition toward accelerated bone loss in the presence of co-morbidity factors such as estrogen deficiency. Existing animal models will continue to be useful for modeling changes in bone metabolism and architecture induced by well-defined local and systemic factors. However, there is a critical unfulfilled need to develop and validate better animal models to allow fruitful investigation of the interaction of the multitude of factors which precipitate senile osteoporosis. Well characterized and validated animal models that can be recommended for investigation of the etiology, prevention and treatment of several forms of osteoporosis have been listed in Table 1. Also listed are models which are provisionally recommended. These latter models have potential but are inadequately characterized, deviate significantly from the human response, require careful choice of strain or age, or are not practical for most investigators to adopt. It cannot be stressed strongly enough that the enormous potential of laboratory animals as models for osteoporosis can only be realized if great care is taken in the choice of an appropriate species, age, experimental design, and measurements. Poor choices will results in misinterpretation of results which ultimately can bring harm to patients who suffer from osteoporosis by delaying advancement of knowledge. PMID:11704974

  19. MECHANISTIC DOSIMETRY MODELS OF NANOMATERIAL DEPOSITION IN THE RESPIRATORY TRACT

    EPA Science Inventory

    Accurate health risk assessments of inhalation exposure to nanomaterials will require dosimetry models that account for interspecies differences in dose delivered to the respiratory tract. Mechanistic models offer the advantage to interspecies extrapolation that physicochemica...

  20. Animal models of tinnitus.

    PubMed

    Brozoski, Thomas J; Bauer, Carol A

    2016-08-01

    Presented is a thematic review of animal tinnitus models from a functional perspective. Chronic tinnitus is a persistent subjective sound sensation, emergent typically after hearing loss. Although the sensation is experientially simple, it appears to have central a nervous system substrate of unexpected complexity that includes areas outside of those classically defined as auditory. Over the past 27 years animal models have significantly contributed to understanding tinnitus' complex neurophysiology. In that time, a diversity of models have been developed, each with its own strengths and limitations. None has clearly become a standard. Animal models trace their origin to the 1988 experiments of Jastreboff and colleagues. All subsequent models derive some of their features from those experiments. Common features include behavior-dependent psychophysical determination, acoustic conditions that contrast objective sound and silence, and inclusion of at least one normal-hearing control group. In the present review, animal models have been categorized as either interrogative or reflexive. Interrogative models use emitted behavior under voluntary control to indicate hearing. An example would be pressing a lever to obtain food in the presence of a particular sound. In this type of model animals are interrogated about their auditory sensations, analogous to asking a patient, "What do you hear?" These models require at least some training and motivation management, and reflect the perception of tinnitus. Reflexive models, in contrast, employ acoustic modulation of an auditory reflex, such as the acoustic startle response. An unexpected loud sound will elicit a reflexive motor response from many species, including humans. Although involuntary, acoustic startle can be modified by a lower-level preceding event, including a silent sound gap. Sound-gap modulation of acoustic startle appears to discriminate tinnitus in animals as well as humans, and requires no training or

  1. Animal models of ADHD.

    PubMed

    Bari, A; Robbins, T W

    2011-01-01

    Studies employing animal models of attention-deficit/hyperactivity disorder (ADHD) present clear inherent advantages over human studies. Animal models are invaluable tools for the study of underlying neurochemical, neuropathological and genetic alterations that cause ADHD, because they allow relatively fast, rigorous hypothesis testing and invasive manipulations as well as selective breeding. Moreover, especially for ADHD, animal models with good predictive validity would allow the assessment of potential new therapeutics. In this chapter, we describe and comment on the most frequently used animal models of ADHD that have been created by genetic, neurochemical and physical alterations in rodents. We then discuss that an emerging and promising direction of the field is the analysis of individual behavioural differences among a normal population of animals. Subjects presenting extreme characteristics related to ADHD can be studied, thereby avoiding some of the problems that are found in other models, such as functional recovery and unnecessary assumptions about aetiology. This approach is justified by the theoretical need to consider human ADHD as the extreme part of a spectrum of characteristics that are distributed normally in the general population, as opposed to the predominant view of ADHD as a separate pathological category. PMID:21287324

  2. Pencil beam scanning dosimetry for large animal irradiation

    PubMed Central

    Lin, Liyong; Solberg, Timothy D.; Carabe, Alexandro; Mcdonough, James E.; Diffenderfer, Eric; Sanzari, Jenine K.; Kennedy, Ann R.; Cengel, Keith

    2014-01-01

    The space radiation environment imposes increased dangers of exposure to ionizing radiation, particularly during a solar particle event. These events consist primarily of low-energy protons that produce a highly inhomogeneous depth–dose distribution. Here we describe a novel technique that uses pencil beam scanning at extended source-to-surface distances and range shifter (RS) to provide robust but easily modifiable delivery of simulated solar particle event radiation to large animals. Thorough characterization of spot profiles as a function of energy, distance and RS position is critical to accurate treatment planning. At 105 MeV, the spot sigma is 234 mm at 4800 mm from the isocentre when the RS is installed at the nozzle. With the energy increased to 220 MeV, the spot sigma is 66 mm. At a distance of 1200 mm from the isocentre, the Gaussian sigma is 68 mm and 23 mm at 105 MeV and 220 MeV, respectively, when the RS is located on the nozzle. At lower energies, the spot sigma exhibits large differences as a function of distance and RS position. Scan areas of 1400 mm (superior–inferior) by 940 mm (anterior–posterior) and 580 mm by 320 mm are achieved at the extended distances of 4800 mm and 1200 mm, respectively, with dose inhomogeneity <2%. To treat large animals with a more sophisticated dose distribution, spot size can be reduced by placing the RS closer than 70 mm to the surface of the animals, producing spot sigmas below 6 mm. PMID:24855043

  3. Pencil beam scanning dosimetry for large animal irradiation.

    PubMed

    Lin, Liyong; Solberg, Timothy D; Carabe, Alexandro; Mcdonough, James E; Diffenderfer, Eric; Sanzari, Jenine K; Kennedy, Ann R; Cengel, Keith

    2014-09-01

    The space radiation environment imposes increased dangers of exposure to ionizing radiation, particularly during a solar particle event. These events consist primarily of low-energy protons that produce a highly inhomogeneous depth-dose distribution. Here we describe a novel technique that uses pencil beam scanning at extended source-to-surface distances and range shifter (RS) to provide robust but easily modifiable delivery of simulated solar particle event radiation to large animals. Thorough characterization of spot profiles as a function of energy, distance and RS position is critical to accurate treatment planning. At 105 MeV, the spot sigma is 234 mm at 4800 mm from the isocentre when the RS is installed at the nozzle. With the energy increased to 220 MeV, the spot sigma is 66 mm. At a distance of 1200 mm from the isocentre, the Gaussian sigma is 68 mm and 23 mm at 105 MeV and 220 MeV, respectively, when the RS is located on the nozzle. At lower energies, the spot sigma exhibits large differences as a function of distance and RS position. Scan areas of 1400 mm (superior-inferior) by 940 mm (anterior-posterior) and 580 mm by 320 mm are achieved at the extended distances of 4800 mm and 1200 mm, respectively, with dose inhomogeneity <2%. To treat large animals with a more sophisticated dose distribution, spot size can be reduced by placing the RS closer than 70 mm to the surface of the animals, producing spot sigmas below 6 mm. PMID:24855043

  4. Application of MOSFET detectors for dosimetry in small animal radiography using short exposure times.

    PubMed

    De Lin, Ming; Toncheva, Greta; Nguyen, Giao; Kim, Sangroh; Anderson-Evans, Colin; Johnson, G Allan; Yoshizumi, Terry T

    2008-08-01

    Digital subtraction angiography (DSA) X-ray imaging for small animals can be used for functional phenotyping given its ability to capture rapid physiological changes at high spatial and temporal resolution. The higher temporal and spatial requirements for small-animal imaging drive the need for short, high-flux X-ray pulses. However, high doses of ionizing radiation can affect the physiology. The purpose of this study was to verify and apply metal oxide semiconductor field effect transistor (MOSFET) technology to dosimetry for small-animal diagnostic imaging. A tungsten anode X-ray source was used to expose a tissue-equivalent mouse phantom. Dose measurements were made on the phantom surface and interior. The MOSFETs were verified with thermoluminescence dosimeters (TLDs). Bland-Altman analysis showed that the MOSFET results agreed with the TLD results (bias, 0.0625). Using typical small animal DSA scan parameters, the dose ranged from 0.7 to 2.2 cGy. Application of the MOSFETs in the small animal environment provided two main benefits: (1) the availability of results in near real-time instead of the hours needed for TLD processes and (2) the ability to support multiple exposures with different X-ray techniques (various of kVp, mA and ms) using the same MOSFET. This MOSFET technology has proven to be a fast, reliable small animal dosimetry method for DSA imaging and is a good system for dose monitoring for serial and gene expression studies. PMID:18666818

  5. Application of MOSFET Detectors for Dosimetry in Small Animal Radiography Using Short Exposure Times

    PubMed Central

    De Lin, Ming; Toncheva, Greta; Nguyen, Giao; Kim, Sangroh; Anderson-Evans, Colin; Johnson, G. Allan; Yoshizumi, Terry T.

    2008-01-01

    Digital subtraction angiography (DSA) X-ray imaging for small animals can be used for functional phenotyping given its ability to capture rapid physiological changes at high spatial and temporal resolution. The higher temporal and spatial requirements for small-animal imaging drive the need for short, high-flux X-ray pulses. However, high doses of ionizing radiation can affect the physiology. The purpose of this study was to verify and apply metal oxide semiconductor field effect transistor (MOSFET) technology to dosimetry for small-animal diagnostic imaging. A tungsten anode X-ray source was used to expose a tissue-equivalent mouse phantom. Dose measurements were made on the phantom surface and interior. The MOSFETs were verified with thermoluminescence dosimeters (TLDs). Bland-Altman analysis showed that the MOSFET results agreed with the TLD results (bias, 0.0625). Using typical small animal DSA scan parameters, the dose ranged from 0.7 to 2.2 cGy. Application of the MOSFETs in the small animal environment provided two main benefits: (1) the availability of results in near real-time instead of the hours needed for TLD processes and (2) the ability to support multiple exposures with different X-ray techniques (various of kVp, mA and ms) using the same MOSFET. This MOSFET technology has proven to be a fast, reliable small animal dosimetry method for DSA imaging and is a good system for dose monitoring for serial and gene expression studies. PMID:18666818

  6. Animal models of fibromyalgia

    PubMed Central

    2013-01-01

    Animal models of disease states are valuable tools for developing new treatments and investigating underlying mechanisms. They should mimic the symptoms and pathology of the disease and importantly be predictive of effective treatments. Fibromyalgia is characterized by chronic widespread pain with associated co-morbid symptoms that include fatigue, depression, anxiety and sleep dysfunction. In this review, we present different animal models that mimic the signs and symptoms of fibromyalgia. These models are induced by a wide variety of methods that include repeated muscle insults, depletion of biogenic amines, and stress. All potential models produce widespread and long-lasting hyperalgesia without overt peripheral tissue damage and thus mimic the clinical presentation of fibromyalgia. We describe the methods for induction of the model, pathophysiological mechanisms for each model, and treatment profiles. PMID:24314231

  7. Animal models of scoliosis.

    PubMed

    Bobyn, Justin D; Little, David G; Gray, Randolph; Schindeler, Aaron

    2015-04-01

    Multiple techniques designed to induce scoliotic deformity have been applied across many animal species. We have undertaken a review of the literature regarding experimental models of scoliosis in animals to discuss their utility in comprehending disease aetiology and treatment. Models of scoliosis in animals can be broadly divided into quadrupedal and bipedal experiments. Quadrupedal models, in the absence of axial gravitation force, depend upon development of a mechanical asymmetry along the spine to initiate a scoliotic deformity. Bipedal models more accurately mimic human posture and consequently are subject to similar forces due to gravity, which have been long appreciated to be a contributing factor to the development of scoliosis. Many effective models of scoliosis in smaller animals have not been successfully translated to primates and humans. Though these models may not clarify the aetiology of human scoliosis, by providing a reliable and reproducible deformity in the spine they are a useful means with which to test interventions designed to correct and prevent deformity. PMID:25492698

  8. Animal Models of Glaucoma

    PubMed Central

    A. Bouhenni, Rachida; Dunmire, Jeffrey; Sewell, Abby; Edward, Deepak P.

    2012-01-01

    Glaucoma is a heterogeneous group of disorders that progressively lead to blindness due to loss of retinal ganglion cells and damage to the optic nerve. It is a leading cause of blindness and visual impairment worldwide. Although research in the field of glaucoma is substantial, the pathophysiologic mechanisms causing the disease are not completely understood. A wide variety of animal models have been used to study glaucoma. These include monkeys, dogs, cats, rodents, and several other species. Although these models have provided valuable information about the disease, there is still no ideal model for studying glaucoma due to its complexity. In this paper we present a summary of most of the animal models that have been developed and used for the study of the different types of glaucoma, the strengths and limitations associated with each species use, and some potential criteria to develop a suitable model. PMID:22665989

  9. A probabilistic gastrointestinal tract dosimetry model

    NASA Astrophysics Data System (ADS)

    Huh, Chulhaeng

    In internal dosimetry, the tissues of the gastrointestinal (GI) tract represent one of the most radiosensitive organs of the body with the hematopoietic bone marrow. Endoscopic ultrasound is a unique tool to acquire in-vivo data on GI tract wall thicknesses of sufficient resolution needed in radiation dosimetry studies. Through their different echo texture and intensity, five layers of differing echo patterns for superficial mucosa, deep mucosa, submucosa, muscularis propria and serosa exist within the walls of organs composing the alimentary tract. Thicknesses for stomach mucosa ranged from 620 +/- 150 mum to 1320 +/- 80 mum (total stomach wall thicknesses from 2.56 +/- 0.12 to 4.12 +/- 0.11 mm). Measurements made for the rectal images revealed rectal mucosal thicknesses from 150 +/- 90 mum to 670 +/- 110 mum (total rectal wall thicknesses from 2.01 +/- 0.06 to 3.35 +/- 0.46 mm). The mucosa thus accounted for 28 +/- 3% and 16 +/- 6% of the total thickness of the stomach and rectal wall, respectively. Radiation transport simulations were then performed using the Monte Carlo N-particle transport code (MCNP) 4C transport code to calculate S values (Gy/Bq-s) for penetrating and nonpenetrating radiations such as photons, beta particles, conversion electrons and auger electrons of selected nuclides, I123, I131, Tc 99m and Y90 under two source conditions: content and mucosa sources, respectively. The results of this study demonstrate generally good agreement with published data for the stomach mucosa wall. The rectal mucosa data are consistently higher than published data compared with the large intestine due to different radiosensitive cell thicknesses (350 mum vs. a range spanning from 149 mum to 729 mum) and different geometry when a rectal content source is considered. Generally, the ICRP models have been designed to predict the amount of radiation dose in the human body from a "typical" or "reference" individual in a given population. The study has been performed to

  10. A dose-reconstruction study of the 1997 Sarov criticality accident using animated dosimetry techniques.

    PubMed

    Vazquez, Justin A; Ding, Aiping; Haley, Thomas; Caracappa, Peter F; Xu, X George

    2014-05-01

    Most computational human phantoms are static, representing a standing individual. There are, however, cases when these phantoms fail to represent accurately the detailed effects on dose that result from considering varying human posture and even whole sequences of motion. In this study, the feasibility of a dynamic and deformable phantom is demonstrated with the development of the Computational Human for Animated Dosimetry (CHAD) phantom. Based on modifications to the limb structure of the previously developed RPI Adult Male, CHAD's posture is adjustable using an optical motion capture system that records real-life human movement. To demonstrate its ability to produce dose results that reflect the changes brought about by posture-deformation, CHAD is employed to perform a dose-reconstruction analysis of the 1997 Sarov criticality accident, and a simulated total body dose of 13.3 Gy is observed, with the total body dose rate dropping from 1.4 Gy s to 0.25 Gy s over the first 4 s of retreat time. Additionally, dose measurements are calculated for individual organs and body regions, including a 36.8-Gy dose to the breast tissue, a 3.8-Gy dose to the bladder, and a 31.1-Gy dose to the thyroid, as well as the changes in dose rates for the individual organs over the course of the accident sequence. Comparison of results obtained using CHAD in an animated dosimetry simulation with reported information on dose and the medical outcome of the case shows that the consideration of posture and movement in dosimetry simulation allows for more detailed and precise analysis of dosimetry information, consideration of the evolution of the dose profile over time in the course of a given scenario, and a better understanding of the physiological impacts of radiation exposure for a given set of circumstances. PMID:24670906

  11. Animal Models of Hemophilia

    PubMed Central

    Sabatino, Denise E.; Nichols, Timothy C.; Merricks, Elizabeth; Bellinger, Dwight A.; Herzog, Roland W.; Monahan, Paul E.

    2013-01-01

    The X-linked bleeding disorder hemophilia is caused by mutations in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Unless prophylactic treatment is provided, patients with severe disease (less than 1% clotting activity) typically experience frequent spontaneous bleeds. Current treatment is largely based on intravenous infusion of recombinant or plasma-derived coagulation factor concentrate. More effective factor products are being developed. Moreover, gene therapies for sustained correction of hemophilia are showing much promise in pre-clinical studies and in clinical trials. These advances in molecular medicine heavily depend on availability of well-characterized small and large animal models of hemophilia, primarily hemophilia mice and dogs. Experiments in these animals represent important early and intermediate steps of translational research aimed at development of better and safer treatments for hemophilia, such a protein and gene therapies or immune tolerance protocols. While murine models are excellent for studies of large groups of animals using genetically defined strains, canine models are important for testing scale-up and for longer-term follow-up as well as for studies that require larger blood volumes. PMID:22137432

  12. Animal models of schizophrenia

    PubMed Central

    Jones, CA; Watson, DJG; Fone, KCF

    2011-01-01

    Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble ‘positive-like’ symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed. LINKED ARTICLES This article is part of a themed issue on

  13. Modeling animal landscapes.

    PubMed

    Porter, W P; Ostrowski, S; Williams, J B

    2010-01-01

    There is an increasing need to assess the effects of climate and land-use change on habitat quality, ideally from a mechanistic basis. The symposium "Molecules to Migration: Pressures of Life" at the Fourth International Conference in Africa for Comparative Physiology and Biochemistry, Maasai Mara National Reserve, Kenya, 2008, illustrated how the principles of biophysical ecology can capture the mechanistic links between organisms, climate, and other habitat features. These principles provide spatially explicit assessments of habitat quality from a physiological perspective (i.e., "animal landscapes") that can be validated independently of the data used to derive and parameterize them. The contents of this symposium showcased how the modeling of animal landscapes can be used to assess key issues in applied and theoretical ecology. The presentations included applications to amphibians, reptiles, birds, and mammals. The rare Arabian oryx on the Arabian Peninsula is used as an example for energetic calculations and their implications for behavior on the landscape. PMID:20670170

  14. Internal Dosimetry Code System Using Biokinetics Models

    Energy Science and Technology Software Center (ESTSC)

    2003-11-12

    Version 00 InDose is an internal dosimetry code to calculate dose estimations using biokinetic models (presented in ICRP-56 to ICRP71) as well as older ones. The code uses the ICRP-66 respiratory tract model and the ICRP-30 gastrointestinal tract model as well as the new and old biokinetic models. The code was written in such a way that the user can change any parameters of any one of the models without recompiling the code. All parametersmore » are given in well annotated parameters files that the user may change. As default, these files contain the values listed in ICRP publications. The full InDose code was planned to have three parts: 1) the main part includes the uptake and systemic models and is used to calculate the activities in the body tissues and excretion as a function of time for a given intake. 2) An optimization module for automatic estimation of the intake for a specific exposure case. 3) A module to calculate the dose due to the estimated intake. Currently, the code is able to perform only it`s main task (part 1) while the other two have to be done externally using other tools. In the future, developers would like to add these modules in order to provide a complete solution. The code was tested extensively to verify accuracy of its results. The verification procedure was divided into three parts: 1) verification of the implementation of each model, 2) verification of the integrity of the whole code, and 3) usability test. The first two parts consisted of comparing results obtained with InDose to published results for the same cases. For example ICRP-78 monitoring data. The last part consisted of participating in the 3rd EIE-IDA and assessing some of the scenarios provided in this exercise. These tests where presented in a few publications. Good agreement was found between the results of InDose and published data.« less

  15. Animal Models of Narcolepsy

    PubMed Central

    Chen, Lichao; Brown, Ritchie E.; McKenna, James T.; McCarley, Robert W.

    2013-01-01

    Narcolepsy is a debilitating sleep disorder with excessive daytime sleepiness and cataplexy as its two major symptoms. Although this disease was first described about one century ago, an animal model was not available until the 1970s. With the establishment of the Stanford canine narcolepsy colony, researchers were able to conduct multiple neurochemical studies to explore the pathophysiology of this disease. It was concluded that there was an imbalance between monoaminergic and cholinergic systems in canine narcolepsy. In 1999, two independent studies revealed that orexin neurotransmission deficiency was pivotal to the development of narcolepsy with cataplexy. This scientific leap fueled the generation of several genetically engineered mouse and rat models of narcolepsy. To facilitate further research, it is imperative that researchers reach a consensus concerning the evaluation of narcoleptic behavioral and EEG phenomenology in these models. PMID:19689311

  16. ANIMAL MODELS FOR IMMUNOTOXICITY

    EPA Science Inventory

    Greater susceptibility to infection is a hallmark of compromised immune function in humans and animals, and is often considered the benchmark against which the predictive value of immune function tests are compared. This focus of this paper is resistance to infection with the pa...

  17. Animal Models of Colorectal Cancer

    PubMed Central

    Johnson, Robert L.; Fleet, James C.

    2012-01-01

    Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the United States. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist. PMID:23076650

  18. Animal Models for Therapeutic Embolization

    SciTech Connect

    Moreira, Patricia L.; An, Yuehuei H.

    2003-04-15

    Embolization techniques have been performed in different animals to accumulate basic data before a clinical trial.Choosing the right embolization model for a specific project is critical. However, there are several variables when defining the best model for embolization research such as the size of the animal to be used, the target organs, the route of introducing the embolization agent, and the feasible methods of evaluation. Commonly used research animals for endovascular embolization include rabbits, dogs, and rats. Frequently used target organs are the kidney and the liver. Most models use a transcatheter for introducing the embolus and occasionally open surgery and direct arterial injection are used. Basic methods of evaluation are straightforward, and commonly include macro observation of the embolized organs, angiogram, and histology. This article concisely reviews the available animal models and their evaluation for embolization research to help researchers to choose the appropriate model.

  19. Animal models in peritoneal dialysis

    PubMed Central

    Nikitidou, Olga; Peppa, Vasiliki I.; Leivaditis, Konstantinos; Eleftheriadis, Theodoros; Zarogiannis, Sotirios G.; Liakopoulos, Vassilios

    2015-01-01

    Peritoneal dialysis (PD) has been extensively used over the past years as a method of kidney replacement therapy for patients with end stage renal disease (ESRD). In an attempt to better understand the properties of the peritoneal membrane and the mechanisms involved in major complications associated with PD, such as inflammation, peritonitis and peritoneal injury, both in vivo and ex vivo animal models have been used. The aim of the present review is to briefly describe the animal models that have been used, and comment on the main problems encountered while working with these models. Moreover, the differences characterizing these animal models, as well as, the differences with humans are highlighted. Finally, it is suggested that the use of standardized protocols is a necessity in order to take full advantage of animal models, extrapolate their results in humans, overcome the problems related to PD and help promote its use. PMID:26388781

  20. Animal models of cerebral ischemia

    NASA Astrophysics Data System (ADS)

    Khodanovich, M. Yu.; Kisel, A. A.

    2015-11-01

    Cerebral ischemia remains one of the most frequent causes of death and disability worldwide. Animal models are necessary to understand complex molecular mechanisms of brain damage as well as for the development of new therapies for stroke. This review considers a certain range of animal models of cerebral ischemia, including several types of focal and global ischemia. Since animal models vary in specificity for the human disease which they reproduce, the complexity of surgery, infarct size, reliability of reproduction for statistical analysis, and adequate models need to be chosen according to the aim of a study. The reproduction of a particular animal model needs to be evaluated using appropriate tools, including the behavioral assessment of injury and non-invasive and post-mortem control of brain damage. These problems also have been summarized in the review.

  1. Animal models in burn research.

    PubMed

    Abdullahi, A; Amini-Nik, S; Jeschke, M G

    2014-09-01

    Burn injury is a severe form of trauma affecting more than 2 million people in North America each year. Burn trauma is not a single pathophysiological event but a devastating injury that causes structural and functional deficits in numerous organ systems. Due to its complexity and the involvement of multiple organs, in vitro experiments cannot capture this complexity nor address the pathophysiology. In the past two decades, a number of burn animal models have been developed to replicate the various aspects of burn injury, to elucidate the pathophysiology, and to explore potential treatment interventions. Understanding the advantages and limitations of these animal models is essential for the design and development of treatments that are clinically relevant to humans. This review aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications. While many animal models of burn exist, we limit our discussion to the skin healing of mouse, rat, and pig. Additionally, we briefly explain hypermetabolic characteristics of burn injury and the animal model utilized to study this phenomena. Finally, we discuss the economic costs associated with each of these models in order to guide decisions of choosing the appropriate animal model for burn research. PMID:24714880

  2. Animal Models in Burn Research

    PubMed Central

    Abdullahi, A.; Amini-Nik, S.; Jeschke, M.G

    2014-01-01

    Burn injury is a severe form of trauma affecting more than two million people in North America each year. Burn trauma is not a single pathophysiological event but a devastating injury that causes structural and functional deficits in numerous organ systems. Due to its complexity and the involvement of multiple organs, in vitro experiments cannot capture this complexity nor address the pathophysiology. In the past two decades, a number of burn animal models have been developed to replicate the various aspects of burn injury; to elucidate the pathophysiology and explore potential treatment interventions. Understanding the advantages and limitations of these animal models is essential for the design and development of treatments that are clinically relevant to humans. This review paper aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications. While many animal models of burn exist, we limit our discussion to the skin healing of mouse, rat, and pig. Additionally, we briefly explain hypermetabolic characteristics of burn injury and the animal model utilized to study this phenomena. Finally, we discuss the economic costs associated with each of these models in order to guide decisions of choosing the appropriate animal model for burn research. PMID:24714880

  3. A small-scale anatomical dosimetry model of the liver

    NASA Astrophysics Data System (ADS)

    Stenvall, Anna; Larsson, Erik; Strand, Sven-Erik; Jönsson, Bo-Anders

    2014-07-01

    Radionuclide therapy is a growing and promising approach for treating and prolonging the lives of patients with cancer. For therapies where high activities are administered, the liver can become a dose-limiting organ; often with a complex, non-uniform activity distribution and resulting non-uniform absorbed-dose distribution. This paper therefore presents a small-scale dosimetry model for various source-target combinations within the human liver microarchitecture. Using Monte Carlo simulations, Medical Internal Radiation Dose formalism-compatible specific absorbed fractions were calculated for monoenergetic electrons; photons; alpha particles; and 125I, 90Y, 211At, 99mTc, 111In, 177Lu, 131I and 18F. S values and the ratio of local absorbed dose to the whole-organ average absorbed dose was calculated, enabling a transformation of dosimetry calculations from macro- to microstructure level. For heterogeneous activity distributions, for example uptake in Kupffer cells of radionuclides emitting low-energy electrons (125I) or high-LET alpha particles (211At) the target absorbed dose for the part of the space of Disse, closest to the source, was more than eight- and five-fold the average absorbed dose to the liver, respectively. With the increasing interest in radionuclide therapy of the liver, the presented model is an applicable tool for small-scale liver dosimetry in order to study detailed dose-effect relationships in the liver.

  4. Animal Models of Bacterial Keratitis

    PubMed Central

    Marquart, Mary E.

