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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. 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.

  3. Age-dependent small-animal internal radiation dosimetry.

    PubMed

    Xie, Tianwu; Zaidi, Habib

    2013-09-01

    Rats at various ages were observed to present with different radiosensitivity and bioavailability for radiotracers commonly used in preclinical research. We evaluated the effect of age-induced changes in body weight on radiation dose calculations. A series of rat models at different age periods were constructed based on the realistic four-dimensional digital rat whole-body (ROBY) computational model. Particle transport was simulated using the MCNPX Monte Carlo code. Absorbed fractions (AFs) and specific absorbed fraction (SAFs) of monoenergetic photons/electrons and S values of eight positron-emitting radionuclides were calculated. The SAFs and S values for most source-target pairs were inversely correlated with body weight. Differences between F-18 S values for most source-target pairs were between -1.5% and -2%/10 g difference in body weight for different computational models. For specific radiotracers, the radiation dose to organs presents a negative correlation with rat body weight. The SAFs for monoenergetic photons/electrons and S values for common positron-emitting radionuclides can be exploited in the assessment of radiation dose delivered to rats at different ages and weights. The absorbed dose to organs is significantly higher in the low-weight young rat model than in the adult model, which would result in steep secondary effects and might be a noteworthy issue in laboratory animal internal dosimetry.

  4. 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.

  5. 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...

  6. 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.

  7. Model selection for radiochromic film dosimetry.

    PubMed

    Méndez, I

    2015-05-21

    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.

  8. 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...

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. Computer simulations for internal dosimetry using voxel models.

    PubMed

    Kinase, Sakae; Mohammadi, Akram; Takahashi, Masa; Saito, Kimiaki; Zankl, Maria; Kramer, Richard

    2011-07-01

    In the Japan Atomic Energy Agency, several studies have been conducted on the use of voxel models for internal dosimetry. Absorbed fractions (AFs) and S values have been evaluated for preclinical assessments of radiopharmaceuticals using human voxel models and a mouse voxel model. Computational calibration of in vivo measurement system has been also made using Japanese and Caucasian voxel models. In addition, for radiation protection of the environment, AFs have been evaluated using a frog voxel model. Each study was performed by using Monte Carlo simulations. Consequently, it was concluded that these data of Monte Carlo simulations and voxel models could adequately reproduce measurement results. Voxel models were found to be a significant tool for internal dosimetry since the models are anatomically realistic. This fact indicates that several studies on correction of the in vivo measurement efficiency for the variability of human subjects and interspecies scaling of organ doses will succeed.

  14. 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

  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. 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.

  17. 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.

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

    PubMed

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

    2014-07-07

    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 (125)I, (90)Y, (211)At, (99m)Tc, (111)In, (177)Lu, (131)I and (18)F. 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 ((125)I) or high-LET alpha particles ((211)At) 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.

  19. 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.

  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 sarcoidosis.

    PubMed

    Hu, Yijie; Yibrehu, Betel; Zabini, Diana; Kuebler, Wolfgang M

    2017-03-01

    Sarcoidosis is a debilitating, inflammatory, multiorgan, granulomatous disease of unknown cause, commonly affecting the lung. In contrast to other chronic lung diseases such as interstitial pulmonary fibrosis or pulmonary arterial hypertension, there is so far no widely accepted or implemented animal model for this disease. This has hampered our insights into the etiology of sarcoidosis, the mechanisms of its pathogenesis, the identification of new biomarkers and diagnostic tools and, last not least, the development and implementation of novel treatment strategies. Over past years, however, a number of new animal models have been described that may provide useful tools to fill these critical knowledge gaps. In this review, we therefore outline the present status quo for animal models of sarcoidosis, comparing their pros and cons with respect to their ability to mimic the etiological, clinical and histological hallmarks of human disease and discuss their applicability for future research. Overall, the recent surge in animal models has markedly expanded our options for translational research; however, given the relative early stage of most animal models for sarcoidosis, appropriate replication of etiological and histological features of clinical disease, reproducibility and usefulness in terms of identification of new therapeutic targets and biomarkers, and testing of new treatments should be prioritized when considering the refinement of existing or the development of new models.

  2. Monte Carlo dosimetry of iodine contrast objects in a small animal microCT

    NASA Astrophysics Data System (ADS)

    Rodríguez-Villafuerte, M.; Martínez-Dávalos, A.