    2011-01-01

    Bacterial keratitis is a disease of the cornea characterized by pain, redness, inflammation, and opacity. Common causes of this disease are Pseudomonas aeruginosa and Staphylococcus aureus. Animal models of keratitis have been used to elucidate both the bacterial factors and the host inflammatory response involved in the disease. Reviewed herein are animal models of bacterial keratitis and some of the key findings in the last several decades. PMID:21274270

  5. Animal models for human diseases.

    PubMed

    Rust, J H

    1982-01-01

    The use of animal models for the study of human disease is, for the most part, a recent development. This discussion of the use of animal models for human diseases directs attention to the sterile period, early advances, some personal experiences, the human as the model, biological oddities among common laboratory animals, malignancies in laboratory animals, problems created by federal regulations, cancer tests with animals, and what the future holds in terms of the use of animal models as an aid to understanding human disease. In terms of early use of animal models, there was a school of rabbis, some of whom were also physicians, in Babylon who studied and wrote extensively on ritual slaughter and the suitability of birds and beasts for food. Considerable detailed information on animal pathology, physiology, anatomy, and medicine in general can be found in the Soncino Babylonian Talmudic Translations. The 1906 edition of the "Jewish Encyclopedia," has been a rich resource. Although it has not been possible to establish what diseases of animals were studied and their relationship to the diseases of humans, there are fascinating clues to pursue, despite the fact that these were sterile years for research in medicine. The quotation from the Talmud is of interest: "The medical knowledge of the Talmudist was based upon tradition, the dissection of human bodies, observation of disease and experiments upon animals." A bright light in the lackluster years of medical research was provided by Galen, considered the originator of research in physiology and anatomy. His dissection of animals and work on apes and other lower animals were models for human anatomy and physiology and the bases for many treatises. Yet, Galen never seemed to suggest that animals could serve as models for human diseases. Most early physicians who can be considered to have been students of disease developed their medical knowledge by observing the sick under their care. 1 early medical investigator

  6. Postured voxel-based human models for electromagnetic dosimetry

    NASA Astrophysics Data System (ADS)

    Nagaoka, Tomoaki; Watanabe, Soichi

    2008-12-01

    High-resolution anatomically realistic whole-body voxel models have recently been developed for electromagnetic dosimetry. However, the posture of most models is similar to the standing one, which strongly limits electromagnetic dosimetry when simulating a realistic exposure scenario. In this paper, we present the development of postured models based on anatomically realistic voxel models with standing posture. Voxel models of the Japanese adult male and female were used as the original upright standing models. The Japanese models were composed of 2 mm cubic voxels, each of which was segmented into 51 different tissue types. We developed several different types of posture models using a novel posture transformation method. These posture models were smoothly transformed, while the continuity of the internal tissues and organs was maintained. In this paper, we also present our calculations of the whole-body averaged specific absorption rates (SARs) of sitting male and female models exposed to electromagnetic plane waves at very high (VHF) and ultra high frequency (UHF) bands.

  7. Animal models in myopia research.

    PubMed

    Schaeffel, Frank; Feldkaemper, Marita

    2015-11-01

    Our current understanding of the development of refractive errors, in particular myopia, would be substantially limited had Wiesel and Raviola not discovered by accident that monkeys develop axial myopia as a result of deprivation of form vision. Similarly, if Josh Wallman and colleagues had not found that simple plastic goggles attached to the chicken eye generate large amounts of myopia, the chicken model would perhaps not have become such an important animal model. Contrary to previous assumptions about the mechanisms of myopia, these animal models suggested that eye growth is visually controlled locally by the retina, that an afferent connection to the brain is not essential and that emmetropisation uses more sophisticated cues than just the magnitude of retinal blur. While animal models have shown that the retina can determine the sign of defocus, the underlying mechanism is still not entirely clear. Animal models have also provided knowledge about the biochemical nature of the signal cascade converting the output of retinal image processing to changes in choroidal thickness and scleral growth; however, a critical question was, and still is, can the results from animal models be applied to myopia in children? While the basic findings from chickens appear applicable to monkeys, some fundamental questions remain. If eye growth is guided by visual feedback, why is myopic development not self-limiting? Why does undercorrection not arrest myopic progression even though positive lenses induce myopic defocus, which leads to the development of hyperopia in emmetropic animals? Why do some spectacle or contact lens designs reduce myopic progression and others not? It appears that some major differences exist between animals reared with imposed defocus and children treated with various optical corrections, although without the basic knowledge obtained from animal models, we would be lost in an abundance of untestable hypotheses concerning human myopia. PMID:26769177

  8. Animal Models of Bone Metastasis.

    PubMed

    Simmons, J K; Hildreth, B E; Supsavhad, W; Elshafae, S M; Hassan, B B; Dirksen, W P; Toribio, R E; Rosol, T J

    2015-09-01

    Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553

  9. Animal Models of Bone Metastasis

    PubMed Central

    Simmons, J. K.; Hildreth, B. E.; Supsavhad, W.; Elshafae, S. M.; Hassan, B. B.; Dirksen, W. P.; Toribio, R. E.; Rosol, T. J.

    2015-01-01

    Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553

  10. Animal Models of Head Trauma

    PubMed Central

    Cernak, Ibolja

    2005-01-01

    Summary: Animal models of traumatic brain injury (TBI) are used to elucidate primary and secondary sequelae underlying human head injury in an effort to identify potential neuroprotective therapies for developing and adult brains. The choice of experimental model depends upon both the research goal and underlying objectives. The intrinsic ability to study injury-induced changes in behavior, physiology, metabolism, the blood/tissue interface, the blood brain barrier, and/or inflammatory- and immune-mediated responses, makes in vivo TBI models essential for neurotrauma research. Whereas human TBI is a highly complex multifactorial disorder, animal trauma models tend to replicate only single factors involved in the pathobiology of head injury using genetically well-defined inbred animals of a single sex. Although such an experimental approach is helpful to delineate key injury mechanisms, the simplicity and hence inability of animal models to reflect the complexity of clinical head injury may underlie the discrepancy between preclinical and clinical trials of neuroprotective therapeutics. Thus, a search continues for new animal models, which would more closely mimic the highly heterogeneous nature of human TBI, and address key factors in treatment optimization. PMID:16389305

  11. Symptomatic animal models for dystonia

    PubMed Central

    Wilson, Bethany K.; Hess, Ellen J.

    2013-01-01

    Symptomatic animal models have clinical features consistent with human disorders and are often used to identify the anatomical and physiological processes involved in the expression of symptoms and to experimentally demonstrate causality where it would be infeasible in the patient population. Rodent and primate models of dystonia have identified basal ganglia abnormalities, including alterations in striatal GABAergic and dopaminergic transmission. Symptomatic animal models have also established the critical role of the cerebellum in dystonia, particularly abnormal glutamate signaling and aberrant Purkinje cell activity. Further, experiments suggest that the basal ganglia and cerebellum are nodes in an integrated network that is dysfunctional in dystonia. The knowledge gained from experiments in symptomatic animal models may serve as the foundation for the development of novel therapeutic interventions to treat dystonia. PMID:23893454

  12. Animal Models of Muscular Dystrophy

    PubMed Central

    Ng, Rainer; Banks, Glen B.; Hall, John K.; Muir, Lindsey A.; Ramos, Julian N.; Wicki, Jacqueline; Odom, Guy L.; Konieczny, Patryk; Seto, Jane; Chamberlain, Joel R.; Chamberlain, Jeffrey S.

    2016-01-01

    The muscular dystrophies (MDs) represent a diverse collection of inherited human disorders, which affect to varying degrees skeletal, cardiac, and sometimes smooth muscle (Emery, 20021). To date, more than 50 different genes have been implicated as causing one or more types of MD (Bansal et al., 20032). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (Arnett et al., 20093). The large number of genes that are associated with MD and the tremendous number of animal models that have been developed preclude a complete discussion of each in the context of this review. However, we summarize here a number of the more commonly used models together with a mixture of different types of gene and MD, which serves to give a general overview of the value of animal models of MD for research and therapeutic development. PMID:22137430

  13. Animal models of pituitary neoplasia

    PubMed Central

    Lines, K.E.; Stevenson, M.; Thakker, R.V.

    2016-01-01

    Pituitary neoplasias can occur as part of a complex inherited disorder, or more commonly as sporadic (non-familial) disease. Studies of the molecular and genetic mechanisms causing such pituitary tumours have identified dysregulation of >35 genes, with many revealed by studies in mice, rats and zebrafish. Strategies used to generate these animal models have included gene knockout, gene knockin and transgenic over-expression, as well as chemical mutagenesis and drug induction. These animal models provide an important resource for investigation of tissue-specific tumourigenic mechanisms, and evaluations of novel therapies, illustrated by studies into multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome in which ∼30% of patients develop pituitary adenomas. This review describes animal models of pituitary neoplasia that have been generated, together with some recent advances in gene editing technologies, and an illustration of the use of the Men1 mouse as a pre clinical model for evaluating novel therapies. PMID:26320859

  14. ANIMAL MODELS FOR FOOD ALLERGY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Animal models have been used to provide insight into the complex immunological and pathophysioligical mechanisms of human Type 1 allergic diseases. Research efforts that include mechanistic studies in search of new therapies and screening models for hazard identification of potential allergens in a...

  15. Explicit dosimetry for photodynamic therapy: macroscopic singlet oxygen modeling

    PubMed Central

    Wang, Ken Kang-Hsin; Finlay, Jarod C.; Busch, Theresa M.; Hahn, Stephen M.; Zhu, Timothy C.

    2011-01-01

    Singlet oxygen (1O2) is the major cytotoxic agent responsible for cell killing for type-II photodynamic therapy (PDT). An empirical four-parameter macroscopic model is proposed to calculate the “apparent reacted 1O2 concentration”, [1O2]rx, as a clinical PDT dosimetry quantity. This model incorporates light diffusion equation and a set of PDT kinetics equations, which can be applied in any clinical treatment geometry. We demonstrate that by introducing a fitting quantity “apparent singlet oxygen threshold concentration” [1O2]rx,sd, it is feasible to determine the model parameters by fitting the computed [1O2]rx to the Photofrin-mediated PDT-induced necrotic distance using interstitially-measured Photofrin concentration and optical properties within each mouse. After determining the model parameters and the [1O2]rx,sd, we expect to use this model as an explicit dosimetry to assess PDT treatment outcome for a specific photosensitizer in an in vivo environment. The results also provide evidence that the [1O2]rx, because it takes into account the oxygen consumption (or light fluence rate) effect, can be a better predictor of PDT outcome than the PDT dose defined as the energy absorbed by the photosensitizer, which is proportional to the product of photosensitizer concentration and light fluence. PMID:20222102

  16. Animal models of cardiac cachexia.

    PubMed

    Molinari, Francesca; Malara, Natalia; Mollace, Vincenzo; Rosano, Giuseppe; Ferraro, Elisabetta

    2016-09-15

    Cachexia is the loss of body weight associated with several chronic diseases including chronic heart failure (CHF). The cachectic condition is mainly due to loss of skeletal muscle mass and adipose tissue depletion. The majority of experimental in vivo studies on cachexia rely on animal models of cancer cachexia while a reliable and appropriate model for cardiac cachexia has not yet been established. A critical issue in generating a cardiac cachexia model is that genetic modifications or pharmacological treatments impairing the heart functionality and used to obtain the heart failure model might likely impair the skeletal muscle, this also being a striated muscle and sharing with the myocardium several molecular and physiological mechanisms. On the other hand, often, the induction of heart damage in the several existing models of heart failure does not necessarily lead to skeletal muscle loss and cachexia. Here we describe the main features of cardiac cachexia and illustrate some animal models proposed for cardiac cachexia studies; they include the genetic calsequestrin and Dahl salt-sensitive models, the monocrotaline model and the surgical models obtained by left anterior descending (LAD) ligation, transverse aortic constriction (TAC) and ascending aortic banding. The availability of a specific animal model for cardiac cachexia is a crucial issue since, besides the common aspects of cachexia in the different syndromes, each disease has some peculiarities in its etiology and pathophysiology leading to cachexia. Such peculiarities need to be unraveled in order to find new targets for effective therapies. PMID:27317993

  17. Lung dosimetry and risk assessment of nanoparticles: Evaluating and extending current models in rats and humans

    SciTech Connect

    Kuempel, E.D.; Tran, C.L.; Castranova, V.; Bailer, A.J.

    2006-09-15

    Risk assessment of occupational exposure to nanomaterials is needed. Human data are limited, but quantitative data are available from rodent studies. To use these data in risk assessment, a scientifically reasonable approach for extrapolating the rodent data to humans is required. One approach is allometric adjustment for species differences in the relationship between airborne exposure and internal dose. Another approach is lung dosimetry modeling, which provides a biologically-based, mechanistic method to extrapolate doses from animals to humans. However, current mass-based lung dosimetry models may not fully account for differences in the clearance and translocation of nanoparticles. In this article, key steps in quantitative risk assessment are illustrated, using dose-response data in rats chronically exposed to either fine or ultrafine titanium dioxide (TiO{sub 2}), carbon black (CB), or diesel exhaust particulate (DEP). The rat-based estimates of the working lifetime airborne concentrations associated with 0.1% excess risk of lung cancer are approximately 0.07 to 0.3 mg/m{sup 3} for ultrafine TiO{sub 2}, CB, or DEP, and 0.7 to 1.3 mg/m{sup 3} for fine TiO{sub 2}. Comparison of observed versus model-predicted lung burdens in rats shows that the dosimetry models predict reasonably well the retained mass lung burdens of fine or ultrafine poorly soluble particles in rats exposed by chronic inhalation. Additional model validation is needed for nanoparticles of varying characteristics, as well as extension of these models to include particle translocation to organs beyond the lungs. Such analyses would provide improved prediction of nanoparticle dose for risk assessment.

  18. Animal Models of Ricin Toxicosis

    PubMed Central

    Song, Kejing; Sivasubramani, Satheesh K.; Gardner, Donald J.; Pincus, Seth H.

    2015-01-01

    Animal models of ricin toxicosis are necessary for testing the efficacy of therapeutic measures, as well studying the mechanisms by which ricin exerts its toxicity in intact animals. Because ricin can serve as a particularly well-characterized model of tissue damage, and the host response to that damage, studies of the mechanisms of ricin toxicity may have more general applicability. For example, our studies of the molecular mechanisms underlying the development of ricin-induced hypoglycemia may help elucidate the relationship of type II diabetes, insulin resistance, and inflammation. Studies in non-human primates are most relevant for testing and developing agents having clinical utility. But these animals are expensive and limited in quantity, and so rodents are used for most mechanistic studies. PMID:21956160

  19. Animal models of drug craving.

    PubMed

    Markou, A; Weiss, F; Gold, L H; Caine, S B; Schulteis, G; Koob, G F

    1993-01-01

    Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of

  20. Animal models of CNS disorders.

    PubMed

    McGonigle, Paul

    2014-01-01

    There is intense interest in the development and application of animal models of CNS disorders to explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic parameters of new chemical entities (NCEs). This is a daunting undertaking, due to the complex and heterogeneous nature of these disorders, the subjective and sometimes contradictory nature of the clinical endpoints and the paucity of information regarding underlying molecular mechanisms. Historically, these models have been invaluable in the discovery of therapeutics for a range of disorders including anxiety, depression, schizophrenia, and Parkinson's disease. Recently, however, they have been increasingly criticized in the wake of numerous clinical trial failures of NCEs with promising preclinical profiles. These failures have resulted from a number of factors including inherent limitations of the models, over-interpretation of preclinical results and the complex nature of clinical trials for CNS disorders. This review discusses the rationale, strengths, weaknesses and predictive validity of the most commonly used models for psychiatric, neurodegenerative and neurological disorders as well as critical factors that affect the variability and reproducibility of these models. It also addresses how progress in molecular genetics and the development of transgenic animals has fundamentally changed the approach to neurodegenerative disorder research. To date, transgenic animal models\\have not been the panacea for drug discovery that many had hoped for. However continual refinement of these models is leading to steady progress with the promise of eventual therapeutic breakthroughs. PMID:23811310

  1. Animal models of polymicrobial pneumonia

    PubMed Central

    Hraiech, Sami; Papazian, Laurent; Rolain, Jean-Marc; Bregeon, Fabienne

    2015-01-01

    Pneumonia is one of the leading causes of severe and occasionally life-threatening infections. The physiopathology of pneumonia has been extensively studied, providing information for the development of new treatments for this condition. In addition to in vitro research, animal models have been largely used in the field of pneumonia. Several models have been described and have provided a better understanding of pneumonia under different settings and with various pathogens. However, the concept of one pathogen leading to one infection has been challenged, and recent flu epidemics suggest that some pathogens exhibit highly virulent potential. Although “two hits” animal models have been used to study infectious diseases, few of these models have been described in pneumonia. Therefore the aims of this review were to provide an overview of the available literature in this field, to describe well-studied and uncommon pathogen associations, and to summarize the major insights obtained from this information. PMID:26170617

  2. Animal Models of Subjective Tinnitus

    PubMed Central

    2014-01-01

    Tinnitus is one of the major audiological diseases, affecting a significant portion of the ageing society. Despite its huge personal and presumed economic impact there are only limited therapeutic options available. The reason for this deficiency lies in the very nature of the disease as it is deeply connected to elementary plasticity of auditory processing in the central nervous system. Understanding these mechanisms is essential for developing a therapy that reverses the plastic changes underlying the pathogenesis of tinnitus. This requires experiments that address individual neurons and small networks, something usually not feasible in human patients. However, in animals such invasive experiments on the level of single neurons with high spatial and temporal resolution are possible. Therefore, animal models are a very critical element in the combined efforts for engineering new therapies. This review provides an overview over the most important features of animal models of tinnitus: which laboratory species are suitable, how to induce tinnitus, and how to characterize the perceived tinnitus by behavioral means. In particular, these aspects of tinnitus animal models are discussed in the light of transferability to the human patients. PMID:24829805

  3. Extrapyramidal system neurotoxicity: animal models.

    PubMed

    Dorman, David

    2015-01-01

    The central nervous system's extrapyramidal system provides involuntary motor control to the muscles of the head, neck, and limbs. Toxicants that affect the extrapyramidal system are generally clinically characterized by impaired motor control, which is usually the result of basal ganglionic dysfunction. A variety of extrapyramidal syndromes are recognized in humans and include Parkinson's disease, secondary parkinsonism, other degenerative diseases of the basal ganglia, and clinical syndromes that result in dystonia, dyskinesia, essential tremor, and other forms of tremor and chorea. This chapter briefly reviews the anatomy of the extrapyramidal system and discusses several naturally occurring and experimental models that target the mammalian (nonhuman) extrapyramidal system. Topics discussed include extrapyramidal syndromes associated with antipsychotic drugs, carbon monoxide, reserpine, cyanide, rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and manganese. In most cases, animals are used as experimental models to improve our understanding of the toxicity and pathogenesis of these agents. Another agent discussed in this chapter, yellowstar thistle poisoning in horses, however, represents an important spontaneous cause of parkinsonism that naturally occurs in animals. The central focus of the chapter is on animal models, especially the concordance between clinical signs, neurochemical changes, and neuropathology between animals and people. PMID:26563791

  4. Animal Models of Sleep Disorders

    PubMed Central

    Toth, Linda A; Bhargava, Pavan

    2013-01-01

    Problems with sleep affect a large part of the general population, with more than half of all people in the United States reporting difficulties with sleep or insufficient sleep at various times and about 40 million affected chronically. Sleep is a complex physiologic process that is influenced by many internal and environmental factors, and problems with sleep are often related to specific personal circumstances or are based on subjective reports from the affected person. Although human subjects are used widely in the study of sleep and sleep disorders, the study of animals has been invaluable in developing our understanding about the physiology of sleep and the underlying mechanisms of sleep disorders. Historically, the use of animals for the study of sleep disorders has arguably been most fruitful for the condition of narcolepsy, in which studies of dogs and mice revealed previously unsuspected mechanisms for this condition. The current overview considers animal models that have been used to study 4 of the most common human sleep disorders—insomnia, narcolepsy, restless legs syndrome, and sleep apnea—and summarizes considerations relevant to the use of animals for the study of sleep and sleep disorders. Animal-based research has been vital to the elucidation of mechanisms that underlie sleep, its regulation, and its disorders and undoubtedly will remain crucial for discovering and validating sleep mechanisms and testing interventions for sleep disorders. PMID:23582416

  5. Radiation dosimetry and biophysical models of space radiation effects

    NASA Technical Reports Server (NTRS)

    Cucinotta, Francis A.; Wu, Honglu; Shavers, Mark R.; George, Kerry

    2003-01-01

    Estimating the biological risks from space radiation remains a difficult problem because of the many radiation types including protons, heavy ions, and secondary neutrons, and the absence of epidemiology data for these radiation types. Developing useful biophysical parameters or models that relate energy deposition by space particles to the probabilities of biological outcomes is a complex problem. Physical measurements of space radiation include the absorbed dose, dose equivalent, and linear energy transfer (LET) spectra. In contrast to conventional dosimetric methods, models of radiation track structure provide descriptions of energy deposition events in biomolecules, cells, or tissues, which can be used to develop biophysical models of radiation risks. In this paper, we address the biophysical description of heavy particle tracks in the context of the interpretation of both space radiation dosimetry and radiobiology data, which may provide insights into new approaches to these problems.

  6. Biliary atresia: the animal models.

    PubMed

    Petersen, Claus

    2012-08-01

    Biliary atresia (BA) is a progressive fibrosing process of the neonatal biliary tree and liver, of unknown origin, and an as-yet unexplained pathologic mechanism. The crucial point is to elucidate the origin of this rare disease to change palliative surgery to etiology-related procedures. Patient-based research can only begin at the time of the Kasai procedure and does not allow retracing of the pathology back to its origin. Basic research has focused on similar diseases in the veterinary literature and started to simulate BA in animal models. Unfortunately, even after 50 years of research, no knowledge has been gained from such models, which has led to a single clinical application. This article reviews BA in the context of the animal models available and discusses whether future studies are promising or futile. PMID:22800971

  7. Animal models of source memory.

    PubMed

    Crystal, Jonathon D

    2016-01-01

    Source memory is the aspect of episodic memory that encodes the origin (i.e., source) of information acquired in the past. Episodic memory (i.e., our memories for unique personal past events) typically involves source memory because those memories focus on the origin of previous events. Source memory is at work when, for example, someone tells a favorite joke to a person while avoiding retelling the joke to the friend who originally shared the joke. Importantly, source memory permits differentiation of one episodic memory from another because source memory includes features that were present when the different memories were formed. This article reviews recent efforts to develop an animal model of source memory using rats. Experiments are reviewed which suggest that source memory is dissociated from other forms of memory. The review highlights strengths and weaknesses of a number of animal models of episodic memory. Animal models of source memory may be used to probe the biological bases of memory. Moreover, these models can be combined with genetic models of Alzheimer's disease to evaluate pharmacotherapies that ultimately have the potential to improve memory. PMID:26609644

  8. Methods and Models of the Hanford Internal Dosimetry Program, PNNL-MA-860

    SciTech Connect

    Carbaugh, Eugene H.; Bihl, Donald E.; Maclellan, Jay A.

    2003-01-03

    This manual describes the technical basis for the design of the routine radiobioassay monitoring program and assessments of internal dose. Its purpose is to provide a historical record of the methods, models, and assumptions used for internal dosimetry at Hanford, and serve as a technical reference for radiation protection and dosimetry staff.

  9. Animal models for human sexuality.

    PubMed

    Beach, F A

    The value of animal models in biomedical research is firmly established, and many basic principles of human psychology have been explicated as the result of comparative studies. There is pressing need for non-human models in the behavioural sciences as represented by psychiatry, psychology and ethology; and such models should be constructed, provided their validity can be assured. Valid models cannot be based exclusively on similarity in the formal properties of behaviour. Commonality of descriptive terms as applied to different species does not guarantee identity of the concepts to which the terms apply. Model builders must evaluate interspecific similarities and differences in the causes, mediating mechanisms and functional outcomes of behaviour. The validity of interspecific generalization can never exceed the reliability of intraspecific analysis; and the latter is an indispensable antecedent of the former. Existing and potential models for homosexuality and other psychosexual characteristics of human beings are evaluated within the perspective provided by the foregoing generalizations. PMID:256826

  10. Animal models for microbicide studies

    PubMed Central

    Veazey, Ronald S.; Shattock, Robin J; Klasse, Per Johan; Moore, John P.

    2013-01-01

    There have been encouraging recent successes in the development of safe and effective topical microbicides to prevent vaginal or rectal HIV-1 transmission, based on the use of anti-retroviral drugs. However, much work remains to be accomplished before a microbicide becomes a standard element of prevention science strategies. Animal models should continue to play an important role in pre-clinical testing, with emphasis on safety, pharmacokinetic and efficacy testing. PMID:22264049

  11. Comparison of old and new ICRP models for respiratory tract dosimetry

    SciTech Connect

    Boecker, B.B.

    1993-12-31

    This paper examines the historical development and application of respiratory tract dosimetry models by the International Commission for Radiological Protection, ICRP, for health protection from inhaled radioactive aerosols. Three different models are discussed, those that were included in ICRP recommendations published in 1960 and 1979, and the new ICRP Publication 66. Basic features of these models are compared and contrasted. These features include model structure, sites and frequencies of particle deposition, processes and rates of clearance of the deposited material from the respiratory tract, and consideration of the parameters involved in these processes and how various factors can influence these parameters. All three models lead to the calculation of absorbed radiation doses with differing degrees of regional and local specificity. These calculations are achieved using different tools ranging from quick hand calculations to sophisticated computerized modeling approaches. A side-by-side review of these models indicates several important trends in respiratory tract dosimetry models, the most obvious of which is the increased complexity of each new model over the past 30+ years. These increases reflect both the increasing size of the knowledge base derived from studies in laboratory animals and in human subjects and the need for models more broadly applicable for both occupational and environmental exposures. It is likely that future research will be directed to those key aspects of the new model having the largest uncertainties. The detailed design of the new model and its associated software provide excellent means of identifying useful research areas and using the resulting new information in organized and productive ways.

  12. Inhalation reference dose (RfDi): an application of interspecies dosimetry modeling for risk assessment of insoluble particles.

    PubMed

    Jarabek, A M; Menache, M G; Overton, J H; Dourson, M L; Miller, F J

    1989-01-01

    Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation. PMID:2606680

  13. Inhalation reference dose (RfDi): An application of interspecies dosimetry modeling for risk assessment of insoluble particles

    SciTech Connect

    Jarabek, A.M.; Menache, M.G.; Overton, J.H. Jr.; Dourson, M.L.; Miller, F.J. )

    1989-01-01

    Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses (the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity) for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated. Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

  14. Animal models of serotonergic psychedelics.

    PubMed

    Hanks, James B; González-Maeso, Javier

    2013-01-16

    The serotonin 5-HT(2A) receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects. PMID:23336043

  15. Software Validation via Model Animation

    NASA Technical Reports Server (NTRS)

    Dutle, Aaron M.; Munoz, Cesar A.; Narkawicz, Anthony J.; Butler, Ricky W.

    2015-01-01

    This paper explores a new approach to validating software implementations that have been produced from formally-verified algorithms. Although visual inspection gives some confidence that the implementations faithfully reflect the formal models, it does not provide complete assurance that the software is correct. The proposed approach, which is based on animation of formal specifications, compares the outputs computed by the software implementations on a given suite of input values to the outputs computed by the formal models on the same inputs, and determines if they are equal up to a given tolerance. The approach is illustrated on a prototype air traffic management system that computes simple kinematic trajectories for aircraft. Proofs for the mathematical models of the system's algorithms are carried out in the Prototype Verification System (PVS). The animation tool PVSio is used to evaluate the formal models on a set of randomly generated test cases. Output values computed by PVSio are compared against output values computed by the actual software. This comparison improves the assurance that the translation from formal models to code is faithful and that, for example, floating point errors do not greatly affect correctness and safety properties.

  16. Animal models of erectile dysfunction

    PubMed Central

    Gajbhiye, Snehlata V.; Jadhav, Kshitij S.; Marathe, Padmaja A.; Pawar, Dattatray B.

    2015-01-01

    Animal models have contributed to a great extent to understanding and advancement in the field of sexual medicine. Many current medical and surgical therapies in sexual medicine have been tried based on these animal models. Extensive literature search revealed that the compiled information is limited. In this review, we describe various experimental models of erectile dysfunction (ED) encompassing their procedures, variables of assessment, advantages and disadvantages. The search strategy consisted of review of PubMed based articles. We included original research work and certain review articles available in PubMed database. The search terms used were “ED and experimental models,” “ED and nervous stimulation,” “ED and cavernous nerve stimulation,” “ED and central stimulation,” “ED and diabetes mellitus,” “ED and ageing,” “ED and hypercholesteremia,” “ED and Peyronie's disease,” “radiation induced ED,” “telemetric recording,” “ED and mating test” and “ED and non-contact erection test.” PMID:25624570

  17. Dosimetry modeling of inhaled formaldehyde: the human respiratory tract.

    PubMed

    Overton, J H; Kimbell, J S; Miller, F J

    2001-11-01

    Formaldehyde (HCHO), which has been shown to be a nasal carcinogen in rats and mice, is used widely and extensively in various manufacturing processes. Studies in rhesus monkeys suggest that the lower respiratory tract may be at risk and some epidemiologic studies have reported an increase in lung cancer associated with HCHO; other studies have not. Thus, an assessment of possible human risk to HCHO exposure based on dosimetry information throughout the respiratory tract (RT) is desirable. To obtain dosimetry estimates for a risk assessment, two types of models were used. The first model (which is the subject of another investigation) used computational fluid dynamics (CFD) to estimate local fluxes in a 3-dimensional model of the nasal region. The subject of the present investigation (the second model) applied a 1-dimensional equation of mass transport to each generation of an adult human symmetric, bifurcating Weibel-type RT anatomical model, augmented by an upper respiratory tract. The two types of modeling approaches were made consistent by requiring that the 1-dimensional version of the nasal passages have the same inspiratory air-flow rate and uptake during inspiration as the CFD simulations for 4 daily human activity levels. Results obtained include the following: (1) More than 95% of the inhaled HCHO is predicted to be retained by the RT. (2) The CFD predictions for inspiration, modified to account for the difference in inspiration and complete breath times, are a good approximation to uptake in the nasal airways during a single breath. (3) In the lower respiratory tract, flux is predicted to increase for several generations and then decrease rapidly. (4) Compared to first pulmonary region generation fluxes, the first few tracheobronchial generations fluxes are over 1000 times larger. Further, there is essentially no flux in the alveolar sacs. (5) Predicted fluxes based on the 1-dimensional model are presented that can be used in a biologically based dose

  18. Animal models of adrenocortical tumorigenesis

    PubMed Central

    Beuschlein, Felix; Galac, Sara; Wilson, David B.

    2011-01-01

    Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species – mouse, ferret, and dog – are reviewed, and their relevance to adrenocortical tumors in humans is discussed. PMID:22100615

  19. An animal model of fetishism.

    PubMed

    Köksal, Falih; Domjan, Michael; Kurt, Adnan; Sertel, Ozlem; Orüng, Sabiha; Bowers, Rob; Kumru, Gulsen

    2004-12-01

    An animal model of sexual fetishism was developed with male Japanese quail based on persistence of conditioned sexual responding during extinction to an inanimate object made of terrycloth (Experiments 1 and 3). This persistent responding occurred only in subjects that came to copulate with the terrycloth object, suggesting that the copulatory behavior served to maintain the fetishistic behavior. Sexual conditioning was carried out by pairing a conditioned stimulus (CS) with the opportunity to copulate with a female (the unconditioned stimulus or US). Copulation with the CS object and persistent responding did not develop if the CS was a light (Experiment 1) or if conditioning was carried out with a food US (Experiment 2). In addition, subjects that showed persistence in responding to the terrycloth CS did not persist in their responding to a light CS (Experiment 3). The results are consistent with the hypothesis that conditioned copulatory behavior creates a form of self-maintenance that leads to persistent responding to an inanimate object. The development of an animal model of such fetishistic behavior should facilitate experimental analysis of the phenomenon. PMID:15500813

  20. Animal models of cartilage repair

    PubMed Central

    Cook, J. L.; Hung, C. T.; Kuroki, K.; Stoker, A. M.; Cook, C. R.; Pfeiffer, F. M.; Sherman, S. L.; Stannard, J. P.

    2014-01-01

    Cartilage repair in terms of replacement, or regeneration of damaged or diseased articular cartilage with functional tissue, is the ‘holy grail’ of joint surgery. A wide spectrum of strategies for cartilage repair currently exists and several of these techniques have been reported to be associated with successful clinical outcomes for appropriately selected indications. However, based on respective advantages, disadvantages, and limitations, no single strategy, or even combination of strategies, provides surgeons with viable options for attaining successful long-term outcomes in the majority of patients. As such, development of novel techniques and optimisation of current techniques need to be, and are, the focus of a great deal of research from the basic science level to clinical trials. Translational research that bridges scientific discoveries to clinical application involves the use of animal models in order to assess safety and efficacy for regulatory approval for human use. This review article provides an overview of animal models for cartilage repair. Cite this article: Bone Joint Res 2014;4:89–94. PMID:24695750

  1. Animal Models of Autoimmune Neuropathy

    PubMed Central

    Soliven, Betty

    2014-01-01

    The peripheral nervous system (PNS) comprises the cranial nerves, the spinal nerves with their roots and rami, dorsal root ganglia neurons, the peripheral nerves, and peripheral components of the autonomic nervous system. Cell-mediated or antibody-mediated immune attack on the PNS results in distinct clinical syndromes, which are classified based on the tempo of illness, PNS component(s) involved, and the culprit antigen(s) identified. Insights into the pathogenesis of autoimmune neuropathy have been provided by ex vivo immunologic studies, biopsy materials, electrophysiologic studies, and experimental models. This review article summarizes earlier seminal observations and highlights the recent progress in our understanding of immunopathogenesis of autoimmune neuropathies based on data from animal models. PMID:24615441

  2. Inhalation reference dose (RfDi): An application of interspecies dosimetry modeling for risk assessment of insoluble particles

    SciTech Connect

    Jarabek, A.M.; Menache, M.G.; Overton, H.; Dourson, M.L.; Miller, F.J.

    1989-01-01

    Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses (the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity) for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of the methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. The paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

  3. Animal models and conserved processes

    PubMed Central

    2012-01-01

    Background The concept of conserved processes presents unique opportunities for using nonhuman animal models in biomedical research. However, the concept must be examined in the context that humans and nonhuman animals are evolved, complex, adaptive systems. Given that nonhuman animals are examples of living systems that are differently complex from humans, what does the existence of a conserved gene or process imply for inter-species extrapolation? Methods We surveyed the literature including philosophy of science, biological complexity, conserved processes, evolutionary biology, comparative medicine, anti-neoplastic agents, inhalational anesthetics, and drug development journals in order to determine the value of nonhuman animal models when studying conserved processes. Results Evolution through natural selection has employed components and processes both to produce the same outcomes among species but also to generate different functions and traits. Many genes and processes are conserved, but new combinations of these processes or different regulation of the genes involved in these processes have resulted in unique organisms. Further, there is a hierarchy of organization in complex living systems. At some levels, the components are simple systems that can be analyzed by mathematics or the physical sciences, while at other levels the system cannot be fully analyzed by reducing it to a physical system. The study of complex living systems must alternate between focusing on the parts and examining the intact whole organism while taking into account the connections between the two. Systems biology aims for this holism. We examined the actions of inhalational anesthetic agents and anti-neoplastic agents in order to address what the characteristics of complex living systems imply for inter-species extrapolation of traits and responses related to conserved processes. Conclusion We conclude that even the presence of conserved processes is insufficient for inter

  4. Comptational comparison of asbestos fibers: Dosimetry model simulations to characterize variabilty and potency (Presentation poster)

    EPA Science Inventory

    Inhaled asbestos fibers result in respiratory diseases such as asbestosis, lung cancer and mesothelioma, but different asbestos fibers exhibit different potency. We applied a recently developed dosimetry model (Asgharian et al., Poster # 104) that describes th...

  5. Computational dosimetry

    SciTech Connect

    Siebert, B.R.L.; Thomas, R.H.

    1996-01-01

    The paper presents a definition of the term ``Computational Dosimetry`` that is interpreted as the sub-discipline of computational physics which is devoted to radiation metrology. It is shown that computational dosimetry is more than a mere collection of computational methods. Computational simulations directed at basic understanding and modelling are important tools provided by computational dosimetry, while another very important application is the support that it can give to the design, optimization and analysis of experiments. However, the primary task of computational dosimetry is to reduce the variance in the determination of absorbed dose (and its related quantities), for example in the disciplines of radiological protection and radiation therapy. In this paper emphasis is given to the discussion of potential pitfalls in the applications of computational dosimetry and recommendations are given for their avoidance. The need for comparison of calculated and experimental data whenever possible is strongly stressed.

  6. Animal models of recurrent or bipolar depression.

    PubMed

    Kato, T; Kasahara, T; Kubota-Sakashita, M; Kato, T M; Nakajima, K

    2016-05-01

    Animal models of mental disorders should ideally have construct, face, and predictive validity, but current animal models do not always satisfy these validity criteria. Additionally, animal models of depression rely mainly on stress-induced behavioral changes. These stress-induced models have limited validity, because stress is not a risk factor specific to depression, and the models do not recapitulate the recurrent and spontaneous nature of depressive episodes. Although animal models exhibiting recurrent depressive episodes or bipolar depression have not yet been established, several researchers are trying to generate such animals by modeling clinical risk factors as well as by manipulating a specific neural circuit using emerging techniques. PMID:26265551

  7. Light delivery and dosimetry for photodynamic therapy in an ovarian cancer mouse model

    NASA Astrophysics Data System (ADS)

    Lilge, Lothar D.; Dabrowski, W.; Holdsworth, David W.; Blake, J.; Kato, D.; Wilson, Brian C.; Hasan, Tayyaba

    1994-07-01

    The Swiss nude mouse model is currently used as an animal model to investigate the efficacy of photodynamic therapy in ovarian cancer treatment. The disease requires treatment illumination of the entire abdominal cavity. The close proximity of the internal organs in the abdomen of a mouse and the vastly different optical properties of these organs present a challenge to light delivery and dosimetry. In this study the efficacy of different internal and transcutaneous light delivery geometries was investigated by scanning a transverse plane of the peritoneum with optical fiber fluence-rate detectors. The placement of the implanted optical fibers in the abdominal cavity was verified post mortem in selected animals by high resolution CT imaging. Preliminary experiments were performed to correlate the biological response with actual total fluence delivered to the abdominal cavity. Optical fiber fluence rate detectors were implanted in the peritoneum and abdominal cavity and the animal was treated with PDT. Cell survival of one hour post light treatment harvested cells from the peritoneum was used as a biological response quantifier.

  8. Analytical modeling of thermoluminescent albedo detectors for neutron dosimetry.

    PubMed

    Glickstein, S S

    1983-02-01

    In order to gain an in-depth understanding of the neutron physics of a 6LiF TLD when used as an albedo neutron dosimeter, an analytical model was developed to simulate the response of a 6LiF chip. The analytical model was used to examine the sensitivity of the albedo TLD response to incident monoenergetic neutrons and to evaluate a multiple chip TLD neutron dosimeter. Contrary to initial experimental studies, which were hampered by statistical uncertainties, the analytical evaluation revealed that a three-energy-group detector could not reliably measure the dose equivalent to personnel exposed to multiple neutron spectra. The analysis clearly illustrates that there may be order of magnitude errors in the measured neutron dose if the dosimeter has not been calibrated for the same flux spectrum to which it is exposed. As a result of this analysis, it was concluded that, for personnel neutron monitoring, a present TLD badge must be calibrated for the neutron spectrum into which the badge is to be introduced. The analytical model used in this study can readily be adopted for evaluating other possible detectors and shield material that might be proposed in the future as suitable for use in neutron dosimetry applications. PMID:6826377

  9. Parathyroid diseases and animal models.

    PubMed

    Imanishi, Yasuo; Nagata, Yuki; Inaba, Masaaki

    2012-01-01

    CIRCULATING CALCIUM AND PHOSPHATE ARE TIGHTLY REGULATED BY THREE HORMONES: the active form of vitamin D (1,25-dihydroxyvitamin D), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). PTH acts to stimulate a rapid increment in serum calcium and has a crucial role in calcium homeostasis. Major target organs of PTH are kidney and bone. The oversecretion of the hormone results in hypercalcemia, caused by increased intestinal calcium absorption, reduced renal calcium clearance, and mobilization of calcium from bone in primary hyperparathyroidism. In chronic kidney disease, secondary hyperparathyroidism of uremia is observed in its early stages, and this finally develops into the autonomous secretion of PTH during maintenance hemodialysis. Receptors in parathyroid cells, such as the calcium-sensing receptor, vitamin D receptor, and FGF receptor (FGFR)-Klotho complex have crucial roles in the regulation of PTH secretion. Genes such as Cyclin D1, RET, MEN1, HRPT2, and CDKN1B have been identified in parathyroid diseases. Genetically engineered animals with these receptors and the associated genes have provided us with valuable information on the patho-physiology of parathyroid diseases. The application of these animal models is significant for the development of new therapies. PMID:22754549

  10. Animal Models of Williams Syndrome

    PubMed Central

    OSBORNE, LUCY R.

    2010-01-01

    In recent years, researchers have generated a variety of mouse models in an attempt to dissect the contribution of individual genes to the complex phenotype associated with Williams syndrome (WS). The mouse genome is easily manipulated to produce animals that are copies of humans with genetic conditions, be it with null mutations, hypomorphic mutations, point mutations, or even large deletions encompassing many genes. The existing mouse models certainly seem to implicate hemizygosity for ELN, BAZ1B, CLIP2, and GTF2IRD1 in WS, and new mice with large deletions of the WS region are helping us to understand both the additive and potential combinatorial effects of hemizygosity for specific genes. However, not all genes that are haploinsufficient in humans prove to be so in mice and the effect of genetic background can also have a significant effect on the penetrance of many phenotypes. Thus although mouse models are powerful tools, the information garnered from their study must be carefully interpreted. Nevertheless, mouse models look set to provide a wealth of information about the neuroanatomy, neurophysiology and molecular pathways that underlie WS and in the future will act as essential tools for the development and testing of therapeutics. PMID:20425782

  11. Tumor dosimetry for I-131 trastuzumab therapy in a Her2+ NCI N87 xenograft mouse model using the Siemens SYMBIA E gamma camera with a pinhole collimator

    NASA Astrophysics Data System (ADS)

    Lee, Young Sub; Kim, Jin Su; Deuk Cho, Kyung; Kang, Joo Hyun; Moo Lim, Sang

    2015-07-01

    We performed imaging and therapy using I-131 trastuzumab and a pinhole collimator attached to a conventional gamma camera for human use in a mouse model. The conventional clinical gamma camera with a 2-mm radius-sized pinhole collimator was used for monitoring the animal model after administration of I-131 trastuzumab The highest and lowest radiation-received organs were osteogenic cells (0.349 mSv/MBq) and skin (0.137 mSv/MBq), respectively. The mean coefficients of variation (%CV) of the effective dose equivalent and effective dose were 0.091 and 0.093 mSv/MBq respectively. We showed the feasibility of the pinholeattached conventional gamma camera for human use for the assessment of dosimetry. Mouse dosimetry and prediction of human dosimetry could be used to provide data for the safety and efficacy of newly developed therapeutic schemes.

  12. Dosimetry Model for Radioactivity Localized to Intestinal Mucosa

    SciTech Connect

    Fisher, Darrell R.; Rajon, Didier; Breitz, Hazel B.; Goris, Michael L.; Bolch, Wesley E.; Knox, Susan J.

    2004-06-30

    This paper provides a new model for calculating radiation absorbed dose to the full thickness of the small and large intestinal walls, and to the mucosal layers. The model was used to estimate the intestinal radiation doses from yttrium-90-labeled-DOTA-biotin binding to NR-LU-10-streptavidin in patients. We selected model parameters from published data and observations and used the model to calculate energy absorbed fractions using the EGS4 radiation transport code. We determined the cumulated 90Y activity in the small and large intestines of patients from gamma camera images and calculated absorbed doses to the mucosal layer and to the whole intestinal wall. The mean absorbed dose to the wall of the small intestine was 16.2 mGy/MBq (60 cGy/mCi) administered from 90Y localized in the mucosa and 70 mGy/MBq (260 cGy/mCi) to the mucosal layer within the wall. Doses to the large intestinal wall and to the mucosa of the large intestine were lower than those for small intestine by a factor of about 2.5. These doses are greater by factors of about 5 to 6 than those that would have been calculated using the standard MIRD models that assume the intestinal activity is in the bowel contents. The specific uptake of radiopharmaceuticals in mucosal tissues may lead to dose-related intestinal toxicities. Tissue dosimetry at the sub-organ level is useful for better understanding intestinal tract radiotoxicity and associated dose-response relationships.

  13. Animal Models of Stress Urinary Incontinence

    PubMed Central

    Jiang, Hai-Hong

    2011-01-01

    Stress urinary incontinence (SUI) is a common health problem significantly affecting the quality of life of women worldwide. Animal models that simulate SUI enable the assessment of the mechanism of risk factors for SUI in a controlled fashion, including childbirth injuries, and enable preclinical testing of new treatments and therapies for SUI. Animal models that simulate childbirth are presently being utilized to determine the mechanisms of the maternal injuries of childbirth that lead to SUI with the goal of developing prophylactic treatments. Methods of assessing SUI in animals that mimic diagnostic methods used clinically have been developed to evaluate the animal models. Use of these animal models to test innovative treatment strategies has the potential to improve clinical management of SUI. This chapter provides a review of the available animal models of SUI, as well as a review of the methods of assessing SUI in animal models, and potential treatments that have been tested on these models. PMID:21290221

  14. Animal models to evaluate bacterial biofilm development.

    PubMed

    Thomsen, Kim; Trøstrup, Hannah; Moser, Claus

    2014-01-01

    Medical biofilms have attracted substantial attention especially in the past decade. Animal models are contributing significantly to understand the pathogenesis of medical biofilms. In addition, animal models are an essential tool in testing the hypothesis generated from clinical observations in patients and preclinical testing of agents showing in vitro antibiofilm effect. Here, we describe three animal models - two non-foreign body Pseudomonas aeruginosa biofilm models and a foreign body Staphylococcus aureus model. PMID:24664830

  15. Potency of Animal Models in KANSEI Engineering

    NASA Astrophysics Data System (ADS)

    Ozaki, Shigeru; Hisano, Setsuji; Iwamoto, Yoshiki

    Various species of animals have been used as animal models for neuroscience and provided critical information about the brain functions. Although it seems difficult to elucidate a highly advanced function of the human brain, animal models have potency to clarify the fundamental mechanisms of emotion, decision-making and social behavior. In this review, we will pick up common animal models and point to both the merits and demerits caused by the characteristics. We will also mention that wide-ranging approaches from animal models are advantageous to understand KANSEI as well as mind in humans.

  16. Laboratory Animal Models for Brucellosis Research

    PubMed Central

    Silva, Teane M. A.; Costa, Erica A.; Paixão, Tatiane A.; Tsolis, Renée M.; Santos, Renato L.

    2011-01-01

    Brucellosis is a chronic infectious disease caused by Brucella spp., a Gram-negative facultative intracellular pathogen that affects humans and animals, leading to significant impact on public health and animal industry. Human brucellosis is considered the most prevalent bacterial zoonosis in the world and is characterized by fever, weight loss, depression, hepato/splenomegaly, osteoarticular, and genital infections. Relevant aspects of Brucella pathogenesis have been intensively investigated in culture cells and animal models. The mouse is the animal model more commonly used to study chronic infection caused by Brucella. This model is most frequently used to investigate specific pathogenic factors of Brucella spp., to characterize the host immune response, and to evaluate therapeutics and vaccines. Other animal species have been used as models for brucellosis including rats, guinea pigs, and monkeys. This paper discusses the murine and other laboratory animal models for human and animal brucellosis. PMID:21403904

  17. Animal Models and Integrated Nested Laplace Approximations

    PubMed Central

    Holand, Anna Marie; Steinsland, Ingelin; Martino, Sara; Jensen, Henrik

    2013-01-01

    Animal models are generalized linear mixed models used in evolutionary biology and animal breeding to identify the genetic part of traits. Integrated Nested Laplace Approximation (INLA) is a methodology for making fast, nonsampling-based Bayesian inference for hierarchical Gaussian Markov models. In this article, we demonstrate that the INLA methodology can be used for many versions of Bayesian animal models. We analyze animal models for both synthetic case studies and house sparrow (Passer domesticus) population case studies with Gaussian, binomial, and Poisson likelihoods using INLA. Inference results are compared with results using Markov Chain Monte Carlo methods. For model choice we use difference in deviance information criteria (DIC). We suggest and show how to evaluate differences in DIC by comparing them with sampling results from simulation studies. We also introduce an R package, AnimalINLA, for easy and fast inference for Bayesian Animal models using INLA. PMID:23708299

  18. Monte Carlo modeling in CT-based geometries: dosimetry for biological modeling experiments with particle beam radiation

    PubMed Central

    Diffenderfer, Eric S.; Dolney, Derek; Schaettler, Maximilian; Sanzari, Jenine K.; Mcdonough, James; Cengel, Keith A.

    2014-01-01

    The space radiation environment imposes increased dangers of exposure to ionizing radiation, particularly during a solar particle event (SPE). These events consist primarily of low energy protons that produce a highly inhomogeneous dose distribution. Due to this inherent dose heterogeneity, experiments designed to investigate the radiobiological effects of SPE radiation present difficulties in evaluating and interpreting dose to sensitive organs. To address this challenge, we used the Geant4 Monte Carlo simulation framework to develop dosimetry software that uses computed tomography (CT) images and provides radiation transport simulations incorporating all relevant physical interaction processes. We found that this simulation accurately predicts measured data in phantoms and can be applied to model dose in radiobiological experiments with animal models exposed to charged particle (electron and proton) beams. This study clearly demonstrates the value of Monte Carlo radiation transport methods for two critically interrelated uses: (i) determining the overall dose distribution and dose levels to specific organ systems for animal experiments with SPE-like radiation, and (ii) interpreting the effect of random and systematic variations in experimental variables (e.g. animal movement during long exposures) on the dose distributions and consequent biological effects from SPE-like radiation exposure. The software developed and validated in this study represents a critically important new tool that allows integration of computational and biological modeling for evaluating the biological outcomes of exposures to inhomogeneous SPE-like radiation dose distributions, and has potential applications for other environmental and therapeutic exposure simulations. PMID:24309720

  19. Testis dosimetry in individual patients by combining a small-scale dosimetry model and pharmacokinetic modeling-application of 111In-Ibritumomab Tiuxetan (Zevalin®)

    NASA Astrophysics Data System (ADS)

    Meerkhan, Suaad A.; Sjögreen-Gleisner, Katarina; Larsson, Erik; Strand, Sven-Erik; Jönsson, Bo-Anders

    2014-12-01

    A heterogeneous distribution of radionuclides emitting low-energy electrons in the testicles may result in a significant difference between an absorbed dose to the radiosensitive spermatogonia and the mean absorbed dose to the whole testis. This study focused on absorbed dose distribution in patients at a finer scale than normally available in clinical dosimetry, which was accomplished by combining a small-scale dosimetry model with patient pharmacokinetic data. The activity in the testes was measured and blood sampling was performed for patients that underwent pre-therapy imaging with 111In-Zevalin®. Using compartment modeling, testicular activity was separated into two components: vascular and extravascular. The uncertainty of absorbed dose due to geometry variations between testicles was explored by an assumed activity micro-distribution and by varying the radius of the interstitial tubule. Results showed that the absorbed dose to germ cells might be strongly dependent on the location of the radioactive source, and may exceed the absorbed dose to the whole testis by as much as a factor of two. Small-scale dosimetry combined with compartmental analysis of clinical data proved useful for gauging tissue dosimetry and interpreting how intrinsic geometric variation influences the absorbed dose.

  20. Animal models of tuberculosis for vaccine development.

    PubMed

    Gupta, U D; Katoch, V M

    2009-01-01

    Animal models for testing different vaccine candidates have been developed since a long time for studying tuberculosis. Mice, guinea pigs and rabbits are animals most frequently used. Each model has its own merits for studying human tuberculosis, and none completely mimics the human disease. Different animal models are being used depending upon the availability of the space, trained manpower as well as other resources. Efforts should continue to develop a vaccine which can replace/outperform the presently available vaccine BCG. PMID:19287053

  1. Respiratory-tract dosimetry modeling of air toxics

    SciTech Connect

    Overton, J.H.

    1988-05-01

    Development of a PBPK for the whole body in which inhalation, exhalation, and metabolism in RT tissues can be simulated is described. As an example of the model's use, the results of several experiments in which rats and humans were exposed to styrene were simulated. The predicted results agreed with the empirical data. This model results were also in agreement with the results of the model of Ramsey and Anderson (1984) which, unlike the present model, does not simulate inhalation and exhalation or explicitly model the URT and TB region. In addition to describing the development and simulation results of a PBPK model, a procedure was illustrated that used such models in combination with laboratory animal data to predict doses in humans.

  2. Pain assessment in animal models of osteoarthritis.

    PubMed

    Piel, Margaret J; Kroin, Jeffrey S; van Wijnen, Andre J; Kc, Ranjan; Im, Hee-Jeong

    2014-03-10

    Assessment of pain in animal models of osteoarthritis is integral to interpretation of a model's utility in representing the clinical condition, and enabling accurate translational medicine. Here we describe behavioral pain assessments available for small and large experimental osteoarthritic pain animal models. PMID:24333346

  3. LOWER RESPIRATORY TRACT STRUCTURE OF LABORATORY ANIMALS AND HUMANS: DOSIMETRY IMPLICATIONS

    EPA Science Inventory

    Significant differences in lower respiratory tract structure exist both within an animal and between species at each level of anatomy. rregular bipodial and tripodial branching patterns of airways are present in human an nonhuman primate lungs. n contrast, the dog and common labo...

  4. Evaluation of spinal cord injury animal models

    PubMed Central

    Zhang, Ning; Fang, Marong; Chen, Haohao; Gou, Fangming; Ding, Mingxing

    2014-01-01

    Because there is no curative treatment for spinal cord injury, establishing an ideal animal model is important to identify injury mechanisms and develop therapies for individuals suffering from spinal cord injuries. In this article, we systematically review and analyze various kinds of animal models of spinal cord injury and assess their advantages and disadvantages for further studies. PMID:25598784

  5. Experimental Animal Models in Periodontology: A Review

    PubMed Central

    Struillou, Xavier; Boutigny, Hervé; Soueidan, Assem; Layrolle, Pierre

    2010-01-01

    In periodontal research, animal studies are complementary to in vitro experiments prior to testing new treatments. Animal models should make possible the validation of hypotheses and prove the safety and efficacy of new regenerating approaches using biomaterials, growth factors or stem cells. A review of the literature was carried out by using electronic databases (PubMed, ISI Web of Science). Numerous animal models in different species such as rats, hamsters, rabbits, ferrets, canines and primates have been used for modeling human periodontal diseases and treatments. However, both the anatomy and physiopathology of animals are different from those of humans, making difficult the evaluation of new therapies. Experimental models have been developed in order to reproduce major periodontal diseases (gingivitis, periodontitis), their pathogenesis and to investigate new surgical techniques. The aim of this review is to define the most pertinent animal models for periodontal research depending on the hypothesis and expected results. PMID:20556202

  6. Animal models for the study of tendinopathy

    PubMed Central

    Warden, S J

    2007-01-01

    Tendinopathy is a common and significant clinical problem characterised by activity‐related pain, focal tendon tenderness and intratendinous imaging changes. Recent histopathological studies have indicated the underlying pathology to be one of tendinosis (degeneration) as opposed to tendinitis (inflammation). Relatively little is known about tendinosis and its pathogenesis. Contributing to this is an absence of validated animal models of the pathology. Animal models of tendinosis represent potential efficient and effective means of furthering our understanding of human tendinopathy and its underlying pathology. By selecting an appropriate species and introducing known risk factors for tendinopathy in humans, it is possible to develop tendon changes in animal models that are consistent with the human condition. This paper overviews the role of animal models in tendinopathy research by discussing the benefits and development of animal models of tendinosis, highlighting potential outcome measures that may be used in animal tendon research, and reviewing current animal models of tendinosis. It is hoped that with further development of animal models of tendinosis, new strategies for the prevention and treatment of tendinopathy in humans will be generated. PMID:17127722

  7. Animal Models in Studying Cerebral Arteriovenous Malformation

    PubMed Central

    Xu, Ming; Xu, Hongzhi; Qin, Zhiyong

    2015-01-01

    Brain arteriovenous malformation (AVM) is an important cause of hemorrhagic stroke. The etiology is largely unknown and the therapeutics are controversial. A review of AVM-associated animal models may be helpful in order to understand the up-to-date knowledge and promote further research about the disease. We searched PubMed till December 31, 2014, with the term “arteriovenous malformation,” limiting results to animals and English language. Publications that described creations of AVM animal models or investigated AVM-related mechanisms and treatments using these models were reviewed. More than 100 articles fulfilling our inclusion criteria were identified, and from them eight different types of the original models were summarized. The backgrounds and procedures of these models, their applications, and research findings were demonstrated. Animal models are useful in studying the pathogenesis of AVM formation, growth, and rupture, as well as in developing and testing new treatments. Creations of preferable models are expected. PMID:26649296

  8. Engineering large animal models of human disease.

    PubMed

    Whitelaw, C Bruce A; Sheets, Timothy P; Lillico, Simon G; Telugu, Bhanu P

    2016-01-01

    The recent development of gene editing tools and methodology for use in livestock enables the production of new animal disease models. These tools facilitate site-specific mutation of the genome, allowing animals carrying known human disease mutations to be produced. In this review, we describe the various gene editing tools and how they can be used for a range of large animal models of diseases. This genomic technology is in its infancy but the expectation is that through the use of gene editing tools we will see a dramatic increase in animal model resources available for both the study of human disease and the translation of this knowledge into the clinic. Comparative pathology will be central to the productive use of these animal models and the successful translation of new therapeutic strategies. PMID:26414877

  9. Animal models of external traumatic wound infections

    PubMed Central

    Dai, Tianhong; Kharkwal, Gitika B; Tanaka, Masamitsu; Huang, Ying-Ying; Bil de Arce, Vida J

    2011-01-01

    Background: Despite advances in traumatic wound care and management, infections remain a leading cause of mortality, morbidity and economic disruption in millions of wound patients around the world. Animal models have become standard tools for studying a wide array of external traumatic wound infections and testing new antimicrobial strategies. Results: Animal models of external traumatic wound infections reported by different investigators vary in animal species used, microorganism strains, the number of microorganisms applied, the size of the wounds and for burn infections, the length of time the heated object or liquid is in contact with the skin. Methods: This review covers experimental infections in animal models of surgical wounds, skin abrasions, burns, lacerations, excisional wounds and open fractures. Conclusions: As antibiotic resistance continues to increase, more new antimicrobial approaches are urgently needed. These should be tested using standard protocols for infections in external traumatic wounds in animal models. PMID:21701256

  10. Application of a canine {sup 238}Pu dosimetry model to human bioassay data

    SciTech Connect

    Hickman, A.W. Jr.

    1991-08-01

    Associated with the use of 2{sup 238}Pu in thermoelectric power sources for space probes and power supplies for cardiac devices is the potential for human exposure to {sup 238}Pu, primarily by inhalation. In the event of human internal exposure, a means is needed for assessing the level of intake and calculating radiation doses. Several bioassay/dosimetry models have been developed for {sup 239}Pu. However, results from studies with laboratory animals have indicated that the biokinetics, and therefore the descriptive models, of {sup 238}Pu are significantly different from those for {sup 239}Pu. A canine model accounting for these differences has been applied in this work to urinary excretion data from seven humans occupationally exposed to low levels of an insoluble {sup 238}Pu compound. The modified model provides a good description of the urinary excretion kinetics observed in the exposed humans. The modified model was also used to provide estimates of the initial intakes of {sup 238}Pu for the seven individuals; these estimates ranged from 4.5 nCi (170 Bq) to 87 nCi (3200 Bq). Autopsy data on the amount and distribution of {sup 238}Pu retained in the organs may be used in the future to validate or refute both these estimates and the assumptions used to formulate the human model. Modification of the human model to simulate an injection exposure to {sup 239}Pu gave patterns of retention in the organs and urinary excretion comparable to those seen previously in humans; further modification of the model using fecal data (unavailable for the subjects of this study) is indicated.

  11. 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

  12. Animal Models of Human Granulocyte Diseases

    PubMed Central

    Schäffer, Alejandro A.; Klein, Christoph

    2012-01-01

    In vivo animal models have proven very useful to understand basic biological pathways of the immune system, a prerequisite for the development of innovate therapies. This manuscript addresses currently available models for defined human monogenetic defects of neutrophil granulocytes, including murine, zebrafish and larger mammalian species. Strengths and weaknesses of each system are summarized, and clinical investigators may thus be inspired to develop further lines of research to improve diagnosis and therapy by use of the appropriate animal model system. PMID:23351993

  13. Skeletal dosimetry models for alpha-particles for use in molecular radiotherapy

    NASA Astrophysics Data System (ADS)

    Watchman, Christopher J.

    Molecular radiotherapy is a cancer treatment methodology whereby a radionuclide is combined with a biologically active molecule to preferentially target cancer cells. Alpha-particle emitting radionuclides show significant potential for use in molecular radiotherapy due to the short range of the alpha-particles in tissue and their high rates of energy deposition. Current radiation dosimetry models used to assess alpha emitter dose in the skeleton were developed originally for occupational applications. In medical dosimetry, individual variability in uptake, translocation and other biological factors can result in poor correlation of clinical outcome with marrow dose estimates determined using existing skeletal models. Methods presented in this work were developed in response to the need for dosimetry models which account for these biological and patient-specific factors. Dosimetry models are presented for trabecular bone alpha particle dosimetry as well as a model for cortical bone dosimetry. These radiation transport models are the 3D chord-based infinite spongiosa transport model (3D-CBIST) and the chord-based infinite cortical transport model (CBICT), respectively. Absorbed fraction data for several skeletal tissues for several subjects are presented. Each modeling strategy accounts for biological parameters, such as bone marrow cellularity, not previously incorporated into alpha-particle skeletal dosimetry models used in radiation protection. Using these data a study investigating the variability in alpha-particle absorbed fractions in the human skeleton is also presented. Data is also offered relating skeletal tissue masses in individual bone sites for a range of ages. These data are necessary for dose calculations and have previously only been available as whole body tissue masses. A revised 3D-CBIST model is also presented which allows for changes in endosteum thickness to account for revised target cell location of tissues involved in the radiological

  14. Modeling the imprecision in prospective dosimetry of internal exposure to uranium.

    PubMed

    Davesne, E; Chojnacki, E; Paquet, F; Blanchardon, E

    2009-02-01

    The dosimetry of internal exposure to radionuclides is performed on the basis of biokinetic and dosimetric models. For prospective purpose, the organ or effective dose resulting from potential conditions of exposure can be calculated by applying these models with dedicated software. However, it is acknowledged that a significant uncertainty is associated with such calculation due to the variability of individual cases and to the possible lack of knowledge about some factors influencing the dosimetry. This uncertainty has been studied in a range of situations by modeling the uncertainty on the model parameters by probability distributions and propagating this uncertainty onto the dose result by Monte Carlo calculation. However, while probability distributions are well adapted to model the known variability of a parameter, they may lead to an unrealistically low estimate of the uncertainty due to a lack of knowledge about some input parameters. Here we present a mathematical method, based on the Dempster-Shafer theory, to deal with such imprecise knowledge. We apply this method to the prospective dosimetry of inhaled uranium dust in the nuclear fuel cycle when its physico-chemical properties are not precisely known. The results show an increased estimation of the range of uncertainty as compared to the application of a probabilistic method. This Dempster-Shafer method may valuably be applied in future prospective dosimetry of internal exposure in order to more realistically estimate the uncertainty resulting from an imprecise knowledge of the parameters of the dose calculation. PMID:19131736

  15. Interspecies dosimetry of reactive gases

    SciTech Connect

    Miller, F.J.; Overton, J.H.; Gerrity, T.R.; Graham, R.C.

    1987-03-01

    The development of dosimetry models that can provide a description of the uptake and distribution of inhaled compounds throughout the body and the availability of animal toxicological data are integral components for a full evaluation of potential risks associated with human exposure. Interspecies dosimetric comparisons must be approached using a model conceptualization that incorporates the major factors affecting the uptake of the gas, such as respiratory tract morphology, route of breathing, depth and rate of breathing, physicochemical properties of the gas, etc. Modeling efforts thus far have primarily focused on ozone. A comparison of theoretical predictions of delivered dose of ozone to the lower respiratory tract of man shows good agreement with dose estimates derived from experimental measurements. Applications to ozone toxicological data in animals and man have been examined that incorporate the use of dosimetry models in studying quantitative dose-response relationships.

  16. TARGETED DELIVERY OF INHALED PHARMACEUTICALS USING AN IN SILICO DOSIMETRY MODEL

    EPA Science Inventory

    We present an in silico dosimetry model which can be used for inhalation toxicology (risk assessment of inhaled air pollutants) and aerosol therapy ( targeted delivery of inhaled drugs). This work presents scientific and clinical advances beyond the development of the original in...

  17. DOSIMETRY MODELING OF INHALED FORMALDEHYDE: BINNING NASAL FLUX PREDICTIONS FOR QUANTITATIVE RISK ASSESSMENT

    EPA Science Inventory

    Dosimetry Modeling of Inhaled Formaldehyde: Binning Nasal Flux Predictions for Quantitative Risk Assessment. Kimbell, J.S., Overton, J.H., Subramaniam, R.P., Schlosser, P.M., Morgan, K.T., Conolly, R.B., and Miller, F.J. (2001). Toxicol. Sci. 000, 000:000.

    Interspecies e...

  18. Animal models for SARS and MERS coronaviruses

    PubMed Central

    Gretebeck, Lisa M; Subbarao, Kanta

    2015-01-01

    The emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV), two strains of animal coronaviruses that crossed the species barrier to infect and cause severe respiratory infections in humans within the last 12 years, have taught us that coronaviruses represent a global threat that does not recognize international borders. We can expect to see other novel coronaviruses emerge in the future. An ideal animal model should reflect the clinical signs, viral replication and pathology seen in humans. In this review, we present factors to consider in establishing an animal model for the study of novel coronaviruses and compare the different animal models that have been employed to study SARS-CoV and MERS-CoV. PMID:26184451

  19. Progress With Nonhuman Animal Models of Addiction.

    PubMed

    Crabbe, John C

    2016-09-01

    Nonhuman animals have been major contributors to the science of the genetics of addiction. Given the explosion of interest in genetics, it is fair to ask, are we making reasonable progress toward our goals with animal models? I will argue that our goals are changing and that overall progress has been steady and seems likely to continue apace. Genetics tools have developed almost incredibly rapidly, enabling both more reductionist and more synthetic or integrative approaches. I believe that these approaches to making progress have been unbalanced in biomedical science, favoring reductionism, particularly in animal genetics. I argue that substantial, novel progress is also likely to come in the other direction, toward synthesis and abstraction. Another area in which future progress with genetic animal models seems poised to contribute more is the reconciliation of human and animal phenotypes, or consilience. The inherent power of the genetic animal models could be more profitably exploited. In the end, animal research has continued to provide novel insights about how genes influence individual differences in addiction risk and consequences. The rules of the genetics game are changing so fast that it is hard to remember how comparatively little we knew even a generation ago. Rather than worry about whether we have been wasting time and resources asking the questions we have been, we should look to the future and see if we can come up with some new ones. The valuable findings from the past will endure, and the sidetracks will be forgotten. PMID:27588527

  20. Animal models in motion sickness research

    NASA Technical Reports Server (NTRS)

    Daunton, Nancy G.

    1990-01-01

    Practical information on candidate animal models for motion sickness research and on methods used to elicit and detect motion sickness in these models is provided. Four good potential models for use in motion sickness experiments include the dog, cat, squirrel monkey, and rat. It is concluded that the appropriate use of the animal models, combined with exploitation of state-of-the-art biomedical techniques, should generate a great step forward in the understanding of motion sickness mechanisms and in the development of efficient and effective approaches to its prevention and treatment in humans.

  1. Preclinical imaging and treatment of cancer: the use of animal models beyond rodents.

    PubMed

    Axiak-Bechtel, S M; Maitz, C A; Selting, K A; Bryan, J N

    2015-09-01

    The development of novel radiopharmaceutical agents for imaging and therapy of neoplastic diseases relies on accurate and reproducible animal models. Rodent models are often used to demonstrate the proof-of-principle tracer and therapeutic agent development, but their small size can make tissue sampling challenging. The dosimetry of decay emissions in the much smaller rodent tumors do not model dosimetry in human tumors well. In addition, rodent models of cancer represent a simplified version of a very complex process. Spontaneous tumors are heterogenous and the response to intervention can be unpredictable; tumor cells can adopt alternate signaling pathways and modify their interaction with the microenvironment. These inconsistencies, while present in humans, are difficult to fully reproduce in a genetically-engineered rodent model. Companion animals, primarily dogs and cats, offer translational models that more accurately reflect the intricate nature of spontaneous neoplasia in humans. Their larger size facilitates tissue and blood sampling when needed, and allows radiopharmaceutical tracers to be studied on human-scale imaging systems to better mimic the clinical application of the agent. This article will review the growing body of literature surrounding the use of radiopharmaceutical agents for both imaging and therapy in companion dogs and cats. Previous investigations have been performed both for the advancement of routine, high-level veterinary care, and in the context of translational research from which the results of imaging and treatment can be readily applied to people. Studies utilizing the spontaneously occurring cancer model in companion animals involving positron emission tomography, radiotracers, dosimetry, theranostics, targeted radiopharmaceuticals, brachytherapy, and boron neutron capture therapy are discussed. PMID:26200223

  2. Animal models of monogenic migraine.

    PubMed

    Chen, Shih-Pin; Tolner, Else A; Eikermann-Haerter, Katharina

    2016-06-01

    Migraine is a highly prevalent and disabling neurological disorder with a strong genetic component. Rare monogenic forms of migraine, or syndromes in which migraine frequently occurs, help scientists to unravel pathogenetic mechanisms of migraine and its comorbidities. Transgenic mouse models for rare monogenic mutations causing familial hemiplegic migraine (FHM), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and familial advanced sleep-phase syndrome (FASPS), have been created. Here, we review the current state of research using these mutant mice. We also discuss how currently available experimental approaches, including epigenetic studies, biomolecular analysis and optogenetic technologies, can be used for characterization of migraine genes to further unravel the functional and molecular pathways involved in migraine. PMID:27154999

  3. Animal models of acute lung injury

    PubMed Central

    Matute-Bello, Gustavo; Frevert, Charles W.; Martin, Thomas R.

    2008-01-01

    Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury. PMID:18621912

  4. Animal Eye Models for Uveal Melanoma.

    PubMed

    Cao, Jinfeng; Jager, Martine J

    2015-04-01

    Animal models play an important role in understanding tumor growth and may be used to develop novel therapies against human malignancies. The significance of the results from animal experiments depends on the selection of the proper model. Many attempts have been made to create appropriate animal models for uveal melanoma and its characteristic metastatic behavior. One approach is to use transgenic animal models or to implant tumor cells. A variety of tumor types have been used for this purpose: tumor cells, such as Greene melanoma, murine B16 melanoma, and human uveal melanoma cells, may be implanted in the eyes of hamsters, rats, rabbits, and mice, among others. Various inoculation routes, including into the anterior chamber and posterior compartment, and retro-orbitally, have been applied to obtain tumor growth mimicking ocular uveal melanoma. However, when we choose animal models, we must be conscious of many disadvantages, such as variable tumor growth, or the need for immunosuppression in xenogeneic grafts. In this paper, we will discuss the various eye models. PMID:27172424

  5. Animal Eye Models for Uveal Melanoma

    PubMed Central

    Cao, Jinfeng; Jager, Martine J.

    2015-01-01

    Animal models play an important role in understanding tumor growth and may be used to develop novel therapies against human malignancies. The significance of the results from animal experiments depends on the selection of the proper model. Many attempts have been made to create appropriate animal models for uveal melanoma and its characteristic metastatic behavior. One approach is to use transgenic animal models or to implant tumor cells. A variety of tumor types have been used for this purpose: tumor cells, such as Greene melanoma, murine B16 melanoma, and human uveal melanoma cells, may be implanted in the eyes of hamsters, rats, rabbits, and mice, among others. Various inoculation routes, including into the anterior chamber and posterior compartment, and retro-orbitally, have been applied to obtain tumor growth mimicking ocular uveal melanoma. However, when we choose animal models, we must be conscious of many disadvantages, such as variable tumor growth, or the need for immunosuppression in xenogeneic grafts. In this paper, we will discuss the various eye models. PMID:27172424

  6. Animal models of human response to dioxins.

    PubMed Central

    Grassman, J A; Masten, S A; Walker, N J; Lucier, G W

    1998-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent member of a class of chlorinated hydrocarbons that interact with the aryl hydrocarbon receptor (AhR). TCDD and dioxinlike compounds are environmentally and biologically stable and as a result, human exposure is chronic and widespread. Studies of highly exposed human populations show that dioxins produce developmental effects, chloracne, and an increase in all cancers and suggest that they may also alter immune and endocrine function. In contrast, the health effects of low-level environmental exposure have not been established. Experimental animal models can enhance the understanding of the effects of low-level dioxin exposure, particularly when there is evidence that humans respond similarly to the animal models. Although there are species differences in pharmacokinetics, experimental animal models demonstrate AhR-dependent health effects that are similar to those found in exposed human populations. Comparisons of biochemical changes show that humans and animal models have similar degrees of sensitivity to dioxin-induced effects. The information gained from animal models is important for developing mechanistic models of dioxin toxicity and critical for assessing the risks to human populations under different circumstances of exposure. PMID:9599728

  7. Animal Models for Adipose Tissue Engineering

    PubMed Central

    Uthamanthil, Rajesh; Beahm, Elisabeth; Frye, Cindy

    2008-01-01

    Abstract There is a critical need for adequate reconstruction of soft tissue defects resulting from tumor resection, trauma, and congenital abnormalities. To be sure, adipose tissue engineering strategies offer promising solutions. However, before clinical translation can occur, efficacy must be proven in animal studies. The aim of this review is to provide an overview of animal models currently employed for adipose tissue engineering. PMID:18544014

  8. Current status: Animal models of nausea

    NASA Technical Reports Server (NTRS)

    Fox, Robert A.

    1991-01-01

    The advantages, and possible benefits of a valid, reliable animal model for nausea are discussed, and difficulties inherent to the development of a model are considered. A principle problem for developing models arises because nausea is a subjective sensation that can be identified only in humans. Several putative measures of nausea in animals are considered, with more detailed consideration directed to variation in cardiac rate, levels of vasopressin, and conditioned taste aversion. Demonstration that putative measures are associated with reported nausea in humans is proposed as a requirement for validating measures to be used in animal models. The necessity for a 'real-time' measure of nausea is proposed as an important factor for future research; and the need for improved understanding of the neuroanatomy underlying the emetic syndrome is discussed.

  9. Animal models of human granulocyte diseases.

    PubMed

    Schäffer, Alejandro A; Klein, Christoph

    2013-02-01

    In vivo animal models have proven very useful to the understanding of basic biologic pathways of the immune system, a prerequisite for the development of innovate therapies. This article addresses currently available models for defined human monogenetic defects of neutrophil granulocytes, including murine, zebrafish, and larger mammalian species. Strengths and weaknesses of each system are summarized, and clinical investigators may thus be inspired to develop further lines of research to improve diagnosis and therapy by use of the appropriate animal model system. PMID:23351993

  10. Retinal Cell Degeneration in Animal Models

    PubMed Central

    Niwa, Masayuki; Aoki, Hitomi; Hirata, Akihiro; Tomita, Hiroyuki; Green, Paul G.; Hara, Akira

    2016-01-01

    The aim of this review is to provide an overview of various retinal cell degeneration models in animal induced by chemicals (N-methyl-d-aspartate- and CoCl2-induced), autoimmune (experimental autoimmune encephalomyelitis), mechanical stress (optic nerve crush-induced, light-induced) and ischemia (transient retinal ischemia-induced). The target regions, pathology and proposed mechanism of each model are described in a comparative fashion. Animal models of retinal cell degeneration provide insight into the underlying mechanisms of the disease, and will facilitate the development of novel effective therapeutic drugs to treat retinal cell damage. PMID:26784179

  11. Optogenetics in animal model of alcohol addiction

    NASA Astrophysics Data System (ADS)

    Nalberczak, Maria; Radwanska, Kasia

    2014-11-01

    Our understanding of the neuronal and molecular basis of alcohol addiction is still not satisfactory. As a consequence we still miss successful therapy of alcoholism. One of the reasons for such state is the lack of appropriate animal models which would allow in-depth analysis of biological basis of addiction. Here we will present our efforts to create the animal model of alcohol addiction in the automated learning device, the IntelliCage setup. Applying this model to optogenetically modified mice with remotely controlled regulation of selected neuronal populations by light may lead to very precise identification of neuronal circuits involved in coding addiction-related behaviors.

  12. Pharmacokinetic modeling in aquatic animals. 1. Models and concepts

    USGS Publications Warehouse

    Barron, M.G.; Stehly, Guy R.; Hayton, W.L.

    1990-01-01

    While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetics modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination.

  13. Animal models of gastrointestinal inflammation and cancer.

    PubMed

    Lu, L; Chan, Ruby L Y; Luo, X M; Wu, William K K; Shin, Vivian Y; Cho, C H

    2014-07-11

    Inflammation and cancer are the two major disorders in the gastrointestinal tract. They are causally related in their pathogenesis. It is important to study animal models' causal relationship and, in particular, to discover new therapeutic agents for such diseases. There are several criteria for these models in order to make them useful in better understanding the etiology and treatment of the said diseases in humans. In this regard, animal models should be similar as possible to human diseases and also be easy to produce and reproducible and also economic to allow a continuous replication in different laboratories. In this review, we summarize the various animal models for inflammatory and cancerous disorders in the upper and lower gastrointestinal tract. Experimental approaches are as simple as by giving a single oral dose of alcohol or other noxious agents or by injections of multiple dosages of ulcer inducing agents or by parenteral administration or in drinking water of carcinogens or by modifying the genetic makeups of animals to produce relatively long-term pathological changes in particular organs. With these methods they could induce consistent inflammatory responses or tumorigenesis in the gastrointestinal mucosa. These animal models are widely used in laboratories in understanding the pathogenesis as well as the mechanisms of action for therapeutic agents in the treatment of gastrointestinal inflammation and cancer. PMID:24825611

  14. Animal Models for HIV Cure Research

    PubMed Central

    Policicchio, Benjamin B.; Pandrea, Ivona; Apetrei, Cristian

    2016-01-01

    The HIV-1/AIDS pandemic continues to spread unabated worldwide, and no vaccine exists within our grasp. Effective antiretroviral therapy (ART) has been developed, but ART cannot clear the virus from the infected patient. A cure for HIV-1 is badly needed to stop both the spread of the virus in human populations and disease progression in infected individuals. A safe and effective cure strategy for human immunodeficiency virus (HIV) infection will require multiple tools, and appropriate animal models are tools that are central to cure research. An ideal animal model should recapitulate the essential aspects of HIV pathogenesis and associated immune responses, while permitting invasive studies, thus allowing a thorough evaluation of strategies aimed at reducing the size of the reservoir (functional cure) or eliminating the reservoir altogether (sterilizing cure). Since there is no perfect animal model for cure research, multiple models have been tailored and tested to address specific quintessential questions of virus persistence and eradication. The development of new non-human primate and mouse models, along with a certain interest in the feline model, has the potential to fuel cure research. In this review, we highlight the major animal models currently utilized for cure research and the contributions of each model to this goal. PMID:26858716

  15. Animal Models for HIV Cure Research.

    PubMed

    Policicchio, Benjamin B; Pandrea, Ivona; Apetrei, Cristian

    2016-01-01

    The HIV-1/AIDS pandemic continues to spread unabated worldwide, and no vaccine exists within our grasp. Effective antiretroviral therapy (ART) has been developed, but ART cannot clear the virus from the infected patient. A cure for HIV-1 is badly needed to stop both the spread of the virus in human populations and disease progression in infected individuals. A safe and effective cure strategy for human immunodeficiency virus (HIV) infection will require multiple tools, and appropriate animal models are tools that are central to cure research. An ideal animal model should recapitulate the essential aspects of HIV pathogenesis and associated immune responses, while permitting invasive studies, thus allowing a thorough evaluation of strategies aimed at reducing the size of the reservoir (functional cure) or eliminating the reservoir altogether (sterilizing cure). Since there is no perfect animal model for cure research, multiple models have been tailored and tested to address specific quintessential questions of virus persistence and eradication. The development of new non-human primate and mouse models, along with a certain interest in the feline model, has the potential to fuel cure research. In this review, we highlight the major animal models currently utilized for cure research and the contributions of each model to this goal. PMID:26858716

  16. Lessons from Animal Models of Arterial Aneurysm

    PubMed Central

    Gertz, S. David; Mintz, Yoav; Beeri, Ronen; Rubinstein, Chen; Gilon, Dan; Gavish, Leah; Berlatzky, Yacov; Appelbaum, Liat; Gavish, Lilach

    2013-01-01

    We review the results from the most common animal models of arterial aneurysm, including recent findings from our novel, laparoscopy-based pig model of abdominal aortic aneurysm, that contribute important insights into early pathogenesis. We emphasize the relevance of these findings for evaluation of treatment protocols and novel device prototypes for mechanism-based prevention of progression and rupture. PMID:26798701

  17. Large animal models for stem cell therapy

    PubMed Central

    2013-01-01

    The field of regenerative medicine is approaching translation to clinical practice, and significant safety concerns and knowledge gaps have become clear as clinical practitioners are considering the potential risks and benefits of cell-based therapy. It is necessary to understand the full spectrum of stem cell actions and preclinical evidence for safety and therapeutic efficacy. The role of animal models for gaining this information has increased substantially. There is an urgent need for novel animal models to expand the range of current studies, most of which have been conducted in rodents. Extant models are providing important information but have limitations for a variety of disease categories and can have different size and physiology relative to humans. These differences can preclude the ability to reproduce the results of animal-based preclinical studies in human trials. Larger animal species, such as rabbits, dogs, pigs, sheep, goats, and non-human primates, are better predictors of responses in humans than are rodents, but in each case it will be necessary to choose the best model for a specific application. There is a wide spectrum of potential stem cell-based products that can be used for regenerative medicine, including embryonic and induced pluripotent stem cells, somatic stem cells, and differentiated cellular progeny. The state of knowledge and availability of these cells from large animals vary among species. In most cases, significant effort is required for establishing and characterizing cell lines, comparing behavior to human analogs, and testing potential applications. Stem cell-based therapies present significant safety challenges, which cannot be addressed by traditional procedures and require the development of new protocols and test systems, for which the rigorous use of larger animal species more closely resembling human behavior will be required. In this article, we discuss the current status and challenges of and several major directions

  18. Animal models for motor neuron disease.

    PubMed

    Green, S L; Tolwani, R J

    1999-10-01

    Motor neuron disease is a general term applied to a broad class of neurodegenerative diseases that are characterized by fatally progressive muscular weakness, atrophy, and paralysis attributable to loss of motor neurons. At present, there is no cure for most motor neuron diseases, including amyotrophic lateral sclerosis (ALS), the most common human motor neuron disease--the cause of which remains largely unknown. Animal models of motor neuron disease (MND) have significantly contributed to the remarkable recent progress in understanding the cause, genetic factors, and pathologic mechanisms proposed for this class of human neurodegenerative disorders. Largely driven by ALS research, animal models of MND have proven their usefulness in elucidating potential causes and specific pathogenic mechanisms, and have helped to advance promising new treatments from "benchside to bedside." This review summarizes important features of selected established animal models of MND: genetically engineered mice and inherited or spontaneously occurring MND in the murine, canine, and equine species. PMID:10551448

  19. Differential Paradigms in Animal Models of Sepsis.

    PubMed

    Kingsley, S Manoj Kumar; Bhat, B Vishnu

    2016-09-01

    Sepsis is a serious clinical problem involving complex mechanisms which requires better understanding and insight. Animal models of sepsis have played a major role in providing insight into the complex pathophysiology of sepsis. There have been various animal models of sepsis with different paradigms. Endotoxin, bacterial infusion, cecal ligation and puncture, and colon ascendens stent peritonitis models are the commonly practiced methods at present. Each of these models has their own advantages and also confounding factors. We have discussed the underlying mechanisms regulating each of these models along with possible reasons why each model failed to translate into the clinic. In animal models, the timing of development of the hemodynamic phases and the varied cytokine patterns could not accurately resemble the progression of clinical sepsis. More often, the exuberant and transient pro-inflammatory cytokine response is only focused in most models. Immunosuppression and apoptosis in the later phase of sepsis have been found to cause more damage than the initial acute phase of sepsis. Likewise, better understanding of the existing models of sepsis could help us create a more relevant model which could provide solution to the currently failed clinical trials in sepsis. PMID:27432263

  20. Animal and cellular models of Friedreich ataxia.

    PubMed

    Perdomini, Morgane; Hick, Aurore; Puccio, Hélène; Pook, Mark A

    2013-08-01

    The development and use of animal and cellular models of Friedreich ataxia (FRDA) are essential requirements for the understanding of FRDA disease mechanisms and the investigation of potential FRDA therapeutic strategies. Although animal and cellular models of lower organisms have provided valuable information on certain aspects of FRDA disease and therapy, it is intuitive that the most useful models are those of mammals and mammalian cells, which are the closest in physiological terms to FRDA patients. To date, there have been considerable efforts put into the development of several different FRDA mouse models and relevant FRDA mouse and human cell line systems. We summarize the principal mammalian FRDA models, discuss the pros and cons of each system, and describe the ways in which such models have been used to address two of the fundamental, as yet unanswered, questions regarding FRDA. Namely, what is the exact pathophysiology of FRDA and what is the detailed genetic and epigenetic basis of FRDA? PMID:23859342

  1. Hierarchical models of animal abundance and occurrence

    USGS Publications Warehouse

    Royle, J. Andrew; Dorazio, R.M.

    2006-01-01

    Much of animal ecology is devoted to studies of abundance and occurrence of species, based on surveys of spatially referenced sample units. These surveys frequently yield sparse counts that are contaminated by imperfect detection, making direct inference about abundance or occurrence based on observational data infeasible. This article describes a flexible hierarchical modeling framework for estimation and inference about animal abundance and occurrence from survey data that are subject to imperfect detection. Within this framework, we specify models of abundance and detectability of animals at the level of the local populations defined by the sample units. Information at the level of the local population is aggregated by specifying models that describe variation in abundance and detection among sites. We describe likelihood-based and Bayesian methods for estimation and inference under the resulting hierarchical model. We provide two examples of the application of hierarchical models to animal survey data, the first based on removal counts of stream fish and the second based on avian quadrat counts. For both examples, we provide a Bayesian analysis of the models using the software WinBUGS.

  2. Animal models of cavitation in pulmonary tuberculosis.

    PubMed

    Helke, Kris L; Mankowski, Joseph L; Manabe, Yukari C

    2006-09-01

    Transmission of tuberculosis occurs with the highest frequency from patients with extensive, cavitary, pulmonary disease and positive sputum smear microscopy. In animal models of tuberculosis, the development of caseous necrosis is an important prerequisite for the formation of cavities although the immunological triggers for liquefaction are unknown. We review the relative merits and the information gleaned from the available animal models of pulmonary cavitation. Understanding the host-pathogen interaction important to the formation of cavities may lead to new strategies to prevent cavitation and thereby, block transmission. PMID:16359922

  3. Animal models of gene-nutrient interactions.

    PubMed

    Reed, Danielle R

    2008-12-01

    Food intake of humans is governed by the food's nutritional value and pleasing taste, but also by other factors such as food cost and availability, cultural imperatives, and social status. The biological determinants of human food intake are not easily parsed from these other factors, making them hard to study against the whirligig aspects of human life in a modern age. The study of animals provides a useful alternative. Humans have a history of studying animal food intake, for agricultural reasons (e.g., pigs and cows), and for personal reasons (e.g., dogs and cats), and these practical concerns have been joined with the appreciation that other models can teach us the principles of behavior, genetics, and nutrition. Thus there is a steady use of the traditional animal models in this type of research, as well as growth in the use of other systems such as worms and flies. Rats and mice occupy a special niche as animal models for two reasons; first, they share with humans a love of the same types of food, and second, they are the target of a number of well-developed genetic tools. The available genetic tools that make mice a popular model include a well-annotated genome (Mouse Build 37), profiles of RNA expression from many tissues, a diverse panel of inbred strains, and the ability to manipulate genes in the whole animal, including removing a gene only in specific tissues (e.g., Cre-lox system). Mice have been harnessed to find genotypes that contribute to sweet-liking, and other studies are underway to understand how genetic variation might at least partially explain other puzzles of human appetites. Animal models provide a way to study the genetic determinants of food selection with experimental rigor and therefore complement human genetics studies. PMID:19037208

  4. Are animal models predictive for humans?

    PubMed Central

    2009-01-01

    It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics. PMID:19146696

  5. [Diabetes mellitus and its animal models].

    PubMed

    Duhault, J; Koenig-Berard, E

    1997-01-01

    This review presents the major animal models usually used for the study of the pathological processes related to insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and to the main diabetic complications. These models can be observed spontaneously or can be obtained by selective cross-breeding or toxic exposure (chemical or viral), as well as genetically induced. They reproduce some aspects of the human pathology without combining them all in a single model. Consequently, a pertinent pharmacological approach may compare the results obtained with several models. The examination of the recent results obtained with transgenesis does not allow these animal models to replace more classical ones but they may constitute a future challenge for gene therapy despite the multifactorial aspect of diabetic disease. PMID:9501560

  6. Animal models for photodynamic therapy (PDT)

    PubMed Central

    Silva, Zenildo Santos; Bussadori, Sandra Kalil; Fernandes, Kristianne Porta Santos; Huang, Ying-Ying; Hamblin, Michael R.

    2015-01-01

    Photodynamic therapy (PDT) employs non-toxic dyes called photosensitizers (PSs), which absorb visible light to give the excited singlet state, followed by the long-lived triplet state that can undergo photochemistry. In the presence of ambient oxygen, reactive oxygen species (ROS), such as singlet oxygen and hydroxyl radicals are formed that are able to kill cancer cells, inactivate microbial pathogens and destroy unwanted tissue. Although there are already several clinically approved PSs for various disease indications, many studies around the world are using animal models to investigate the further utility of PDT. The present review will cover the main groups of animal models that have been described in the literature. Cancer comprises the single biggest group of models including syngeneic mouse/rat tumours that can either be subcutaneous or orthotopic and allow the study of anti-tumour immune response; human tumours that need to be implanted in immunosuppressed hosts; carcinogen-induced tumours; and mice that have been genetically engineered to develop cancer (often by pathways similar to those in patients). Infections are the second biggest class of animal models and the anatomical sites include wounds, burns, oral cavity, ears, eyes, nose etc. Responsible pathogens can include Gram-positive and Gram-negative bacteria, fungi, viruses and parasites. A smaller and diverse group of miscellaneous animal models have been reported that allow PDT to be tested in ophthalmology, atherosclerosis, atrial fibrillation, dermatology and wound healing. Successful studies using animal models of PDT are blazing the trail for tomorrow's clinical approvals. PMID:26415497

  7. An animated model of reticulorumen motility.

    PubMed

    Gookin, Jody L; Foster, Derek M; Harvey, Alice M; McWhorter, Dan

    2009-01-01

    Understanding reticulorumen motility is important to the assessment of ruminant health and optimal production, and in the recognition, diagnosis, and treatment of disease. Accordingly, the teaching of reticulorumen motility is a staple of all veterinary curricula. This teaching has historically been based on written descriptions, line drawings, or pressure tracings obtained during contraction sequences. We developed an animated model of reticulorumen motility and hypothesized that veterinary students would prefer use of the model over traditional instructional methods. First-year veterinary students were randomly allocated to one of two online learning exercises: with the animated model (Group A) or with text and line drawings (Group B) depicting reticulorumen motility. Learning was assessed with a multiple-choice quiz and feedback on the learning alternatives was obtained by survey. Seventy-four students participated in the study, including 38/42 in Group A and 36/36 in Group B. Sixty-four out of 72 students (89%) responded that they would prefer use of the animated model if only one of the two learning methods was available. A majority of students agreed or strongly agreed that the animated model was easy to understand and improved their knowledge and appreciation of the importance of reticulorumen motility, and would recommend the model to other veterinary students. Interestingly, students in Group B achieved higher scores on examination than students in Group A. This could be speculatively attributed to the inclusion of an itemized list of contraction sequences in the text provided to Group B and failure of Group A students to read the text associated with the animations. PMID:20054084

  8. A radiation dosimetry model for radiolabeled monoclonal antibodies: Indium-111-labeled B72. 3-GYK-DTPA for colorectal cancer

    SciTech Connect

    Wilson, L.A.

    1990-01-01

    A foundation was developed for a dosimetry methodology that could be used to calculate absorbed doses in target and nontarget tissues using uniformly and nonuniformly distributed activity. In this methodology, a dosimetry model was developed which consisted of three independent models: (1) the SPECT Model, (2) the Monte Carlo Model, and (3) the Dosimetry Model. The SPECT Model uses Single-Photon Emission Computed Tomography (SPECT) images to determine the volume and radioactive uptake. A computer program was written to automatically read and analyze SPECT images. This program uses an edge detection method to determine the volume. Voxel elements within the identified volume are used to calculate the activity concentrations. THe Monte Carlo Model uses a monte carlso simulation method and results of the SPECT Model to calculate the fraction of photon energy deposited in target and nontarget tissues. The Dosimetry Model combines the results of the SPECT and Monte Carlo Models to determine the absorbed dose in target and nontarget tissues. Several phantom studies were conducted to verify the ability of the Dosimetry Model to evaluate organ and tumor uptake, sizes, and to calculate absorbed doses. Comparisons were made between the Dosimetry Model, other calculational methods (MIRDOSE2, Geometric Factor Method, MIRD Pamphlet No. 3), and TLD measurements. For diagnostic activity doses, the SPECT Model was found to calculate organ volumes of the order of 1,000 ml to within fifteen percent of the actual volumes but it failed to accurately calculate organ volumes of 200 ml or less. No meaningful relationship was found between the actual and SPECT measured activity concentrations. The Dosimetry Model agreed within 12% when compared with the Geometric Factor Method and the MIRD Pamphlet No. 3 results using homogeneously and heterogeneously distributed [sup 111]In. The TLD measurements were within 30% at most of the other methods.

  9. Henipavirus infections: lessons from animal models.

    PubMed

    Dhondt, Kévin P; Horvat, Branka

    2013-01-01

    The Henipavirus genus contains two highly lethal viruses, the Hendra and Nipah viruses and one, recently discovered, apparently nonpathogenic member; Cedar virus. These three, negative-sense single-stranded RNA viruses, are hosted by fruit bats and use EphrinB2 receptors for entry into cells. The Hendra and Nipah viruses are zoonotic pathogens that emerged in the middle of 90s and have caused severe, and often fatal, neurologic and/or respiratory diseases in both humans and different animals; including spillover into equine and porcine species. Development of relevant models is critical for a better understanding of viral pathogenesis, generating new diagnostic tools, and assessing anti-viral therapeutics and vaccines. This review summarizes available data on several animal models where natural and/or experimental infection has been demonstrated; including pteroid bats, horses, pigs, cats, hamsters, guinea pigs, ferrets, and nonhuman primates. It recapitulates the principal features of viral pathogenesis in these animals and current knowledge on anti-viral immune responses. Lastly it describes the recently characterized murine animal model, which provides the possibility to use numerous and powerful tools available for mice to further decipher henipaviruses immunopathogenesis, prophylaxis, and treatment. The utility of different models to analyze important aspects of henipaviruses-induced disease in humans, potential routes of transmission, and therapeutic approaches are equally discussed. PMID:25437037

  10. Animation of finite element models and results

    NASA Technical Reports Server (NTRS)

    Lipman, Robert R.

    1992-01-01

    This is not intended as a complete review of computer hardware and software that can be used for animation of finite element models and results, but is instead a demonstration of the benefits of visualization using selected hardware and software. The role of raw computational power, graphics speed, and the use of videotape are discussed.

  11. Animal models for genetic neuromuscular diseases.

    PubMed

    Vainzof, Mariz; Ayub-Guerrieri, Danielle; Onofre, Paula C G; Martins, Poliana C M; Lopes, Vanessa F; Zilberztajn, Dinorah; Maia, Lucas S; Sell, Karen; Yamamoto, Lydia U

    2008-03-01

    The neuromuscular disorders are a heterogeneous group of genetic diseases, caused by mutations in genes coding sarcolemmal, sarcomeric, and citosolic muscle proteins. Deficiencies or loss of function of these proteins leads to variable degree of progressive loss of motor ability. Several animal models, manifesting phenotypes observed in neuromuscular diseases, have been identified in nature or generated in laboratory. These models generally present physiological alterations observed in human patients and can be used as important tools for genetic, clinic, and histopathological studies. The mdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD). Although it is a good genetic and biochemical model, presenting total deficiency of the protein dystrophin in the muscle, this mouse is not useful for clinical trials because of its very mild phenotype. The canine golden retriever MD model represents a more clinically similar model of DMD due to its larger size and significant muscle weakness. Autosomal recessive limb-girdle MD forms models include the SJL/J mice, which develop a spontaneous myopathy resulting from a mutation in the Dysferlin gene, being a model for LGMD2B. For the human sarcoglycanopahties (SG), the BIO14.6 hamster is the spontaneous animal model for delta-SG deficiency, whereas some canine models with deficiency of SG proteins have also been identified. More recently, using the homologous recombination technique in embryonic stem cell, several mouse models have been developed with null mutations in each one of the four SG genes. All sarcoglycan-null animals display a progressive muscular dystrophy of variable severity and share the property of a significant secondary reduction in the expression of the other members of the sarcoglycan subcomplex and other components of the Dystrophin-glycoprotein complex. Mouse models for congenital MD include the dy/dy (dystrophia-muscularis) mouse and the allelic mutant dy(2J)/dy(2J) mouse

  12. Animal models of chronic obstructive pulmonary disease.

    PubMed

    Pérez-Rial, Sandra; Girón-Martínez, Álvaro; Peces-Barba, Germán

    2015-03-01

    Animal models of disease have always been welcomed by the scientific community because they provide an approach to the investigation of certain aspects of the disease in question. Animal models of COPD cannot reproduce the heterogeneity of the disease and usually only manage to represent the disease in its milder stages. Moreover, airflow obstruction, the variable that determines patient diagnosis, not always taken into account in the models. For this reason, models have focused on the development of emphysema, easily detectable by lung morphometry, and have disregarded other components of the disease, such as airway injury or associated vascular changes. Continuous, long-term exposure to cigarette smoke is considered the main risk factor for this disease, justifying the fact that the cigarette smoke exposure model is the most widely used. Some variations on this basic model, related to exposure time, the association of other inducers or inhibitors, exacerbations or the use of transgenic animals to facilitate the identification of pathogenic pathways have been developed. Some variations or heterogeneity of this disease, then, can be reproduced and models can be designed for resolving researchers' questions on disease identification or treatment responses. PMID:25201221

  13. The modelling cycle for collective animal behaviour

    PubMed Central

    Sumpter, David J. T.; Mann, Richard P.; Perna, Andrea

    2012-01-01

    Collective animal behaviour is the study of how interactions between individuals produce group level patterns, and why these interactions have evolved. This study has proved itself uniquely interdisciplinary, involving physicists, mathematicians, engineers as well as biologists. Almost all experimental work in this area is related directly or indirectly to mathematical models, with regular movement back and forth between models, experimental data and statistical fitting. In this paper, we describe how the modelling cycle works in the study of collective animal behaviour. We classify studies as addressing questions at different levels or linking different levels, i.e. as local, local to global, global to local or global. We also describe three distinct approaches—theory-driven, data-driven and model selection—to these questions. We show, with reference to our own research on species across different taxa, how we move between these different levels of description and how these various approaches can be applied to link levels together. PMID:23173077

  14. Traumatic Brain Injury Models in Animals.

    PubMed

    Rostami, Elham

    2016-01-01

    Traumatic brain injury (TBI) is the leading cause of death in young adults in industrialized nations and in the developing world the WHO considers TBI a silent epidemic caused by an increasing number of traffic accidents. Despite the major improvement of TBI outcome in the acute setting in the past 20 years, the assessment, therapeutic interventions, and prevention of long-term complications remain a challenge. In order to get a deeper insight into the pathology of TBI and advancement of medical understanding and clinical progress experimental animal models are an essential requirement. This chapter provides an overview of most commonly used experimental animal TBI models and the pathobiological findings based on current data. In addition, limitations and advantages of each TBI model are mentioned. This will hopefully give an insight into the possibilities of each model and be of value in choosing one when designing a study. PMID:27604712

  15. Animal models for meniscus repair and regeneration.

    PubMed

    Deponti, Daniela; Di Giancamillo, Alessia; Scotti, Celeste; Peretti, Giuseppe M; Martin, Ivan

    2015-05-01

    The meniscus plays an important role in knee function and mechanics. Meniscal lesions, however, are common phenomena and this tissue is not able to achieve spontaneous successful repair, particularly in the inner avascular zone. Several animal models have been studied and proposed for testing different reparative approaches, as well as for studying regenerative methods aiming to restore the original shape and function of this structure. This review summarizes the gross anatomy, function, ultrastructure and biochemical composition of the knee meniscus in several animal models in comparison with the human meniscus. The relevance of the models is discussed from the point of view of basic research as well as of clinical translation for meniscal repair, substitution and regeneration. Finally, the advantages and disadvantages of each model for various research directions are critically discussed. PMID:23712959

  16. Evaluation of Surrogate Animal Models of Melioidosis

    PubMed Central

    Warawa, Jonathan Mark

    2010-01-01

    Burkholderia pseudomallei is the Gram-negative bacterial pathogen responsible for the disease melioidosis. B. pseudomallei establishes disease in susceptible individuals through multiple routes of infection, all of which may proceed to a septicemic disease associated with a high mortality rate. B. pseudomallei opportunistically infects humans and a wide range of animals directly from the environment, and modeling of experimental melioidosis has been conducted in numerous biologically relevant models including mammalian and invertebrate hosts. This review seeks to summarize published findings related to established animal models of melioidosis, with an aim to compare and contrast the virulence of B. pseudomallei in these models. The effect of the route of delivery on disease is also discussed for intravenous, intraperitoneal, subcutaneous, intranasal, aerosol, oral, and intratracheal infection methodologies, with a particular focus on how they relate to modeling clinical melioidosis. The importance of the translational validity of the animal models used in B. pseudomallei research is highlighted as these studies have become increasingly therapeutic in nature. PMID:21772830

  17. Nonmurine animal models of food allergy.

    PubMed Central

    Helm, Ricki M; Ermel, Richard W; Frick, Oscar L

    2003-01-01

    Food allergy can present as immediate hypersensitivity [manifestations mediated by immunoglobulin (Ig)E], delayed-type hypersensitivity (reactions associated with specific T lymphocytes), and inflammatory reactions caused by immune complexes. For reasons of ethics and efficacy, investigations in humans to determine sensitization and allergic responses of IgE production to innocuous food proteins are not feasible. Therefore, animal models are used a) to bypass the innate tendency to develop tolerance to food proteins and induce specific IgE antibody of sufficient avidity/affinity to cause sensitization and upon reexposure to induce an allergic response, b) to predict allergenicity of novel proteins using characteristics of known food allergens, and c) to treat food allergy by using immunotherapeutic strategies to alleviate life-threatening reactions. The predominant hypothesis for IgE-mediated food allergy is that there is an adverse reaction to exogenous food proteins or food protein fragments, which escape lumen hydrolysis, and in a polarized helper T cell subset 2 (Th2) environment, immunoglobulin class switching to allergen-specific IgE is generated in the immune system of the gastrointestinal-associated lymphoid tissues. Traditionally, the immunologic characterization and toxicologic studies of small laboratory animals have provided the basis for development of animal models of food allergy; however, the natural allergic response in large animals, which closely mimic allergic diseases in humans, can also be useful as models for investigations involving food allergy. PMID:12573913

  18. A Model for Micro-Dosimetry in Virtual Liver Tissues

    EPA Science Inventory

    Motivation: Humans are potentially exposed to over 6,000 environmental chemicals. The liver is the primary organ for metabolism and often the first site of chemical-induced toxicity in animal testing, but it remains difficult to translate these outcomes to humans. To address thi...

  19. Airway geometry models of children's lungs for use in dosimetry modeling.

    PubMed

    Ménache, M G; Hofmann, W; Ashgarian, B; Miller, F J

    2008-01-01

    geometry model airway dimensions for all ages are appropriate for use with dosimetry models, but dosimetry modelers need to assess carefully the reasonableness of TLC and functional residual capacity volumes to which airway dimensions are scaled for children 3 yr of age and under. PMID:18236226

  20. Three-Dimensional Radiobiologic Dosimetry: Application of Radiobiologic Modeling to Patient-Specific 3-Dimensional Imaging–Based Internal Dosimetry

    PubMed Central

    Prideaux, Andrew R.; Song, Hong; Hobbs, Robert F.; He, Bin; Frey, Eric C.; Ladenson, Paul W.; Wahl, Richard L.; Sgouros, George

    2010-01-01

    Phantom-based and patient-specific imaging-based dosimetry methodologies have traditionally yielded mean organ-absorbed doses or spatial dose distributions over tumors and normal organs. In this work, radiobiologic modeling is introduced to convert the spatial distribution of absorbed dose into biologically effective dose and equivalent uniform dose parameters. The methodology is illustrated using data from a thyroid cancer patient treated with radioiodine. Methods Three registered SPECT/CT scans were used to generate 3-dimensional images of radionuclide kinetics (clearance rate) and cumulated activity. The cumulated activity image and corresponding CT scan were provided as input into an EGSnrc-based Monte Carlo calculation: The cumulated activity image was used to define the distribution of decays, and an attenuation image derived from CT was used to define the corresponding spatial tissue density and composition distribution. The rate images were used to convert the spatial absorbed dose distribution to a biologically effective dose distribution, which was then used to estimate a single equivalent uniform dose for segmented volumes of interest. Equivalent uniform dose was also calculated from the absorbed dose distribution directly. Results We validate the method using simple models; compare the dose-volume histogram with a previously analyzed clinical case; and give the mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for an illustrative case of a pediatric thyroid cancer patient with diffuse lung metastases. The mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for the tumor were 57.7, 58.5, and 25.0 Gy, respectively. Corresponding values for normal lung tissue were 9.5, 9.8, and 8.3 Gy, respectively. Conclusion The analysis demonstrates the impact of radiobiologic modeling on response prediction. The 57% reduction in the equivalent dose value for the tumor reflects a high level of dose

  1. Fantastic animals as an experimental model to teach animal adaptation

    PubMed Central

    Guidetti, Roberto; Baraldi, Laura; Calzolai, Caterina; Pini, Lorenza; Veronesi, Paola; Pederzoli, Aurora

    2007-01-01

    Background Science curricula and teachers should emphasize evolution in a manner commensurate with its importance as a unifying concept in science. The concept of adaptation represents a first step to understand the results of natural selection. We settled an experimental project of alternative didactic to improve knowledge of organism adaptation. Students were involved and stimulated in learning processes by creative activities. To set adaptation in a historic frame, fossil records as evidence of past life and evolution were considered. Results The experimental project is schematized in nine phases: review of previous knowledge; lesson on fossils; lesson on fantastic animals; planning an imaginary world; creation of an imaginary animal; revision of the imaginary animals; adaptations of real animals; adaptations of fossil animals; and public exposition. A rubric to evaluate the student's performances is reported. The project involved professors and students of the University of Modena and Reggio Emilia and of the "G. Marconi" Secondary School of First Degree (Modena, Italy). Conclusion The educational objectives of the project are in line with the National Indications of the Italian Ministry of Public Instruction: knowledge of the characteristics of living beings, the meanings of the term "adaptation", the meaning of fossils, the definition of ecosystem, and the particularity of the different biomes. At the end of the project, students will be able to grasp particular adaptations of real organisms and to deduce information about the environment in which the organism evolved. This project allows students to review previous knowledge and to form their personalities. PMID:17767729

  2. Animal models of HIV peripheral neuropathy

    PubMed Central

    Burdo, Tricia H; Miller, Andrew D

    2014-01-01

    The use of animal models in the study of HIV and AIDS has advanced our understanding of the underlying pathophysiologic mechanisms of infection. Of the multitude of HIV disease manifestations, peripheral neuropathy remains one of the most common long-term side effects. Several of the most important causes of peripheral neuropathy in AIDS patients include direct association with HIV infection with or without antiretroviral medication and infection with opportunistic agents. Because the pathogeneses of these diseases are difficult to study in human patients, animal models have allowed for significant advancement in the understanding of the role of viral infection and the immune system in disease genesis. This review focuses on rodent, rabbit, feline and rhesus models used to study HIV-associated peripheral neuropathies, focusing specifically on sensory neuropathy and antiretroviral-associated neuropathies. PMID:25214880

  3. Pathogenesis of Epilepsy: Challenges in Animal Models

    PubMed Central

    Hui Yin, Yow; Ahmad, Nurulumi; Makmor-Bakry, Mohd

    2013-01-01

    Epilepsy is one of the most common chronic disorders affecting individuals of all ages. A greater understanding of pathogenesis in epilepsy will likely provide the basis fundamental for development of new antiepileptic therapies that aim to prevent the epileptogenesis process or modify the progression of epilepsy in addition to treatment of epilepsy symptomatically. Therefore, several investigations have embarked on advancing knowledge of the mechanism underlying epileptogenesis, understanding in mechanism of pharmacoresistance and discovering antiepileptogenic or disease-modifying therapy. Animal models play a crucial and significant role in providing additional insight into mechanism of epileptogenesis. With the help of these models, epileptogenesis process has been demonstrated to be involved in various molecular and biological pathways or processes. Hence, this article will discuss the known and postulated mechanisms of epileptogenesis and challenges in using the animal models. PMID:24494063

  4. Animal models of antimuscle specific kinase myasthenia

    PubMed Central

    Richman, David P.; Nishi, Kayoko; Ferns, Michael J.; Schnier, Joachim; Pytel, Peter; Maselli, Ricardo A.; Agius, Mark A.

    2014-01-01

    Antimuscle specific kinase (anti-MuSK) myasthenia (AMM) differs from antiacetylcholine receptor myasthenia gravis in exhibiting more focal muscle involvement (neck, shoulder, facial, and bulbar muscles) with wasting of the involved, primarily axial, muscles. AMM is not associated with thymic hyperplasia and responds poorly to anticholinesterase treatment. Animal models of AMM have been induced in rabbits, mice, and rats by immunization with purified xenogeneic MuSK ectodomain, and by passive transfer of large quantities of purified serum IgG from AMM patients into mice. The models have confirmed the pathogenic role of the MuSK antibodies in AMM and have demonstrated the involvement of both the presynaptic and postsynaptic components of the neuromuscular junction. The observations in this human disease and its animal models demonstrate the role of MuSK not only in the formation of this synapse but also in its maintenance. PMID:23252909

  5. Dosimetry Modeling for Focal Low-Dose-Rate Prostate Brachytherapy

    SciTech Connect

    Al-Qaisieh, Bashar; Mason, Josh; Bownes, Peter; Henry, Ann; Dickinson, Louise; Ahmed, Hashim U.; Emberton, Mark; Langley, Stephen

    2015-07-15

    Purpose: Focal brachytherapy targeted to an individual lesion(s) within the prostate may reduce side effects experienced with whole-gland brachytherapy. The outcomes of a consensus meeting on focal prostate brachytherapy were used to investigate optimal dosimetry of focal low-dose-rate (LDR) prostate brachytherapy targeted using multiparametric magnetic resonance imaging (mp-MRI) and transperineal template prostate mapping (TPM) biopsy, including the effects of random and systematic seed displacements and interseed attenuation (ISA). Methods and Materials: Nine patients were selected according to clinical characteristics and concordance of TPM and mp-MRI. Retrospectively, 3 treatment plans were analyzed for each case: whole-gland (WG), hemi-gland (hemi), and ultra-focal (UF) plans, with 145-Gy prescription dose and identical dose constraints for each plan. Plan robustness to seed displacement and ISA were assessed using Monte Carlo simulations. Results: WG plans used a mean 28 needles and 81 seeds, hemi plans used 17 needles and 56 seeds, and UF plans used 12 needles and 25 seeds. Mean D90 (minimum dose received by 90% of the target) and V100 (percentage of the target that receives 100% dose) values were 181.3 Gy and 99.8% for the prostate in WG plans, 195.7 Gy and 97.8% for the hemi-prostate in hemi plans, and 218.3 Gy and 99.8% for the focal target in UF plans. Mean urethra D10 was 205.9 Gy, 191.4 Gy, and 92.4 Gy in WG, hemi, and UF plans, respectively. Mean rectum D2 cm{sup 3} was 107.5 Gy, 77.0 Gy, and 42.7 Gy in WG, hemi, and UF plans, respectively. Focal plans were more sensitive to seed displacement errors: random shifts with a standard deviation of 4 mm reduced mean target D90 by 14.0%, 20.5%, and 32.0% for WG, hemi, and UF plans, respectively. ISA has a similar impact on dose-volume histogram parameters for all plan types. Conclusions: Treatment planning for focal LDR brachytherapy is feasible. Dose constraints are easily met with a notable

  6. Tumor reactive ringlet oxygen approach for Monte Carlo modeling of photodynamic therapy dosimetry.

    PubMed

    Lopez, N; Mulet, R; Rodríguez, R

    2016-07-01

    Photodynamic therapy (PDT) is an emergent technique used for the treatment of several diseases. It requires the interaction of three components: a photosensitizer, a light source and tissue oxygen. Knowledge of the biophysical aspects of PDT is important for improving dosimetry protocols and treatment planning. In this paper we propose a model to simulate the spatial and temporal distribution of ground state oxygen ((3)O2), cumulative singlet excited state oxygen ((1)O2)rx and photosensitizer, in this case protoporphyrin IX (PpIX) in an ALA mediated PDT treatment. The results are analyzed in order to improve the treatment dosimetry. We compute the light fluence in the tissue using Monte Carlo simulations running in a GPU system. The concentration of (3)O2, ((1)O2)rx and the photosensitizer are calculated using this light fluence and a set of differential equations describing the photochemical reactions involved in PDT. In the model the initial photosensitizer concentration depends on tissue depth and type, moreover we consider blood vessel damage and its effect in the ground state oxygen concentration in the tissue. We introduce the tumor reactive single oxygen (TRSO) as a new dosimetry metric. It represents the amount of singlet oxygen per tumor volume that reacts, during the treatment, with the molecules in the tumor. This quantity integrates the effect of the light irradiance, the optical properties of the tumor and the normal tissue, the oxygen consumption and supply, and the photosensitizer biodistribution on the skin. PMID:27197059

  7. Towards an animal model of food addiction.

    PubMed

    de Jong, Johannes W; Vanderschuren, Louk J M J; Adan, Roger A H

    2012-01-01

    The dramatically increasing prevalence of obesity, associated with potentially life-threatening health problems, including cardiovascular diseases and type II diabetes, poses an enormous public health problem. It has been proposed that the obesity epidemic can be explained by the concept of 'food addiction'. In this review we focus on possible similarities between binge eating disorder (BED), which is highly prevalent in the obese population, and drug addiction. Indeed, both behavioral and neural similarities between addiction and BED have been demonstrated. Behavioral similarities are reflected in the overlap in DSM-IV criteria for drug addiction with the (suggested) criteria for BED and by food addiction-like behavior in animals after prolonged intermittent access to palatable food. Neural similarities include the overlap in brain regions involved in food and drug craving. Decreased dopamine D2 receptor availability in the striatum has been found in animal models of binge eating, after cocaine self-administration in animals as well as in drug addiction and obesity in humans. To further explore the neurobiological basis of food addiction, it is essential to have an animal model to test the addictive potential of palatable food. A recently developed animal model for drug addiction involves three behavioral characteristics that are based on the DSM-IV criteria: i) extremely high motivation to obtain the drug, ii) difficulty in limiting drug seeking even in periods of explicit non-availability, iii) continuation of drug-seeking despite negative consequences. Indeed, it has been shown that a subgroup of rats, after prolonged cocaine self-administration, scores positive on these three criteria. If food possesses addictive properties, then food-addicted rats should also meet these criteria while searching for and consuming food. In this review we discuss evidence from literature regarding food addiction-like behavior. We also suggest future experiments that could

  8. Animal Models of Depression: Molecular Perspectives

    PubMed Central

    Krishnan, Vaishnav; Nestler, Eric J.

    2012-01-01

    Much of the current understanding about the pathogenesis of altered mood, impaired concentration and neurovegetative symptoms in major depression has come from animal models. However, because of the unique and complex features of human depression, the generation of valid and insightful depression models has been less straightforward than modeling other disabling diseases like cancer or autoimmune conditions. Today’s popular depression models creatively merge ethologically valid behavioral assays with the latest technological advances in molecular biology and automated video-tracking. This chapter reviews depression assays involving acute stress (e.g., forced swim test), models consisting of prolonged physical or social stress (e.g., social defeat), models of secondary depression, genetic models, and experiments designed to elucidate the mechanisms of antidepressant action. These paradigms are critically evaluated in relation to their ease, validity and replicability, the molecular insights that they have provided, and their capacity to offer the next generation of therapeutics for depression. PMID:21225412

  9. Animal models of epilepsy: use and limitations

    PubMed Central

    Kandratavicius, Ludmyla; Balista, Priscila Alves; Lopes-Aguiar, Cleiton; Ruggiero, Rafael Naime; Umeoka, Eduardo Henrique; Garcia-Cairasco, Norberto; Bueno-Junior, Lezio Soares; Leite, Joao Pereira

    2014-01-01

    Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Comprehension of the complex mechanisms underlying epileptogenesis and seizure generation in temporal lobe epilepsy and other forms of epilepsy cannot be fully acquired in clinical studies with humans. As a result, the use of appropriate animal models is essential. Some of these models replicate the natural history of symptomatic focal epilepsy with an initial epileptogenic insult, which is followed by an apparent latent period and by a subsequent period of chronic spontaneous seizures. Seizures are a combination of electrical and behavioral events that are able to induce chemical, molecular, and anatomic alterations. In this review, we summarize the most frequently used models of chronic epilepsy and models of acute seizures induced by chemoconvulsants, traumatic brain injury, and electrical or sound stimuli. Genetic models of absence seizures and models of seizures and status epilepticus in the immature brain were also examined. Major uses and limitations were highlighted, and neuropathological, behavioral, and neurophysiological similarities and differences between the model and the human equivalent were considered. The quest for seizure mechanisms can provide insights into overall brain functions and consciousness, and animal models of epilepsy will continue to promote the progress of both epilepsy and neurophysiology research. PMID:25228809

  10. Pediatric Epileptic Encephalopathies: Pathophysiology and Animal Models.

    PubMed

    Shao, Li-Rong; Stafstrom, Carl E

    2016-05-01

    Epileptic encephalopathies are syndromes in which seizures or interictal epileptiform activity contribute to or exacerbate brain function, beyond that caused by the underlying pathology. These severe epilepsies begin early in life, are associated with poor lifelong outcome, and are resistant to most treatments. Therefore, they represent an immense challenge for families and the medical care system. Furthermore, the pathogenic mechanisms underlying the epileptic encephalopathies are poorly understood, hampering attempts to devise novel treatments. This article reviews animal models of the three classic epileptic encephalopathies-West syndrome (infantile spasms), Lennox-Gastaut syndrome, and continuous spike waves during sleep or Landau-Kleffner syndrome-with discussion of how animal models are revealing underlying pathophysiological mechanisms that might be amenable to targeted therapy. PMID:27544466

  11. Standardised animal models of host microbial mutualism

    PubMed Central

    Macpherson, A J; McCoy, K D

    2015-01-01

    An appreciation of the importance of interactions between microbes and multicellular organisms is currently driving research in biology and biomedicine. Many human diseases involve interactions between the host and the microbiota, so investigating the mechanisms involved is important for human health. Although microbial ecology measurements capture considerable diversity of the communities between individuals, this diversity is highly problematic for reproducible experimental animal models that seek to establish the mechanistic basis for interactions within the overall host-microbial superorganism. Conflicting experimental results may be explained away through unknown differences in the microbiota composition between vivaria or between the microenvironment of different isolated cages. In this position paper, we propose standardised criteria for stabilised and defined experimental animal microbiotas to generate reproducible models of human disease that are suitable for systematic experimentation and are reproducible across different institutions. PMID:25492472

  12. Modeling interdependent animal movement in continuous time.

    PubMed

    Niu, Mu; Blackwell, Paul G; Skarin, Anna

    2016-06-01

    This article presents a new approach to modeling group animal movement in continuous time. The movement of a group of animals is modeled as a multivariate Ornstein Uhlenbeck diffusion process in a high-dimensional space. Each individual of the group is attracted to a leading point which is generally unobserved, and the movement of the leading point is also an Ornstein Uhlenbeck process attracted to an unknown attractor. The Ornstein Uhlenbeck bridge is applied to reconstruct the location of the leading point. All movement parameters are estimated using Markov chain Monte Carlo sampling, specifically a Metropolis Hastings algorithm. We apply the method to a small group of simultaneously tracked reindeer, Rangifer tarandus tarandus, showing that the method detects dependency in movement between individuals. PMID:26812666

  13. Experimental Diabetes Mellitus in Different Animal Models.

    PubMed

    Al-Awar, Amin; Kupai, Krisztina; Veszelka, Médea; Szűcs, Gergő; Attieh, Zouhair; Murlasits, Zsolt; Török, Szilvia; Pósa, Anikó; Varga, Csaba

    2016-01-01

    Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. PMID:27595114

  14. Animal models of age related macular degeneration

    PubMed Central

    Pennesi, Mark E.; Neuringer, Martha; Courtney, Robert J.

    2013-01-01

    Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations. PMID:22705444

  15. Experimental Diabetes Mellitus in Different Animal Models

    PubMed Central

    Al-awar, Amin; Veszelka, Médea; Szűcs, Gergő; Attieh, Zouhair; Murlasits, Zsolt; Török, Szilvia; Pósa, Anikó; Varga, Csaba

    2016-01-01

    Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. PMID:27595114

  16. Diabetic Retinopathy: Animal Models, Therapies, and Perspectives

    PubMed Central

    Cai, Xue; McGinnis, James F.

    2016-01-01

    Diabetic retinopathy (DR) is one of the major complications of diabetes. Although great efforts have been made to uncover the mechanisms underlying the pathology of DR, the exact causes of DR remain largely unknown. Because of multifactor involvement in DR etiology, currently no effective therapeutic treatments for DR are available. In this paper, we review the pathology of DR, commonly used animal models, and novel therapeutic approaches. Perspectives and future directions for DR treatment are discussed. PMID:26881246

  17. Animal models of smoke inhalation induced injuries.

    PubMed

    David, Poon; Dunsford, Denny; Lu, Jia; Moochhala, Shabbir

    2009-01-01

    Smoke inhalation injury is the leading cause of mortality from structural fires, as a result of complications such as systemic inflammatory response syndrome and chronic obstructive pulmonary disease, which can be caused by a localized or systemic response. In this review, the pathophysiology of smoke inhalation injury, along with the characteristics found in clinical settings, common animal models, current treatment methods and future potential therapeutics are discussed. PMID:19273376

  18. Animal models of human microsporidial infections.

    PubMed

    Snowden, K F; Didier, E S; Orenstein, J M; Shadduck, J A

    1998-12-01

    Two new models have been described for Enterocytozoon bieneusi, non-human primates and immuno-suppressed gnotobiotic pigs, but there still is no successful cell culture system. The intestinal xenograft system holds promise as an animal model for Encephalitozoon intestinalis. Encephalitozoon hellem is easily propagated in mice, and also may be an important cause of spontaneous disease of psittacine birds. Encephalitozoon cuniculi occurs spontaneously in a wide variety of animals and can be induced experimentally in athymic mice. This is a useful experimental system and animal model, but the infection is relatively rare in man. Mammalian microsporidioses first were recognized as spontaneous diseases of animals that later confounded studies intended to elucidate the nature of diseases of humans. Much was learned about both experimental and spontaneous animal microsporidial infections that subsequently has been applied to the human diseases. In addition, new diseases have appeared, in both animals and humans, for which models are being developed. Since there are now animal models for almost all the known human microsporidioses, information on pathogenesis, host defenses, and effective treatments may become available soon. The microsporidioses provide a good example of the value of comparative pathology. Dr. Payne: Joe Payne. How much accidental infection has occurred with adjacent laboratory animals? Dr. Shadduck: A hard question. The organisms are thought to spread horizontally, and there is some pretty good evidence for that in rabbits. One assumes that this also is the explanation for the occurrence in infected kennels. Horizontal transmission probably occurs via contaminated urine, at least in the case of rabbits and dogs. Experimentally, horizontal transmission has been difficult to demonstrate in mice. Relative to the danger in people, I don't know how to answer that. I have always treated this as one of those things where you should be careful, but you shouldn

  19. Animal Models of Compulsive Eating Behavior

    PubMed Central

    Di Segni, Matteo; Patrono, Enrico; Patella, Loris; Puglisi-Allegra, Stefano; Ventura, Rossella

    2014-01-01

    Eating disorders are multifactorial conditions that can involve a combination of genetic, metabolic, environmental, and behavioral factors. Studies in humans and laboratory animals show that eating can also be regulated by factors unrelated to metabolic control. Several studies suggest a link between stress, access to highly palatable food, and eating disorders. Eating “comfort foods” in response to a negative emotional state, for example, suggests that some individuals overeat to self-medicate. Clinical data suggest that some individuals may develop addiction-like behaviors from consuming palatable foods. Based on this observation, “food addiction” has emerged as an area of intense scientific research. A growing body of evidence suggests that some aspects of food addiction, such as compulsive eating behavior, can be modeled in animals. Moreover, several areas of the brain, including various neurotransmitter systems, are involved in the reinforcement effects of both food and drugs, suggesting that natural and pharmacological stimuli activate similar neural systems. In addition, several recent studies have identified a putative connection between neural circuits activated in the seeking and intake of both palatable food and drugs. The development of well-characterized animal models will increase our understanding of the etiological factors of food addiction and will help identify the neural substrates involved in eating disorders such as compulsive overeating. Such models will facilitate the development and validation of targeted pharmacological therapies. PMID:25340369

  20. Neuroteratology and Animal Modeling of Brain Disorders.

    PubMed

    Archer, Trevor; Kostrzewa, Richard M

    2016-01-01

    Over the past 60 years, a large number of selective neurotoxins were discovered and developed, making it possible to animal-model a broad range of human neuropsychiatric and neurodevelopmental disorders. In this paper, we highlight those neurotoxins that are most commonly used as neuroteratologic agents, to either produce lifelong destruction of neurons of a particular phenotype, or a group of neurons linked by a specific class of transporter proteins (i.e., dopamine transporter) or body of receptors for a specific neurotransmitter (i.e., NMDA class of glutamate receptors). Actions of a range of neurotoxins are described: 6-hydroxydopamine (6-OHDA), 6-hydroxydopa, DSP-4, MPTP, methamphetamine, IgG-saporin, domoate, NMDA receptor antagonists, and valproate. Their neuroteratologic features are outlined, as well as those of nerve growth factor, epidermal growth factor, and that of stress. The value of each of these neurotoxins in animal modeling of human neurologic, neurodegenerative, and neuropsychiatric disorders is discussed in terms of the respective value as well as limitations of the derived animal model. Neuroteratologic agents have proven to be of immense importance for understanding how associated neural systems in human neural disorders may be better targeted by new therapeutic agents. PMID:26857462

  1. Neurologic autoimmunity: mechanisms revealed by animal models.

    PubMed

    Bradl, Monika; Lassmann, Hans

    2016-01-01

    Over the last decade, neurologic autoimmunity has become a major consideration in the diagnosis and management of patients with many neurologic presentations. The nature of the associated antibodies and their targets has led to appreciation of the importance of the accessibility of the target antigen to antibodies, and a partial understanding of the different mechanisms that can follow antibody binding. This chapter will first describe the basic principles of autoimmune inflammation and tissue damage in the central and peripheral nervous system, and will then demonstrate what has been learnt about neurologic autoimmunity from circumstantial clinical evidence and from passive, active, and occasionally spontaneous or genetic animal models. It will cover neurologic autoimmune diseases ranging from disorders of neuromuscular transmission, peripheral and ganglionic neuropathy, to diseases of the central nervous system, where autoantibodies are either pathogenic and cause destruction or changes in function of their targets, where they are harmless bystanders of T-cell-mediated tissue damage, or are not involved at all. Finally, this chapter will summarize the relevance of current animal models for studying the different neurologic autoimmune diseases, and it will identify aspects where future animal models need to be improved to better reflect the disease reality experienced by affected patients, e.g., the chronicity or the relapsing/remitting nature of their disease. PMID:27112675

  2. Colon Preneoplastic Lesions in Animal Models

    PubMed Central

    Suzui, Masumi; Morioka, Takamitsu; Yoshimi, Naoki

    2013-01-01

    The animal model is a powerful and fundamental tool in the field of biochemical research including toxicology, carcinogenesis, cancer therapeutics and prevention. In the carcinogenesis animal model system, numerous examples of preneoplastic lesions have been isolated and investigated from various perspectives. This may indicate that several options of endpoints to evaluate carcinogenesis effect or therapeutic outcome are presently available; however, classification of preneoplastic lesions has become complicated. For instance, these lesions include aberrant crypt foci (ACF), dysplastic ACF, flat ACF, β-catenin accumulated crypts, and mucin-depleted foci. These lesions have been induced by commonly used chemical carcinogens such as azoxymethane (AOM), 1,2-dimethylhydrazine (DMH), methylnitrosourea (MUN), or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Investigators can choose any procedures or methods to examine colonic preneoplastic lesions according to their interests and the objectives of their experiments. Based on topographical, histopathological, and biological features of colon cancer preneoplastic lesions in the animal model, we summarize and discuss the character and implications of these lesions. PMID:24526805

  3. Animal model for anaerobic lung abscess.

    PubMed Central

    Kannangara, D W; Thadepalli, H; Bach, V T; Webb, D

    1981-01-01

    There are no satisfactory animal models for the study of anaerobic lung abscess. Aspiration of food, gastric mucin, or hydrochloric acid, or any combination of these, along with oropharyngeal bacteria, is commonly believed to cause aspiration pneumonia and lung abscess. In the animal model described, none of the adjuvants was effective in producing anaerobic lung abscesses. Anaerobic bacteria derived from dental scrapings of a healthy adult (Peptococcus morbillorum, Fusobacterium nucleatum, Eubacterium lentum, and Bacteroides fragilis), when inoculated transtracheally without any adjuvants into New Zealand male white rabbits, consistently produced lung abscesses. Neither B fragilis by itself nor a mixture of P. morbillorum, F. nucleatum, and E. lentum without the addition of B. fragilis produced lung abscesses. The bacterial isolates used in this study were stored in prereduced chopped-meat-glucose medium and subcultured several times and were found effective in reproducing anaerobic lung abscesses repeatedly. This animal model is suitable for the study of pathogenesis, diagnosis, and treatment of B. fragilis-associated anaerobic lung abscess. Images PMID:7216463

  4. Animal models of compulsive eating behavior.

    PubMed

    Di Segni, Matteo; Patrono, Enrico; Patella, Loris; Puglisi-Allegra, Stefano; Ventura, Rossella

    2014-10-01

    Eating disorders are multifactorial conditions that can involve a combination of genetic, metabolic, environmental, and behavioral factors. Studies in humans and laboratory animals show that eating can also be regulated by factors unrelated to metabolic control. Several studies suggest a link between stress, access to highly palatable food, and eating disorders. Eating "comfort foods" in response to a negative emotional state, for example, suggests that some individuals overeat to self-medicate. Clinical data suggest that some individuals may develop addiction-like behaviors from consuming palatable foods. Based on this observation, "food addiction" has emerged as an area of intense scientific research. A growing body of evidence suggests that some aspects of food addiction, such as compulsive eating behavior, can be modeled in animals. Moreover, several areas of the brain, including various neurotransmitter systems, are involved in the reinforcement effects of both food and drugs, suggesting that natural and pharmacological stimuli activate similar neural systems. In addition, several recent studies have identified a putative connection between neural circuits activated in the seeking and intake of both palatable food and drugs. The development of well-characterized animal models will increase our understanding of the etiological factors of food addiction and will help identify the neural substrates involved in eating disorders such as compulsive overeating. Such models will facilitate the development and validation of targeted pharmacological therapies. PMID:25340369

  5. On source models for 192Ir HDR brachytherapy dosimetry using model based algorithms

    NASA Astrophysics Data System (ADS)

    Pantelis, Evaggelos; Zourari, Kyveli; Zoros, Emmanouil; Lahanas, Vasileios; Karaiskos, Pantelis; Papagiannis, Panagiotis

    2016-06-01

    A source model is a prerequisite of all model based dose calculation algorithms. Besides direct simulation, the use of pre-calculated phase space files (phsp source models) and parameterized phsp source models has been proposed for Monte Carlo (MC) to promote efficiency and ease of implementation in obtaining photon energy, position and direction. In this work, a phsp file for a generic 192Ir source design (Ballester et al 2015) is obtained from MC simulation. This is used to configure a parameterized phsp source model comprising appropriate probability density functions (PDFs) and a sampling procedure. According to phsp data analysis 15.6% of the generated photons are absorbed within the source, and 90.4% of the emergent photons are primary. The PDFs for sampling photon energy and direction relative to the source long axis, depend on the position of photon emergence. Photons emerge mainly from the cylindrical source surface with a constant probability over  ±0.1 cm from the center of the 0.35 cm long source core, and only 1.7% and 0.2% emerge from the source tip and drive wire, respectively. Based on these findings, an analytical parameterized source model is prepared for the calculation of the PDFs from data of source geometry and materials, without the need for a phsp file. The PDFs from the analytical parameterized source model are in close agreement with those employed in the parameterized phsp source model. This agreement prompted the proposal of a purely analytical source model based on isotropic emission of photons generated homogeneously within the source core with energy sampled from the 192Ir spectrum, and the assignment of a weight according to attenuation within the source. Comparison of single source dosimetry data obtained from detailed MC simulation and the proposed analytical source model show agreement better than 2% except for points lying close to the source longitudinal axis.

  6. On source models for (192)Ir HDR brachytherapy dosimetry using model based algorithms.

    PubMed

    Pantelis, Evaggelos; Zourari, Kyveli; Zoros, Emmanouil; Lahanas, Vasileios; Karaiskos, Pantelis; Papagiannis, Panagiotis

    2016-06-01

    A source model is a prerequisite of all model based dose calculation algorithms. Besides direct simulation, the use of pre-calculated phase space files (phsp source models) and parameterized phsp source models has been proposed for Monte Carlo (MC) to promote efficiency and ease of implementation in obtaining photon energy, position and direction. In this work, a phsp file for a generic (192)Ir source design (Ballester et al 2015) is obtained from MC simulation. This is used to configure a parameterized phsp source model comprising appropriate probability density functions (PDFs) and a sampling procedure. According to phsp data analysis 15.6% of the generated photons are absorbed within the source, and 90.4% of the emergent photons are primary. The PDFs for sampling photon energy and direction relative to the source long axis, depend on the position of photon emergence. Photons emerge mainly from the cylindrical source surface with a constant probability over  ±0.1 cm from the center of the 0.35 cm long source core, and only 1.7% and 0.2% emerge from the source tip and drive wire, respectively. Based on these findings, an analytical parameterized source model is prepared for the calculation of the PDFs from data of source geometry and materials, without the need for a phsp file. The PDFs from the analytical parameterized source model are in close agreement with those employed in the parameterized phsp source model. This agreement prompted the proposal of a purely analytical source model based on isotropic emission of photons generated homogeneously within the source core with energy sampled from the (192)Ir spectrum, and the assignment of a weight according to attenuation within the source. Comparison of single source dosimetry data obtained from detailed MC simulation and the proposed analytical source model show agreement better than 2% except for points lying close to the source longitudinal axis. PMID:27191179

  7. Proliferative retinopathies: animal models and therapeutic opportunities.

    PubMed

    Villacampa, Pilar; Haurigot, Virginia; Bosch, Fatima

    2015-01-01

    Proliferative retinopathies are the leading causes of blindness in Western societies. The development of new, more efficacious treatments that take advantage of recent advances in the fields of gene and cell therapy requires further investigations on the mechanisms underlying disease onset and progression, and adequate animal models that recapitulate the pathogenesis of human proliferative retinopathy and allow evaluation of the long-term therapeutic benefits that these therapies can offer. Unfortunately, most models of retinal neovascularization have short-term evolution and diabetic rodents show a very mild retinal phenotype, limited to non-proliferative changes, and do not develop proliferative retinopathy at all. Transgenic mice overexpressing Insulin-like Growth Factor-I (IGF-I) in the retina (TgIGF-I) constitute the only rodent model currently available that develops most of the retinal alterations observed in diabetic eyes, with a temporal evolution that resembles that of the human disease. TgIGF-I have retinal vascular alterations that progress as animals age from non-proliferative to proliferative disease, making these mice an excellent model of proliferative retinopathy that, due to its slow progression, allows long-term evaluation of novel antiangiogenic therapies. At the molecular level, transgenic retinas recapitulate a variety of changes that are also observed in diabetic retinas, which reinforces the validity of this model. In addition to vascular and glial alterations, Tg-IGF-I mice show progressive neurodegeneration that leads to blindness in old animals. Thus, TgIGF-I are a useful model for testing the long-term efficacy and safety of innovative antiangiogenic, glial-modulating and neuroprotective therapies for the treatment of diabetic retinopathy and other retinal proliferative disorders. PMID:25760215

  8. Animal Models in Pressure Ulcer Research

    PubMed Central

    Salcido, Richard; Popescu, Adrian; Ahn, Chulhyun

    2007-01-01

    Background/Objective: Research targeting the pathophysiology, prevention, and treatment of pressure ulcers (PrUs) continue to be a significant priority for clinical and basic science research. Spinal cord injury patients particularly benefit from PrU research, because the prevalence of chronic wounds in this category is increasing despite standardized medical care. Because of practical, ethical, and safety considerations, PrUs in the human environment are limited to studies involving patients with pre-existing ulcers. Therefore, we are limited in our basic knowledge pertaining to the development, progression, and healing environment in this devastating disease. Methods: This review provides a synopsis of literature and a discussion of techniques used to induce PrUs in animal models. The question of what animal model best mimics the human PrU environment has been a subject of debate by investigators, peer review panels, and editors. The similarities in wound development and healing in mammalian tissue make murine models a relevant model for understanding the causal factors as well as the wound healing elements. Although we are beginning to understand some of the mechanisms of PrU development, a key dilemma of what makes an apparently healthy tissue develop a PrU waits to be solved. Results and Conclusions: No single method of induction and exploring PrUs in animals can address all the aspects of the pathology of chronic wounds. Each model has its particular strengths and weaknesses. Certain types of models can selectively identify specific aspects of wound development, quantify the extent of lesions, and assess outcomes from interventions. The appropriate interpretation of these methods is significant for proper study design, an understanding of the results, and extrapolation to clinical relevance. PMID:17591222

  9. Small animals models for drug discovery.

    PubMed

    Martin, James G; Novali, Mauro

    2011-10-01

    There has been an explosion of studies of animal models of asthma in the past 20 years. The elucidation of fundamental immunological mechanisms underlying the development of allergy and the complex cytokine and chemokines networks underlying the responses have been substantially unraveled. Translation of findings to human asthma have been slow and hindered by the varied phenotypes that human asthma represents. New areas for expansion of modeling include virally mediated airway inflammation, oxidant stress, and the interactions of stimuli triggering innate immune and adaptive immune responses. PMID:21601000

  10. Clinical relevance of animal models of schizophrenia.

    PubMed

    Koch, Michael

    2013-01-01

    Animal models and endophenotypes of mental disorders are regarded as preclinical heuristic approaches aiming at understanding the etiopathogenesis of these diseases, and at developing drug treatment strategies. A frequently used translational model of sensorimotor gating and its deficits in some neuropsychiatric disorders is prepulse inhibition (PPI) of startle. PPI is reduced in schizophrenia patients, but the exact relationship between symptoms and reduced PPI is still unclear. Recent findings suggest that the levels of PPI in humans and animals may be predictive of certain cognitive functions. Hence, this simple measure of reflex suppression may be of use for clinical research. PPI is the reduction of the acoustic startle response that occurs when a weak prestimulus is presented shortly prior to a startling noise pulse. It is considered a measure of sensorimotor gating and is regulated by a cortico-limbic striato-pallidal circuit. However, PPI does not only occur in the domain of startle. PPI of alpha, gamma, and theta oscillations at frontal and central locations has been found, suggesting a relationship between PPI and cognitive processes. In fact, levels of PPI in healthy subjects and in animals predict their performance in cognitive tasks mainly mediated by the frontal cortex. Taken together, PPI might reflect a more general filtering performance leading to gating of intrusive sensory, motor, and cognitive input, thereby improving cognitive function. Hence, PPI might be used in clinical settings to predict the impact of drugs or psychotherapy on cognitive performance in neuropsychiatric patients. PMID:24053035

  11. Animal models of addiction: fat and sugar.

    PubMed

    Morgan, Drake; Sizemore, Glen M

    2011-01-01

    The concept of "food addiction" is gaining acceptance among the scientific community, and much is known about the influence of various components of food (e.g. high-fat, sugar, carbohydrate, salt) on behavior and physiology. Most of the studies to date have studied these consequences following relatively long-term diet manipulations and/or relatively free access to the food of interest. It is suggested that these types of studies are primarily tapping into the energy regulation and homeostatic processes that govern food intake and consumption. More recently, the overlap between the neurobiology of "reward-related" or hedonic effects of food ingestion and other reinforcers such as drugs of abuse has been highlighted, contributing to the notion that "food addiction" exists and that various components of food may be the substance of abuse. Based on preclinical animal models of drug addiction, a new direction for this field is using self-administration procedures and identifying an addiction-like behavioral phenotype in animals following various environmental, genetic, pharmacological, and neurobiological manipulations. Here we provide examples from this research area, with a focus on fat and sugar self-administration, and how the sophisticated animal models of drug addiction can be used to study the determinants and consequences of food addiction. PMID:21492084

  12. Animal models of chronic liver diseases.

    PubMed

    Liu, Yan; Meyer, Christoph; Xu, Chengfu; Weng, Honglei; Hellerbrand, Claus; ten Dijke, Peter; Dooley, Steven

    2013-03-01

    Chronic liver diseases are frequent and potentially life threatening for humans. The underlying etiologies are diverse, ranging from viral infections, autoimmune disorders, and intoxications (including alcohol abuse) to imbalanced diets. Although at early stages of disease the liver regenerates in the absence of the insult, advanced stages cannot be healed and may require organ transplantation. A better understanding of underlying mechanisms is mandatory for the design of new drugs to be used in clinic. Therefore, rodent models are being developed to mimic human liver disease. However, no model to date can completely recapitulate the "corresponding" human disorder. Limiting factors are the time frame required in humans to establish a certain liver disease and the fact that rodents possess a distinct immune system compared with humans and have different metabolic rates affecting liver homeostasis. These features account for the difficulties in developing adequate rodent models for studying disease progression and for testing new pharmaceuticals to be translated into the clinic. Nevertheless, traditional and new promising animal models that mimic certain attributes of chronic liver diseases are established and being used to deepen our understanding in the underlying mechanisms of distinct liver diseases. This review aims at providing a comprehensive overview of recent advances in animal models recapitulating different features and etiologies of human liver diseases. PMID:23275613

  13. Animal models of depression: are there any?

    PubMed

    O'Neil, Michael F; Moore, Nicholas A

    2003-06-01

    Simple tests for antidepressant-like activity, such as 5-HTP-induced syndrome or reserpine-induced hypomotility, are often mechanism-based tests, pharmacologically specific for certain known classes of therapeutically successful antidepressant agents. Many of these behavioural assays have been superseded by neurochemical techniques such as in vivo microdialysis. In contrast to these mechanistic-based models, investigators have also endeavoured to reproduce in the laboratory, factors that are believed to precipitate depression in people. It is a strong assumption in this approach that depression is a response to stress. This strategy profiles the consequences of chronic stress particularly psychosocial stress or early life events, in order to reproduce in animals the behavioural signs and pathologies associated with depression. The advances in the social psychological, clinical pathological and new areas such as neuroimaging research offer the possibility of establishing more sophisticated models for depression in animals with a broader range of biomarkers from the immunological and endocrinological to neurochemical and behavioural. Combining these novel insights with more traditional tests of depression may not only increase our understanding of the neurobiology of depression but also afford more precise and predictive preclinical models of depression. The responsiveness of different strains or genetically modified animals to stress is likely to be a key area of study. Furthermore we must look to individual differences in subjects, even within the same strain, to more fully understand why some individuals show pathological responses to stress whereas others appear unaffected. Conversely in validating our models using currently available treatments we must include the concept of non-responders so as not to disregard models that may extend therapeutic possibilities in these patients. PMID:12766928

  14. Barrett’s esophagus and animal models

    PubMed Central

    Macke, Ryan A.; Nason, Katie S.; Mukaisho, Ken-ichi; Hattori, Takanori; Fujimura, Takashi; Sasaki, Shozo; Oyama, Katsunobu; Miyashita, Tomoharu; Ohta, Tetsuo; Miwa, Koichi; Zaidi, Ali; Malhotra, Usha; Atasoy, Ajlan; Foxwell, Tyler; Jobe, Blair

    2014-01-01

    Concise summaries Significant progress has been made in the last few decades using animal models to recreate the esophagitis–metaplasia–carcinoma sequence similar to that seen in human Barrett’s esophagus (BE) and EAC. More recent works focus on molecular pathways associated with intestinal metaplasia and carcinogenesis, as well as similarities between genetic mutations occurring in humans and animal models, mouse, rat, pig, rabbit, guinea pig, dog, cat, ferret, and possum. Despite the lack of a perfect model, there is still significant potential in using these models to clarify the contribution of different types of reflux (gastric, biliary, and pancreatic) to esophageal adenocarcinoma and to determine how the different types of refluxate interact. Refluxed duodenal contents cause gastric and esophageal carcinoma in rats without exposure to carcinogens, and several rat duodenal contents reflux models have been developed. BE in the animal models has well-developed goblet cells positive forMUC2, gastric pyloric-type mucins positive for MUC6, and sometimes intermingled with gastric foveolar-type mucins positive for MUC5AC. A gut regenerative cell lineage, characterized by pyloric–foveolar metaplasia followed by the appearance of goblet cells, occurs in the regenerative process in response to chronic inflammation. High animal-fat dietary intake causes severe obesity, resulting in the development of increased abdominal pressure and increased refluxate, particularly of the duodenal contents. The N-nitroso bile acid conjugates, which have mutagenecity, play an important role in Barrett’s carcinogenesis, and are stabilized by gastric acid. Experiments have been made in a rodent duodeno-esophageal reflux model using thioproline or cyclooxygenase-2 inhibitor to prevent the inflammation–metaplasia– adenocarcinoma sequence. Thioproline is one of the nitrite scavengers, which reduce the production of carcinogenic nitroso-compounds. Celecoxib could postpone the

  15. Infants and young children modeling method for numerical dosimetry studies: application to plane wave exposure

    NASA Astrophysics Data System (ADS)

    Dahdouh, S.; Varsier, N.; Nunez Ochoa, M. A.; Wiart, J.; Peyman, A.; Bloch, I.

    2016-02-01

    Numerical dosimetry studies require the development of accurate numerical 3D models of the human body. This paper proposes a novel method for building 3D heterogeneous young children models combining results obtained from a semi-automatic multi-organ segmentation algorithm and an anatomy deformation method. The data consist of 3D magnetic resonance images, which are first segmented to obtain a set of initial tissues. A deformation procedure guided by the segmentation results is then developed in order to obtain five young children models ranging from the age of 5 to 37 months. By constraining the deformation of an older child model toward a younger one using segmentation results, we assure the anatomical realism of the models. Using the proposed framework, five models, containing thirteen tissues, are built. Three of these models are used in a prospective dosimetry study to analyze young child exposure to radiofrequency electromagnetic fields. The results lean to show the existence of a relationship between age and whole body exposure. The results also highlight the necessity to specifically study and develop measurements of child tissues dielectric properties.

  16. Infants and young children modeling method for numerical dosimetry studies: application to plane wave exposure.

    PubMed

    Dahdouh, S; Varsier, N; Nunez Ochoa, M A; Wiart, J; Peyman, A; Bloch, I

    2016-02-21

    Numerical dosimetry studies require the development of accurate numerical 3D models of the human body. This paper proposes a novel method for building 3D heterogeneous young children models combining results obtained from a semi-automatic multi-organ segmentation algorithm and an anatomy deformation method. The data consist of 3D magnetic resonance images, which are first segmented to obtain a set of initial tissues. A deformation procedure guided by the segmentation results is then developed in order to obtain five young children models ranging from the age of 5 to 37 months. By constraining the deformation of an older child model toward a younger one using segmentation results, we assure the anatomical realism of the models. Using the proposed framework, five models, containing thirteen tissues, are built. Three of these models are used in a prospective dosimetry study to analyze young child exposure to radiofrequency electromagnetic fields. The results lean to show the existence of a relationship between age and whole body exposure. The results also highlight the necessity to specifically study and develop measurements of child tissues dielectric properties. PMID:26815765

  17. Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model

    SciTech Connect

    Tornero-Velez, Rogelio; Mirfazaelian, Ahmad; Kim, Kyu-Bong; Anand, Sathanandam S.; Kim, Hyo J.; Haines, Wendy T.; Bruckner, James V.; Fisher, Jeffrey W.

    2010-04-15

    Immature rats are more susceptible than adults to the acute neurotoxicity of pyrethroid insecticides like deltamethrin (DLM). A companion kinetics study (Kim et al., in press) revealed that blood and brain levels of the neuroactive parent compound were inversely related to age in rats 10, 21, 40 and 90 days old. The objective of the current study was to modify a physiologically based pharmacokinetic (PBPK) model of DLM disposition in the adult male Sprague-Dawley rat (Mirfazaelian et al., 2006), so blood and target organ dosimetry could be accurately predicted during maturation. Age-specific organ weights and age-dependent changes in the oxidative and hydrolytic clearance of DLM were modeled with a generalized Michaelis-Menten model for growth and the summary equations incorporated into the PBPK model. The model's simulations compared favorably with empirical DLM time-courses in plasma, blood, brain and fat for the four age-groups evaluated (10, 21, 40 and 90 days old). PND 10 pups' area under the 24-h brain concentration time curve (AUC{sub 0-24h}) was 3.8-fold higher than that of the PND 90 adults. Our maturing rat PBPK model allows for updating with age- and chemical-dependent parameters, so pyrethroid dosimetry can be forecast in young and aged individuals. Hence, this model provides a methodology for risk assessors to consider age-specific adjustments to oral Reference Doses on the basis of PK differences.

  18. A respiratory tract dosimetry model for air toxics

    SciTech Connect

    Overton, J.H. )

    1990-10-01

    The development of a physiologically based pharmacokinetic model for the whole body in which inhalation, exhalation, and metabolism in respiratory tract tissues are taken into account is described. As an example of the model's use, the results of several experiments in which rats and humans were exposed to styrene were simulated; these results are discussed. The predicted results agree with the empirical data and with the modeling results of others.

  19. A respiratory tract dosimetry model for air toxics.

    PubMed

    Overton, J H

    1990-10-01

    The development of a physiologically based pharmacokinetic model for the whole body in which inhalation, exhalation, and metabolism in respiratory tract tissues are taken into account is described. As an example of the model's use, the results of several experiments in which rats and humans were exposed to styrene were simulated; these results are discussed. The predicted results agree with the empirical data and with the modeling results of others. PMID:2274981

  20. Respiratory-tract dosimetry model for air toxics (October 1990)

    SciTech Connect

    Overton, J.H.

    1990-01-01

    The development of a physiologically based pharmacokinetic model for the whole body in which inhalation, exhalation, and metabolism in respiratory tract tissues are taken into account is described. As an example of the model's use, the results of several experiments in which rats and humans were exposed to styrene were simulated; these results are discussed. The predicted results agree with the empirical data and with the modeling results of others.

  1. Patient-Specific Dosimetry and Radiobiological Modeling of Targeted Radionuclide Therapy Grant - final report

    SciTech Connect

    George Sgouros, Ph.D.

    2007-03-20

    The broad, long-term objectives of this application are to 1. develop easily implementable tools for radionuclide dosimetry that can be used to predict normal organ toxicity and tumor response in targeted radionuclide therapy; and 2. to apply these tools to the analysis of clinical trial data in order to demonstrate dose-response relationships for radionuclide therapy treatment planning. The work is founded on the hypothesis that robust dose-response relationships have not been observed in targeted radionuclide therapy studies because currently available internal dosimetry methodologies are inadequate, failing to adequately account for individual variations in patient anatomy, radionuclide activity distribution/kinetics, absorbed dose-distribution, and absorbed dose-rate. To reduce development time the previously available software package, 3D-ID, one of the first dosimetry software packages to incorporate 3-D radionuclide distribution with individual patient anatomy; and the first to be applied for the comprehensive analysis of patient data, will be used as a platform to build the functionality listed above. The following specific aims are proposed to satisfy the long-term objectives stated above: 1. develop a comprehensive and validated methodology for converting one or more SPECT images of the radionuclide distribution to a 3-D representation of the cumulated activity distribution; 2. account for differences in tissue density and atomic number by incorporating an easily implementable Monte Carlo methodology for the 3-D dosimetry calculations; 3. incorporate the biologically equivalent dose (BED) and equivalent uniform dose (EUD) models to convert the spatial distribution of absorbed dose and dose-rate into equivalent single values that account for differences in dose uniformity and rate and that may be correlated with tumor response and normal organ toxicity; 4. test the hypothesis stated above by applying the resulting package to patient trials of targeted

  2. Physicochemical processes and the formulation of dosimetry models. [Transport and absorption of ozone and nitrogen dioxide in the respiratory tract

    SciTech Connect

    Overton, J.H. Jr.

    1984-01-01

    The major physical and chemical processes involved in the transport and absorption of O/sub 3/ or NO/sub 2/ in the lower respiratory tract are discussed. This included the development of respiratory tract models, flow patterns, and transport in tube networks, the mucous, surfactant, and tissue layers, and chemical reactions and transport of O/sub 3/ or NO/sub 2/ within these layers. Descriptions of the individual processes are simplified and integrated to illustrate the formulation of dosimetry models. Data from a dosimetry model, formulated from the concepts discussed, are used to illustrate the types of information obtained by modeling. 31 references.

  3. Animal models of craving for ethanol.

    PubMed

    Koob, G F

    2000-08-01

    Craving has various meanings but can be defined generally in terms of a desire for the previously experienced effects of ethanol. Animal models provide a means by which to study the underlying mechanisms associated with craving and are most useful when they fulfill the requirements for predictive validity and reliability. Craving is a key part of the process of addiction that can lead to relapse and is conceptualized as having at least three components: preoccupation/anticipation, binge/intoxication and withdrawal/negative affect. Animal models of craving are hypothesized at this time to involve three domains of motivation to take drugs: excessive drinking, negative affective states and conditioned reinforcement. Excessive drinking includes the alcohol deprivation effect, drinking during withdrawal and drinking after a history of dependence. Models of the negative affective state include increases in brain reward thresholds, and conditioned reinforcement models include cue-induced resistance to extinction or cue-induced reinstatement. Experimental psychology is a rich resource of sensitive behavioral techniques by which to measure hypothetical constructs associated with the motivation to drink ethanol. Rigorous tests of predictive validity and reliability will be necessary to make them useful for understanding the neurobiology of craving and for the development of new medications for treating craving. PMID:11002904

  4. Animal models for HIV/AIDS research

    PubMed Central

    Hatziioannou, Theodora; Evans, David T.

    2015-01-01

    The AIDS pandemic continues to present us with unique scientific and public health challenges. Although the development of effective antiretroviral therapy has been a major triumph, the emergence of drug resistance requires active management of treatment regimens and the continued development of new antiretroviral drugs. Moreover, despite nearly 30 years of intensive investigation, we still lack the basic scientific knowledge necessary to produce a safe and effective vaccine against HIV-1. Animal models offer obvious advantages in the study of HIV/AIDS, allowing for a more invasive investigation of the disease and for preclinical testing of drugs and vaccines. Advances in humanized mouse models, non-human primate immunogenetics and recombinant challenge viruses have greatly increased the number and sophistication of available mouse and simian models. Understanding the advantages and limitations of each of these models is essential for the design of animal studies to guide the development of vaccines and antiretroviral therapies for the prevention and treatment of HIV-1 infection. PMID:23154262

  5. Large animal models of cardiovascular disease.

    PubMed

    Tsang, H G; Rashdan, N A; Whitelaw, C B A; Corcoran, B M; Summers, K M; MacRae, V E

    2016-04-01

    The human cardiovascular system is a complex arrangement of specialized structures with distinct functions. The molecular landscape, including the genome, transcriptome and proteome, is pivotal to the biological complexity of both normal and abnormal mammalian processes. Despite our advancing knowledge and understanding of cardiovascular disease (CVD) through the principal use of rodent models, this continues to be an increasing issue in today's world. For instance, as the ageing population increases, so does the incidence of heart valve dysfunction. This may be because of changes in molecular composition and structure of the extracellular matrix, or from the pathological process of vascular calcification in which bone-formation related factors cause ectopic mineralization. However, significant differences between mice and men exist in terms of cardiovascular anatomy, physiology and pathology. In contrast, large animal models can show considerably greater similarity to humans. Furthermore, precise and efficient genome editing techniques enable the generation of tailored models for translational research. These novel systems provide a huge potential for large animal models to investigate the regulatory factors and molecular pathways that contribute to CVD in vivo. In turn, this will help bridge the gap between basic science and clinical applications by facilitating the refinement of therapies for cardiovascular disease. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26914991

  6. Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract.

    PubMed

    Asgharian, B; Price, O T; Oldham, M; Chen, Lung-Chi; Saunders, E L; Gordon, T; Mikheev, V B; Minard, K R; Teeguarden, J G

    2014-12-01

    Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles. PMID:25373829

  7. Computational Modeling of Nanoscale and Microscale Particle Deposition, Retention and Dosimetry in the Mouse Respiratory Tract

    PubMed Central

    Asgharian, B.; Price, O.T.; Oldham, M.; Chen, L.C.; Saunders, E.L.; Gordon, T.; Mikheev, V.B.; Minard, K.R.; Teeguarden, J. G.

    2015-01-01

    Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat, human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles. PMID:25373829

  8. Measurement of Libby Amphibole (LA) Elongated Particle Dissolution Rates and Alteration of Size/Shape Distributions in Support of Human Dosimetry Model Development and Relative Potency Determinations

    EPA Science Inventory

    To maximize the value of toxicological data in development of human health risk assessment models of inhaled elongated mineral particles, improvements in human dosimetry modeling are needed. In order to extend the dosimetry model of deposited fibers (Asgharian et aI., Johnson 201...

  9. Domestic animals as models for biomedical research

    PubMed Central

    Andersson, Leif

    2016-01-01

    Domestic animals are unique models for biomedical research due to their long history (thousands of years) of strong phenotypic selection. This process has enriched for novel mutations that have contributed to phenotype evolution in domestic animals. The characterization of such mutations provides insights in gene function and biological mechanisms. This review summarizes genetic dissection of about 50 genetic variants affecting pigmentation, behaviour, metabolic regulation, and the pattern of locomotion. The variants are controlled by mutations in about 30 different genes, and for 10 of these our group was the first to report an association between the gene and a phenotype. Almost half of the reported mutations occur in non-coding sequences, suggesting that this is the most common type of polymorphism underlying phenotypic variation since this is a biased list where the proportion of coding mutations are inflated as they are easier to find. The review documents that structural changes (duplications, deletions, and inversions) have contributed significantly to the evolution of phenotypic diversity in domestic animals. Finally, we describe five examples of evolution of alleles, which means that alleles have evolved by the accumulation of several consecutive mutations affecting the function of the same gene. PMID:26479863

  10. Far-field microwave dosimetry in a rhesus monkey model

    SciTech Connect

    Olsen, R.G.; Griner, T.A.; Prettyman, G.D.

    1980-01-01

    Dosimetric measurements were made in a muscle-equivalent model of an adult rhesus monkey subjected to far-field irradiation at 1.29 GHz. Profiles of microwave-induced heating in the model were obtained at eight locations, and a gradient-layer whole-body calorimeter was used to measure total absorbed energy. Average specific absorption rate (SAR) was calculated both from the calorimeter experiments and from the local temperature measurements. Thermographic imaging techniques were used to qualitatively show the microwave-induced surface heating patterns. For this model the calculated average SAR was 0.15 9W/dg)/(mW/cm2) which, at 1.29 GHs, makes the absorption cross section 84% of the geometric shadow cross section. The SAR is about three times that predicted for a prolate spheroidal model of similar mass. A disproportionally high absorption occurred in the legs of the model positioned parallel to the E-polarization because of what is believed to be partial-body resonance.

  11. Lattice animal model of chromosome organization

    NASA Astrophysics Data System (ADS)

    Iyer, Balaji V. S.; Arya, Gaurav

    2012-07-01

    Polymer models tied together by constraints of looping and confinement have been used to explain many of the observed organizational characteristics of interphase chromosomes. Here we introduce a simple lattice animal representation of interphase chromosomes that combines the features of looping and confinement constraints into a single framework. We show through Monte Carlo simulations that this model qualitatively captures both the leveling off in the spatial distance between genomic markers observed in fluorescent in situ hybridization experiments and the inverse decay in the looping probability as a function of genomic separation observed in chromosome conformation capture experiments. The model also suggests that the collapsed state of chromosomes and their segregation into territories with distinct looping activities might be a natural consequence of confinement.

  12. Macrophages and Uveitis in Experimental Animal Models

    PubMed Central

    Mérida, Salvador; Palacios, Elena; Bosch-Morell, Francisco

    2015-01-01

    Resident and infiltrated macrophages play relevant roles in uveitis as effectors of innate immunity and inductors of acquired immunity. They are major effectors of tissue damage in uveitis and are also considered to be potent antigen-presenting cells. In the last few years, experimental animal models of uveitis have enabled us to enhance our understanding of the leading role of macrophages in eye inflammation processes, including macrophage polarization in experimental autoimmune uveoretinitis and the major role of Toll-like receptor 4 in endotoxin-induced uveitis. This improved knowledge should guide advantageous iterative research to establish mechanisms and possible therapeutic targets for human uveitis resolution. PMID:26078494

  13. Monte Carlo modeling of a conventional X-ray computed tomography scanner for gel dosimetry purposes.

    PubMed

    Hayati, Homa; Mesbahi, Asghar; Nazarpoor, Mahmood

    2016-01-01

    Our purpose in the current study was to model an X-ray CT scanner with the Monte Carlo (MC) method for gel dosimetry. In this study, a conventional CT scanner with one array detector was modeled with use of the MCNPX MC code. The MC calculated photon fluence in detector arrays was used for image reconstruction of a simple water phantom as well as polyacrylamide polymer gel (PAG) used for radiation therapy. Image reconstruction was performed with the filtered back-projection method with a Hann filter and the Spline interpolation method. Using MC results, we obtained the dose-response curve for images of irradiated gel at different absorbed doses. A spatial resolution of about 2 mm was found for our simulated MC model. The MC-based CT images of the PAG gel showed a reliable increase in the CT number with increasing absorbed dose for the studied gel. Also, our results showed that the current MC model of a CT scanner can be used for further studies on the parameters that influence the usability and reliability of results, such as the photon energy spectra and exposure techniques in X-ray CT gel dosimetry. PMID:26205316

  14. A Revised Model for Dosimetry in the Human Small Intestine

    SciTech Connect

    John Poston; Nasir U. Bhuiyan; R. Alex Redd; Neil Parham; Jennifer Watson

    2005-02-28

    A new model for an adult human gastrointestinal tract (GIT) has been developed for use in internal dose estimations to the wall of the GIT and to the other organs and tissues of the body from radionuclides deposited in the lumenal contents of the five sections of the GIT. These sections were the esophasgus, stomach, small intestine, upper large intestine, and the lower large intestine. The wall of each section was separated from its lumenal contents.

  15. Animal model of neuropathic tachycardia syndrome

    NASA Technical Reports Server (NTRS)

    Carson, R. P.; Appalsamy, M.; Diedrich, A.; Davis, T. L.; Robertson, D.

    2001-01-01

    Clinically relevant autonomic dysfunction can result from either complete or partial loss of sympathetic outflow to effector organs. Reported animal models of autonomic neuropathy have aimed to achieve complete lesions of sympathetic nerves, but incomplete lesions might be more relevant to certain clinical entities. We hypothesized that loss of sympathetic innervation would result in a predicted decrease in arterial pressure and a compensatory increase in heart rate. Increased heart rate due to loss of sympathetic innervation is seemingly paradoxical, but it provides a mechanistic explanation for clinical autonomic syndromes such as neuropathic postural tachycardia syndrome. Partially dysautonomic animals were generated by selectively lesioning postganglionic sympathetic neurons with 150 mg/kg 6-hydroxydopamine hydrobromide in male Sprague-Dawley rats. Blood pressure and heart rate were monitored using radiotelemetry. Systolic blood pressure decreased within hours postlesion (Delta>20 mm Hg). Within 4 days postlesion, heart rate rose and remained elevated above control levels. The severity of the lesion was determined functionally and pharmacologically by spectral analysis and responsiveness to tyramine. Low-frequency spectral power of systolic blood pressure was reduced postlesion and correlated with the diminished tyramine responsiveness (r=0.9572, P=0.0053). The tachycardia was abolished by treatment with the beta-antagonist propranolol, demonstrating that it was mediated by catecholamines acting on cardiac beta-receptors. Partial lesions of the autonomic nervous system have been hypothesized to underlie many disorders, including neuropathic postural tachycardia syndrome. This animal model may help us better understand the pathophysiology of autonomic dysfunction and lead to development of therapeutic interventions.

  16. Animal models for protein respiratory sensitizers.

    PubMed

    Ward, Marsha D W; Selgrade, Maryjane K

    2007-01-01

    Protein induced respiratory hypersensitivity, particularly atopic disease in general, and allergic asthma in particular, has increased dramatically over the last several decades in the US and other industrialized nations as a result of ill-defined changes in living conditions in modern western society. In addition, work-related asthma has become the most frequently diagnosed occupational respiratory illness. Animal models have demonstrated great utility in developing an understanding of the etiology and mechanisms of many diseases. A few models been developed as predictive models to identify a protein as an allergen or to characterize its potency. Here we describe animal models that have been used to investigate and identify protein respiratory sensitizers. In addition to prototypical experimental design, methods for exposure route, sample collection, and endpoint assessment are described. Some of the most relevant endpoints in assessing the potential for a given protein to induce atopic or allergic asthma respiratory hypersensitivity are the development of cytotropic antibodies (IgE, IgG1), eosinophil influx into the lung, and airway hyperresponsiveness to the sensitizing protein and/or to non-antigenic stimuli (Mch). The utility of technologies such as PCR and multiplexing assay systems is also described. These models and methods have been used to elucidate the potential for protein sources to induce allergy, identify environmental conditions (pollutants) to impact allergy responsiveness, and establish safe exposure limits. As an example, data are presented from an experiment designed to compare the allergenicity of a fungal biopesticide Metarhizium anisopliae (MACA) crude extract with the one of its components, conidia (CON) extract. PMID:17161304

  17. Confirmation of a realistic reactor model for BNCT dosimetry at the TRIGA Mainz

    SciTech Connect

    Ziegner, Markus; Schmitz, Tobias; Hampel, Gabriele; Khan, Rustam; Blaickner, Matthias; Palmans, Hugo; Sharpe, Peter; Böck, Helmuth

    2014-11-01

    Purpose: In order to build up a reliable dose monitoring system for boron neutron capture therapy (BNCT) applications at the TRIGA reactor in Mainz, a computer model for the entire reactor was established, simulating the radiation field by means of the Monte Carlo method. The impact of different source definition techniques was compared and the model was validated by experimental fluence and dose determinations. Methods: The depletion calculation code ORIGEN2 was used to compute the burn-up and relevant material composition of each burned fuel element from the day of first reactor operation to its current core. The material composition of the current core was used in a MCNP5 model of the initial core developed earlier. To perform calculations for the region outside the reactor core, the model was expanded to include the thermal column and compared with the previously established ATTILA model. Subsequently, the computational model is simplified in order to reduce the calculation time. Both simulation models are validated by experiments with different setups using alanine dosimetry and gold activation measurements with two different types of phantoms. Results: The MCNP5 simulated neutron spectrum and source strength are found to be in good agreement with the previous ATTILA model whereas the photon production is much lower. Both MCNP5 simulation models predict all experimental dose values with an accuracy of about 5%. The simulations reveal that a Teflon environment favorably reduces the gamma dose component as compared to a polymethyl methacrylate phantom. Conclusions: A computer model for BNCT dosimetry was established, allowing the prediction of dosimetric quantities without further calibration and within a reasonable computation time for clinical applications. The good agreement between the MCNP5 simulations and experiments demonstrates that the ATTILA model overestimates the gamma dose contribution. The detailed model can be used for the planning of structural

  18. Marijuana withdrawal syndrome in the animal model.

    PubMed

    Lichtman, Aron H; Martin, Billy R

    2002-11-01

    Although the proposition that repeated marijuana use can lead to marijuana dependence has long been accepted, only recently has evidence emerged suggesting that abstinence leads to clinically significant withdrawal symptoms. Converging evidence from human and animal studies has increased our understanding of cannabinoid dependence. One of the most powerful tools to advance this area of research is the CB1 cannabinoid receptor antagonist SR 141716A, which reliably precipitates withdrawal syndromes in mice, rats, and dogs that have been treated repeatedly with cannabinoids. In addition, the use of CB1 receptor knockout mice has revealed that not only cannabinoid dependence is mediated through a CB1 receptor mechanism of action, but CB1 receptors also modulate opioid dependence. Moreover, the results of other genetically altered mouse models suggest the existence of a reciprocal relationship between cannabinoid and opioid systems in drug dependence. Undoubtedly, these animal models will play pivotal roles in further characterizing cannabinoid dependence and elucidating the mechanisms of action, as well as developing potential pharmacotherapies for cannabinoid dependence. PMID:12412832

  19. Using animal models in osteoarthritis biomarker research.

    PubMed

    Garner, Bridget C; Stoker, Aaron M; Kuroki, Keiichi; Evans, Richard; Cook, Cristi Reeves; Cook, James L

    2011-12-01

    Osteoarthritis (OA) is a disease that commonly affects human and veterinary patients. Animal models are routinely used for OA research, and the dog is a nearly ideal species for translational investigation of human OA biomarkers. The cytokine, chemokine, and matrix metalloprotease (MMP) profiles of synovial fluid, serum, and urine from dogs with surgically induced and naturally occurring OA were compared with dogs without OA using xMAP technology (Qiagen Inc., Valencia, CA). Markers that exhibited significant differences between groups were identified (monocyte chemoattractant protein 1 [MCP1], interleukin 8 [IL8], keratinocyte-derived chemoattractant [KC], and MMP2 and MMP3), and their sensitivities and specificities were calculated to determine their diagnostic usefulness in a future biomarker panel. Synovial fluid IL8 was the most sensitive, but MCP1 was also highly sensitive and specific. The alterations in KC suggested that it may differentiate between cruciate disease and other types of OA, and the MMPs were most sensitive and specific in the serum. This study provided additional insight to the participation of cytokines, chemokines, and MMPs in OA, and potential diagnostic biomarker candidates were identified. A brief literature review of other biomarker candidates previously examined using animal models is discussed. PMID:22303754

  20. Animal Models of Colitis-Associated Carcinogenesis

    PubMed Central

    Kanneganti, Manasa; Mino-Kenudson, Mari; Mizoguchi, Emiko

    2011-01-01

    Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that affect individuals throughout life. Although the etiology and pathogenesis of IBD are largely unknown, studies with animal models of colitis indicate that dysregulation of host/microbial interactions are requisite for the development of IBD. Patients with long-standing IBD have an increased risk for developing colitis-associated cancer (CAC), especially 10 years after the initial diagnosis of colitis, although the absolute number of CAC cases is relatively small. The cancer risk seems to be not directly related to disease activity, but is related to disease duration/extent, complication of primary sclerosing cholangitis, and family history of colon cancer. In particular, high levels and continuous production of inflammatory mediators, including cytokines and chemokines, by colonic epithelial cells (CECs) and immune cells in lamina propria may be strongly associated with the pathogenesis of CAC. In this article, we have summarized animal models of CAC and have reviewed the cellular and molecular mechanisms underlining the development of carcinogenic changes in CECs secondary to the chronic inflammatory conditions in the intestine. It may provide us some clues in developing a new class of therapeutic agents for the treatment of IBD and CAC in the near future. PMID:21274454

  1. Animal Models of Parkinson's Disease: Vertebrate Genetics

    PubMed Central

    Lee, Yunjong; Dawson, Valina L.; Dawson, Ted M.

    2012-01-01

    Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed. PMID:22960626

  2. Emerging and Evolving Ovarian Cancer Animal Models

    PubMed Central

    Bobbs, Alexander S; Cole, Jennifer M; Cowden Dahl, Karen D

    2015-01-01

    Ovarian cancer (OC) is the leading cause of death from a gynecological malignancy in the United States. By the time a woman is diagnosed with OC, the tumor has usually metastasized. Mouse models that are used to recapitulate different aspects of human OC have been evolving for nearly 40 years. Xenograft studies in immunocompromised and immunocompetent mice have enhanced our knowledge of metastasis and immune cell involvement in cancer. Patient-derived xenografts (PDXs) can accurately reflect metastasis, response to therapy, and diverse genetics found in patients. Additionally, multiple genetically engineered mouse models have increased our understanding of possible tissues of origin for OC and what role individual mutations play in establishing ovarian tumors. Many of these models are used to test novel therapeutics. As no single model perfectly copies the human disease, we can use a variety of OC animal models in hypothesis testing that will lead to novel treatment options. The goal of this review is to provide an overview of the utility of different mouse models in the study of OC and their suitability for cancer research. PMID:26380555

  3. Two-parametric model of electron beam in computational dosimetry for radiation processing

    NASA Astrophysics Data System (ADS)

    Lazurik, V. M.; Lazurik, V. T.; Popov, G.; Zimek, Z.

    2016-07-01

    Computer simulation of irradiation process of various materials with electron beam (EB) can be applied to correct and control the performances of radiation processing installations. Electron beam energy measurements methods are described in the international standards. The obtained results of measurements can be extended by implementation computational dosimetry. Authors have developed the computational method for determination of EB energy on the base of two-parametric fitting of semi-empirical model for the depth dose distribution initiated by mono-energetic electron beam. The analysis of number experiments show that described method can effectively consider random displacements arising from the use of aluminum wedge with a continuous strip of dosimetric film and minimize the magnitude uncertainty value of the electron energy evaluation, calculated from the experimental data. Two-parametric fitting method is proposed for determination of the electron beam model parameters. These model parameters are as follow: E0 - energy mono-energetic and mono-directional electron source, X0 - the thickness of the aluminum layer, located in front of irradiated object. That allows obtain baseline data related to the characteristic of the electron beam, which can be later on applied for computer modeling of the irradiation process. Model parameters which are defined in the international standards (like Ep- the most probably energy and Rp - practical range) can be linked with characteristics of two-parametric model (E0, X0), which allows to simulate the electron irradiation process. The obtained data from semi-empirical model were checked together with the set of experimental results. The proposed two-parametric model for electron beam energy evaluation and estimation of accuracy for computational dosimetry methods on the base of developed model are discussed.

  4. Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma

    SciTech Connect

    Merchant, Thomas E. . E-mail: thomas.merchant@stjude.org; Kiehna, Erin N.; Li Chenghong; Shukla, Hemant; Sengupta, Saikat; Xiong Xiaoping; Gajjar, Amar; Mulhern, Raymond K.

    2006-05-01

    Purpose: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. Methods and Materials: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. Results: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. Conclusions: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts.

  5. Animal models for investigating chronic pancreatitis

    PubMed Central

    2011-01-01

    Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. PMID:22133269

  6. Animal models for investigating chronic pancreatitis.

    PubMed

    Aghdassi, Alexander A; Mayerle, Julia; Christochowitz, Sandra; Weiss, Frank U; Sendler, Matthias; Lerch, Markus M

    2011-01-01

    Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. PMID:22133269

  7. An animal model of human cytomegalovirus infection.

    PubMed

    Gao, L; Qian, S; Zeng, L; Wang, R; Wei, G; Fan, J; Zheng, S

    2007-12-01

    To develop a rat model that allowed in vivo progressive human cytomegalovirus (HCMV) infection, allogeneic liver transplantation was performed across a rat combination of Dark Agouti (DA) to Brown Norway (BN). AD169, a well-characterized laboratory strain of HCMV, was used to establish a rat model of HCMV infection by injection of 0.4 mL (30.0 logTCID50) supernate into the rat peritoneum. Histological and blood specimens were obtained from animals sacrificed at predetermined timepoints. We performed immunohistochemical staining in liver, heart, kidney, spleen, and lung for HCMV immediate-early antigen (IE), lower matrix protein (pp65) detection in peripheral blood leukocytes, and HCMV early antigen (EA) and late antigen (LA). We compared survival rates. Our results showed positive HCMV IE and pp65 antigenemia detected in peripheral blood leukocytes in transplanted recipients from day 1 to day 30. Positive HCMV EA and LA staining cells were only detected in sections 10 days after liver transplantation, namely, in hepatocytes, mononuclear cells, bile duct epithelial cells, and endothelial cells. Successful HCMV replication was due to the combination of liver transplantation and cyclosporine (CsA) immunosuppression. Survival analysis showed no significant differences between the HCMV-infected group and HCMV-uninfected group. This new rat model of HCMV infection may be helpful to understand immune system modulation of HCMV infection. PMID:18089401

  8. Peroxisome deficient invertebrate and vertebrate animal models

    PubMed Central

    Van Veldhoven, Paul P.; Baes, Myriam

    2013-01-01

    Although peroxisomes are ubiquitous organelles in all animal species, their importance for the functioning of tissues and organs remains largely unresolved. Because peroxins are essential for the biogenesis of peroxisomes, an obvious approach to investigate their physiological role is to inactivate a Pex gene or to suppress its translation. This has been performed in mice but also in more primitive organisms including D. melanogaster, C. elegans, and D. rerio, and the major findings and abnormalities in these models will be highlighted. Although peroxisomes are generally not essential for embryonic development and organogenesis, a generalized inactivity of peroxisomes affects lifespan and posthatching/postnatal growth, proving that peroxisomal metabolism is necessary for the normal maturation of these organisms. Strikingly, despite the wide variety of model organisms, corresponding tissues are affected including the central nervous system and the testis. By inactivating peroxisomes in a cell type selective way in the brain of mice, it was also demonstrated that peroxisomes are necessary to prevent neurodegeneration. As these peroxisome deficient model organisms recapitulate pathologies of patients affected with peroxisomal diseases, their further analysis will contribute to the elucidation of still elusive pathogenic mechanisms. PMID:24319432

  9. Animal models of tumorigenic herpesviruses--an update.

    PubMed

    Dittmer, Dirk P; Damania, Blossom; Sin, Sang-Hoon

    2015-10-01

    Any one model system, be it culture or animal, only recapitulates one aspect of the viral life cycle in the human host. By providing recent examples of animal models for Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, we would argue that multiple animal models are needed to gain a comprehensive understanding of the pathogenesis associated with human oncogenic herpesviruses. Transgenic mice, homologous animal herpesviruses, and tumorgraft and humanized mouse models all complement each other in the study of viral pathogenesis. The use of animal model systems facilitates the exploration of novel anti-viral and anti-cancer treatment modalities for diseases associated with oncogenic herpesviruses. PMID:26476352

  10. Computational dosimetry for grounded and ungrounded human models due to contact current.

    PubMed

    Chan, Kwok Hung; Hattori, Junya; Laakso, Ilkka; Hirata, Akimasa; Taki, Masao

    2013-08-01

    This study presents the computational dosimetry of contact currents for grounded and ungrounded human models. The uncertainty of the quasi-static (QS) approximation of the in situ electric field induced in a grounded/ungrounded human body due to the contact current is first estimated. Different scenarios of cylindrical and anatomical human body models are considered, and the results are compared with the full-wave analysis. In the QS analysis, the induced field in the grounded cylindrical model is calculated by the QS finite-difference time-domain (QS-FDTD) method, and compared with the analytical solution. Because no analytical solution is available for the grounded/ungrounded anatomical human body model, the results of the QS-FDTD method are then compared with those of the conventional FDTD method. The upper frequency limit for the QS approximation in the contact current dosimetry is found to be 3 MHz, with a relative local error of less than 10%. The error increases above this frequency, which can be attributed to the neglect of the displacement current. The QS or conventional FDTD method is used for the dosimetry of induced electric field and/or specific absorption rate (SAR) for a contact current injected into the index finger of a human body model in the frequency range from 10 Hz to 100 MHz. The in situ electric fields or SAR are compared with the basic restrictions in the international guidelines/standards. The maximum electric field or the 99th percentile value of the electric fields appear not only in the fat and muscle tissues of the finger, but also around the wrist, forearm, and the upper arm. Some discrepancies are observed between the basic restrictions for the electric field and SAR and the reference levels for the contact current, especially in the extremities. These discrepancies are shown by an equation that relates the current density, tissue conductivity, and induced electric field in the finger with a cross-sectional area of 1 cm(2). PMID

  11. Computational dosimetry for grounded and ungrounded human models due to contact current

    NASA Astrophysics Data System (ADS)

    Chan, Kwok Hung; Hattori, Junya; Laakso, Ilkka; Hirata, Akimasa; Taki, Masao

    2013-08-01

    This study presents the computational dosimetry of contact currents for grounded and ungrounded human models. The uncertainty of the quasi-static (QS) approximation of the in situ electric field induced in a grounded/ungrounded human body due to the contact current is first estimated. Different scenarios of cylindrical and anatomical human body models are considered, and the results are compared with the full-wave analysis. In the QS analysis, the induced field in the grounded cylindrical model is calculated by the QS finite-difference time-domain (QS-FDTD) method, and compared with the analytical solution. Because no analytical solution is available for the grounded/ungrounded anatomical human body model, the results of the QS-FDTD method are then compared with those of the conventional FDTD method. The upper frequency limit for the QS approximation in the contact current dosimetry is found to be 3 MHz, with a relative local error of less than 10%. The error increases above this frequency, which can be attributed to the neglect of the displacement current. The QS or conventional FDTD method is used for the dosimetry of induced electric field and/or specific absorption rate (SAR) for a contact current injected into the index finger of a human body model in the frequency range from 10 Hz to 100 MHz. The in situ electric fields or SAR are compared with the basic restrictions in the international guidelines/standards. The maximum electric field or the 99th percentile value of the electric fields appear not only in the fat and muscle tissues of the finger, but also around the wrist, forearm, and the upper arm. Some discrepancies are observed between the basic restrictions for the electric field and SAR and the reference levels for the contact current, especially in the extremities. These discrepancies are shown by an equation that relates the current density, tissue conductivity, and induced electric field in the finger with a cross-sectional area of 1 cm2.

  12. Animal Model of Acute Deep Vein Thrombosis

    SciTech Connect

    Roy, Sumit; Laerum, Frode; Brosstad, Frank; Kvernebo, Knut; Sakariassen, Kjell S.

    1998-07-15

    Purpose: To develop an animal model of acute deep vein thrombosis (DVT). Methods: In part I of the study nine juvenile domestic pigs were used. Each external iliac vein was transluminally occluded with a balloon catheter. Thrombin was infused through a microcatheter in one leg according to one of the following protocols: (1) intraarterial (IA): 1250 U at 25 U/min in the common femoral artery (n= 3); (2) intravenous (IV): 5000 U in the popliteal vein at 500 U/min (n= 3), or at 100 U/min (n= 3). Saline was administered in the opposite leg. After the animals were killed, the mass of thrombus in the iliofemoral veins was measured. The pudendoepiploic (PEV), profunda femoris (PF), and popliteal veins (PV) were examined. Thrombosis in the tributaries of the superficial femoral vein (SFVt) was graded according to a three-point scale (0, +, ++). In part II of the study IV administration was further investigated in nine pigs using the following three regimens with 1000 U at 25 U/min serving as the control: (1) 1000 U at 100 U/min, (2) 250 U at 25 U/min, (3) 250 U at 6.25 U/min. Results: All animals survived. In part I median thrombus mass in the test limbs was 1.40 g as compared with 0.25 g in the controls (p= 0.01). PEV, PFV and PV were thrombosed in all limbs infused with thrombin. IV infusion was more effective in inducing thrombosis in both the parent veins (mass 1.32-1.78 g) and SVFt (++ in 4 of 6 legs), as compared with IA infusion (mass 0.0-1.16 g; SFVt ++ in 1 of 3 legs). In part II thrombus mass in axial veins ranged from 1.23 to 2.86 g, and showed no relationship with the dose of thrombin or the rate of infusion. Tributary thrombosis was less extensive with 250 U at 25 U/min than with the other regimens. Conclusion: Slow distal intravenous thrombin infusion in the hind legs of pigs combined with proximal venous occlusion induces thrombosis in the leg veins that closely resembles clinical DVT in distribution.

  13. Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling.

    PubMed

    Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

    2016-09-01

    Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

  14. Animal Models of Q Fever (Coxiella burnetii)

    PubMed Central

    Bewley, Kevin R

    2013-01-01

    Q fever, caused by the pathogen Coxiella burnetii, is an acute disease that can progress to become a serious chronic illness. The organism leads an obligate, intracellular lifecycle, during which it multiplies in the phagolytic compartments of the phagocytic cells of the immune system of its hosts. This characteristic makes study of the organism particularly difficult and is perhaps one of the reasons why, more than 70 y after its discovery, much remains unknown about the organism and its pathogenesis. A variety of animal species have been used to study both the acute and chronic forms of the disease. Although none of the models perfectly mimics the disease process in humans, each opens a window onto an important aspect of the pathology of the disease. We have learned that immunosuppression, overexpression of IL10, or physical damage to the heart muscle in mice and guinea pigs can induce disease that is similar to the chronic disease seen in humans, suggesting that this aspect of disease may eventually be fully understood. Models using species from mice to nonhuman primates have been used to evaluate and characterize vaccines to protect against the disease and may ultimately yield safer, less expensive vaccines. PMID:24326221

  15. RASopathies: unraveling mechanisms with animal models

    PubMed Central

    Jindal, Granton A.; Goyal, Yogesh; Burdine, Rebecca D.; Rauen, Katherine A.; Shvartsman, Stanislav Y.

    2015-01-01

    ABSTRACT RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment. PMID:26203125

  16. RASopathies: unraveling mechanisms with animal models.

    PubMed

    Jindal, Granton A; Goyal, Yogesh; Burdine, Rebecca D; Rauen, Katherine A; Shvartsman, Stanislav Y

    2015-08-01

    RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment. PMID:26203125

  17. Development and Validation of an Animal Susceptibility Model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An individual animal’s stress level is the summation of stresses from three areas: the environment, animal, and management. A model was developed to predict the susceptibility of an individual animal to heat stress. The model utilizes a hierarchal knowledge-based fuzzy inference system with 11 anim...

  18. Mathematical Phantom Modelled with MCNP-4B code for Individual Patient Dosimetry

    NASA Astrophysics Data System (ADS)

    Gual, Maritza Rodríguez; Valle, Saúl Hernández

    2002-08-01

    In this work was modeled the ORNL mathematical phantom designed by Cristy and Eckerman in 1987 using the MCNP-4B code with the objective of validating the systems of patient specific dosimetry used in the hospitals. The mathematical phantoms modeling with Monte Carlo guarantee estimates doses more exact in the therapy of the cancer with radionuclides because of difference of the anthropomorphic phantoms, are free of engines that are one of the reason of present errors in the experimental mesurements. As a result of this work will be provided mathematical phantom that reproduces the anatomy of the human organism for a standard "reference man". This paper show the specific absorbed fraction of photon energy in the different organ source for energy of 1 MeV and the results are compared with the published values by Cristy and Eckerman in 1987[1].

  19. A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry

    PubMed Central

    Hobbs, Robert F; Song, Hong; Huso, David L; Sundel, Margaret; Sgouros, George

    2013-01-01

    Objective Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction –based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply the model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. Methods We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin go those used in the Cristy-Eckermann phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured, ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus vs. proximal tubule vs. distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. Results The S-values were calculated for the α-emitters and their descendants between the different nephron compartments

  20. A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry

    NASA Astrophysics Data System (ADS)

    Hobbs, Robert F.; Song, Hong; Huso, David L.; Sundel, Margaret H.; Sgouros, George

    2012-07-01

    Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. The S-values were calculated for the α-emitters and their descendants between the different nephron compartments for both the

  1. TestDose: A nuclear medicine software based on Monte Carlo modeling for generating gamma camera acquisitions and dosimetry

    SciTech Connect

    Garcia, Marie-Paule Villoing, Daphnée; Ferrer, Ludovic; Cremonesi, Marta; Botta, Francesca; Ferrari, Mahila; Bardiès, Manuel

    2015-12-15

    Purpose: The TestDose platform was developed to generate scintigraphic imaging protocols and associated dosimetry by Monte Carlo modeling. TestDose is part of a broader project (www.dositest.com) whose aim is to identify the biases induced by different clinical dosimetry protocols. Methods: The TestDose software allows handling the whole pipeline from virtual patient generation to resulting planar and SPECT images and dosimetry calculations. The originality of their approach relies on the implementation of functional segmentation for the anthropomorphic model representing a virtual patient. Two anthropomorphic models are currently available: 4D XCAT and ICRP 110. A pharmacokinetic model describes the biodistribution of a given radiopharmaceutical in each defined compartment at various time-points. The Monte Carlo simulation toolkit GATE offers the possibility to accurately simulate scintigraphic images and absorbed doses in volumes of interest. The TestDose platform relies on GATE to reproduce precisely any imaging protocol and to provide reference dosimetry. For image generation, TestDose stores user’s imaging requirements and generates automatically command files used as input for GATE. Each compartment is simulated only once and the resulting output is weighted using pharmacokinetic data. Resulting compartment projections are aggregated to obtain the final image. For dosimetry computation, emission data are stored in the platform database and relevant GATE input files are generated for the virtual patient model and associated pharmacokinetics. Results: Two samples of software runs are given to demonstrate the potential of TestDose. A clinical imaging protocol for the Octreoscan™ therapeutical treatment was implemented using the 4D XCAT model. Whole-body “step and shoot” acquisitions at different times postinjection and one SPECT acquisition were generated within reasonable computation times. Based on the same Octreoscan™ kinetics, a dosimetry

  2. The maternal deprivation animal model revisited.

    PubMed

    Marco, Eva M; Llorente, Ricardo; López-Gallardo, Meritxell; Mela, Virginia; Llorente-Berzal, Álvaro; Prada, Carmen; Viveros, María-Paz

    2015-04-01

    Early life stress, in the form of MD (24h at pnd 9), interferes with brain developmental trajectories modifying both behavioral and neurobiochemical parameters. MD has been reported to enhance neuroendocrine responses to stress, to affect emotional behavior and to impair cognitive function. More recently, changes in body weight gain, metabolic parameters and immunological responding have also been described. Present data give support to the fact that neuronal degeneration and/or astrocyte proliferation are present in specific brain regions, mainly hippocampus, prefrontal cortex and hypothalamus, which are particularly vulnerable to the effects of neonatal stress. The MD animal model arises as a valuable tool for the investigation of the brain processes occurring at the narrow time window comprised between pnd 9 and 10 that are critical for the establishment of brain circuitries critical for the regulation of behavior, metabolism and energy homeostasis. In the present review we will discuss three possible mechanisms that might be crucial for the effects of MD, namely, the rapid increase in glucocorticoids, the lack of the neonatal leptin surge, and the enhanced endocannabinoid signaling during the specific critical period of MD. A better understanding of the mechanisms underlying the detrimental consequences of MD is a concern for public health and may provide new insights into mental health prevention strategies and into novel therapeutic approaches in neuropsychiatry. PMID:25616179

  3. Animal model of Mycoplasma fermentans respiratory infection

    PubMed Central

    2013-01-01

    Background Mycoplasma fermentans has been associated with respiratory, genitourinary tract infections and rheumatoid diseases but its role as pathogen is controversial. The purpose of this study was to probe that Mycoplasma fermentans is able to produce respiratory tract infection and migrate to several organs on an experimental infection model in hamsters. One hundred and twenty six hamsters were divided in six groups (A-F) of 21 hamsters each. Animals of groups A, B, C were intratracheally injected with one of the mycoplasma strains: Mycoplasma fermentans P 140 (wild strain), Mycoplasma fermentans PG 18 (type strain) or Mycoplasma pneumoniae Eaton strain. Groups D, E, F were the negative, media, and sham controls. Fragments of trachea, lungs, kidney, heart, brain and spleen were cultured and used for the histopathological study. U frequency test was used to compare recovery of mycoplasmas from organs. Results Mycoplasmas were detected by culture and PCR. The three mycoplasma strains induced an interstitial pneumonia; they also migrated to several organs and persisted there for at least 50 days. Mycoplasma fermentans P 140 induced a more severe damage in lungs than Mycoplasma fermentans PG 18. Mycoplasma pneumoniae produced severe damage in lungs and renal damage. Conclusions Mycoplasma fermentans induced a respiratory tract infection and persisted in different organs for several weeks in hamsters. This finding may help to explain the ability of Mycoplasma fermentans to induce pneumonia and chronic infectious diseases in humans. PMID:23298636

  4. A global calibration model for a-Si EPIDs used for transit dosimetry.

    PubMed

    Nijsten, S M J J G; van Elmpt, W J C; Jacobs, M; Mijnheer, B J; Dekker, A L A J; Lambin, P; Minken, A W H

    2007-10-01

    Electronic portal imaging devices (EPIDs) are not only applied for patient setup verification and detection of organ motion but are also increasingly used for dosimetric verification. The aim of our work is to obtain accurate dose distributions from a commercially available amorphous silicon (a-Si) EPID for transit dosimetry applications. For that purpose, a global calibration model was developed, which includes a correction procedure for ghosting effects, field size dependence and energy dependence of the a-Si EPID response. In addition, the long-term stability and additional buildup material for this type of EPID were determined. Differences in EPID response due to photon energy spectrum changes have been measured for different absorber thicknesses and field sizes, yielding off-axis spectrum correction factors based on transmission measurements. Dose measurements performed with an ionization chamber in a water tank were used as reference data, and the accuracy of the dosimetric calibration model was determined for a large range of treatment conditions. Gamma values using 3% as dose-difference criterion and 3 mm as distance-to-agreement criterion were used for evaluation. The field size dependence of the response could be corrected by a single kernel, fulfilling the gamma evaluation criteria in case of virtual wedges and intensity modulated radiation therapy fields. Differences in energy spectrum response amounted up to 30%-40%, but could be reduced to less than 3% using our correction model. For different treatment fields and (in)homogeneous phantoms, transit dose distributions satisfied in almost all situations the gamma criteria. We have shown that a-Si EPIDs can be accurately calibrated for transit dosimetry purposes. PMID:17985633

  5. WHOLE-BODY DOSIMETRY OF MICROWAVE RADIATION IN SMALL ANIMALS: THE EFFECT OF BODY MASS AND EXPOSURE GEOMETRY

    EPA Science Inventory

    Whole-body absorption of 2450-MHz radiation was measured in rats that ranged from 6 to 440 grams and mice that ranged from 30 to 50 grams. Simultaneous exposure of groups of animals in varying numbers and various configurations were made under free-field conditions in an electric...

  6. Reference dosimetry during diagnostic CT examination using XR-QA radiochromic film model

    SciTech Connect

    Boivin, Jonathan; Tomic, Nada; Fadlallah, Bassam; DeBlois, Francois; Devic, Slobodan

    2011-09-15

    Purpose: The authors applied 2D reference dosimetry protocol for dose measurements using XR-QA radiochromic film model during diagnostic computed tomography (CT) examinations carried out on patients and humanoid Rando phantom. Methods: Response of XR-QA model GAFCHROMIC film reference dosimetry system was calibrated in terms of Air-Kerma in air. Four most commonly used CT protocols were selected on their CT scanner (GE Lightspeed VCT 64), covering three anatomical sites (head, chest, and abdomen). For each protocol, 25 patients ongoing planned diagnostic CT examination were recruited. Surface dose was measured using four or eight film strips taped on patients' skin and on Rando phantom. Film pieces were scanned prior to and after irradiation using Epson Expression 10000XL document scanner. Optical reflectance of the unexposed film piece was subtracted from exposed one to obtain final net reflectance change, which is subsequently converted to dose using previously established calibration curves. Results: The authors' measurements show that body skin dose variation has a sinusoidal pattern along the scanning axis due to the helical movement of the x-ray tube, and a comb pattern for head dose measurements due to its axial movement. Results show that the mean skin dose at anterior position for patients is (51 {+-} 6) mGy, (29 {+-} 11) mGy, (45 {+-} 13) mGy and (38 {+-} 20) mGy for head, abdomen, angio Abdomen, and chest and abdomen protocol (UP position), respectively. The obtained experimental dose length products (DLP) show higher values than CT based DLP taken from the scanner console for body protocols, but lower values for the head protocol. Internal dose measurements inside the phantom's head indicate nonuniformity of dose distribution within scanned volume. Conclusions: In this work, the authors applied an Air-Kerma in air based radiochromic film reference dosimetry protocol for in vivo skin dose measurements. In this work, they employed green channel extracted

  7. Clinical Forms and Animal Models of Hypophosphatasia.

    PubMed

    Salles, Jean Pierre

    2015-01-01

    Hypophosphatasia (HPP) is due to mutations of the tissue non-specific alkaline phosphatase (TNAP) gene expressed in the liver, kidney, and bone. TNAP substrates include inorganic pyrophosphate cleaved into inorganic phosphate (Pi) in bone, pyridoxal-5'-phosphate (PLP), the circulating form of vitamin B6, and phosphoethanolamine (PEA). As an autosomal recessive or dominant disease, HPP results in a range of clinical forms. Its hallmarks are low alkaline phosphatase (AP) and elevated PLP and PEA levels. Perinatal HPP may cause early death with respiratory insufficiency and hypomineralization resulting in deformed limbs and sometimes near-absence of bones and skull. Infantile HPP is diagnosed before 6 months of life. Respiratory failure, rib fractures and seizures due to vitamin B6 deficiency in the brain indicate poor prognosis. Craniosynostosis is frequent. Unlike in other forms of rickets, calcium and phosphorus are not decreased, resulting in hypercalciuria and nephrocalcinosis. Hypercalcemic crisis may occur. Failure to thrive and growth retardation are concerns. In infantile and adult forms of HPP, non-traumatic fractures may be the prominent manifestation, with otherwise unexplained chronic pain. Progressive myopathy has been described. Dental manifestations with early loss of teeth are usual in HPP and in a specific form, odontohypophosphatasia. HPP has been studied in knock-out mice models which mimic its severe form. Animal models have made a major contribution to the development of an original enzyme therapy for human infantile HPP, which is however essentially targeted at mineralized tissues. Better knowledge of its extraskeletal manifestations, including pain and neurological symptoms, is therefore required. PMID:26219704

  8. ISDD: A Computational Model of Particle Sedimentation, Diffusion and Target Cell Dosimetry for In Vitro Toxicity Studies

    SciTech Connect

    Hinderliter, Paul M.; Minard, Kevin R.; Orr, Galya; Chrisler, William B.; Thrall, Brian D.; Pounds, Joel G.; Teeguarden, Justin G.

    2010-11-30

    Background: The difficulty of directly measuring cellular dose is a significant obstacle to application of target tissue dosimetry for nanoparticle and microparticle toxicity assessment. As a consequence, the target tissue paradigm for dosimetry and hazard assessment of nanoparticles has largely been ignored in favor of using metrics of exposure (e.g. μg particle/mL culture medium, particle surface area/mL, particle number/mL). We have developed a computational model of solution particokinetics (sedimentation, diffusion) and dosimetry for non-interacting spherical particles and their agglomerates in monolayer cell culture systems. Particle transport to cells is calculated by simultaneous solution of Stokes Law (sedimentation) and the Stokes-Einstein equation (diffusion). Results: The In vitro Sedimentation, Diffusion and Dosimetry model (ISDD) was tested against measured transport rates or cellular doses for multiple sizes of polystyrene spheres (20-1100 nm), 35 nm amorphous silica, and large agglomerates of 30 nm iron oxide particles. Overall, without adjusting any parameters, model predicted doses were in close agreement with the experimental data, differing from as little as 5% to as much as three-fold, but in most cases approximately two-fold, within the limits of the accuracy of the measurement systems. Applying the model, we generalize the effects of particle size, particle density, agglomeration state and agglomerate characteristics on target cell dosimetry in vitro. Conclusions: Our results confirm our hypothesis that the dose-rates for all particles are not equal, but can vary significantly, in direct contrast to the assumption of dose-equivalency implicit in the use of mass-based media concentrations as metrics of exposure for dose-response assessment. The difference between equivalent nominal media concentration exposures on a μg/mL basis and target cell doses on a particle surface area or number basis can be as high as three to six orders of magnitude

  9. ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies

    PubMed Central

    2010-01-01

    Background The difficulty of directly measuring cellular dose is a significant obstacle to application of target tissue dosimetry for nanoparticle and microparticle toxicity assessment, particularly for in vitro systems. As a consequence, the target tissue paradigm for dosimetry and hazard assessment of nanoparticles has largely been ignored in favor of using metrics of exposure (e.g. μg particle/mL culture medium, particle surface area/mL, particle number/mL). We have developed a computational model of solution particokinetics (sedimentation, diffusion) and dosimetry for non-interacting spherical particles and their agglomerates in monolayer cell culture systems. Particle transport to cells is calculated by simultaneous solution of Stokes Law (sedimentation) and the Stokes-Einstein equation (diffusion). Results The In vitro Sedimentation, Diffusion and Dosimetry model (ISDD) was tested against measured transport rates or cellular doses for multiple sizes of polystyrene spheres (20-1100 nm), 35 nm amorphous silica, and large agglomerates of 30 nm iron oxide particles. Overall, without adjusting any parameters, model predicted cellular doses were in close agreement with the experimental data, differing from as little as 5% to as much as three-fold, but in most cases approximately two-fold, within the limits of the accuracy of the measurement systems. Applying the model, we generalize the effects of particle size, particle density, agglomeration state and agglomerate characteristics on target cell dosimetry in vitro. Conclusions Our results confirm our hypothesis that for liquid-based in vitro systems, the dose-rates and target cell doses for all particles are not equal; they can vary significantly, in direct contrast to the assumption of dose-equivalency implicit in the use of mass-based media concentrations as metrics of exposure for dose-response assessment. The difference between equivalent nominal media concentration exposures on a μg/mL basis and target cell

  10. Animal models of rheumatoid arthritis: How informative are they?

    PubMed

    McNamee, Kay; Williams, Richard; Seed, Michael

    2015-07-15

    Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo. PMID:25824900