    2011-08-01

    Small animal microcomputed tomography (microCT) studies with iodine-based contrast media are commonly used in preclinical research. While the use of contrast media improves the quality of the images, it can also result in an increase in the absorbed dose to organs with high concentration of the contrast agent, which might cause radiation damage to the animal. In this work we present the results of a Monte Carlo investigation of a microCT dosimetry study using mouse-sized cylindrical water phantoms with iodine contrast insets for different X-ray spectra (Mo and W targets, 30-80 kVp), iodine concentrations (0, 5, 10 and 15 mg mL-1) and contrast object sizes (3 and 10 mm diameter). Our results indicate an absorbed dose increase in the contrast-inset regions with respect to the absorbed dose distribution within a reference uniform water phantom. The calculated spatial absorbed dose distributions show large gradients due to beam hardening effects, and large absorbed dose enhancement as the mean energy of the beam and iodine concentration increase. We have found that absorbed doses in iodine contrast objects can increase by a factor of up to 12 for a realistic 80 kVp X-ray spectra and an iodine concentration of 15 mg mL-1.

  3. Animal models for osteoporosis.

    PubMed

    Komori, Toshihisa

    2015-07-15

    The major types of osteoporosis in humans are postmenopausal osteoporosis, disuse osteoporosis, and glucocorticoid-induced osteoporosis. Animal models for postmenopausal osteoporosis are generated by ovariectomy. Bone loss occurs in estrogen deficiency due to enhanced bone resorption and impaired osteoblast function. Estrogen receptor α induces osteoclast apoptosis, but the mechanism for impaired osteoblast function remains to be clarified. Animal models for unloading are generated by tail suspension or hind limb immobilization by sciatic neurectomy, tenotomy, or using plaster cast. Unloading inhibits bone formation and enhances bone resorption, and the involvement of the sympathetic nervous system in it needs to be further investigated. The osteocyte network regulates bone mass by responding to mechanical stress. Osteoblast-specific BCL2 transgenic mice, in which the osteocyte network is completely disrupted, can be a mouse model for the evaluation of osteocyte functions. Glucocorticoid treatment inhibits bone formation and enhances bone resorption, and markedly reduces cancellous bone in humans and large animals, but not consistently in rodents.

  4. Complexity and Animal Models

    DTIC Science & Technology

    2015-01-01

    SEP 2015 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Complexity and animal models 5a. CONTRACT NUMBER 5b. GRANT NUMBER...decrease W/Wmax, thereby maintaining the relationship between variability and W/Wmax. doi:10.1016/j.jcrc.2010.05.012 Complexity and animal models...may not be possible during mass casualty and natural disaster situations or may need to be postponed during combat to avoid danger to the medic’s life

  5. New developments in internal dosimetry models.

    PubMed

    Nosske, D; Blanchardon, E; Bolch, W E; Breustedt, B; Eckerman, K F; Giussani, A; Harrison, J D; Klein, W; Leggett, R W; Lopez, M A; Luciani, A; Zankl, M

    2011-03-01

    This paper describes new biokinetic and dosimetric models, especially those being developed by ICRP which will be used in the forthcoming documents on Occupational Intakes of Radionuclides. It also presents the results of a working group within the European project CONRAD which is being continued within EURADOS. This group is implementing the new models, performing quality assurance of the model implementation (including their description) and giving guidance to the scientific community on the application of the models for individual dose assessment.

  6. Cyclic Hematopoiesis: animal models

    SciTech Connect

    Jones, J.B.; Lange, R.D.

    1983-08-01

    The four existing animal models of cyclic hematopoiesis are briefly described. The unusual erythropoietin (Ep) responses of the W/Wv mouse, the Sl/Sld mouse, and cyclic hematopoietic dog are reviewed. The facts reviewed indicate that the bone marrow itself is capable of influencing regulatory events of hematopoiesis.

  7. 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.

  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 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

  10. 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.

  11. 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.

  12. Animal models of narcolepsy.

    PubMed

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

    2009-08-01

    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.

  13. 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...

  14. Comparison between X-rays spectra and their effective energies in small animal CT tomographic imaging and dosimetry.

    PubMed

    Hamdi, Mahdjoub; Mimi, Malika; Bentourkia, M'hamed

    2017-03-01

    Small animal CT imaging and dosimetry usually rely on X-ray radiation produced by X-ray tubes. These X-rays typically cover a large energy range. In this study, we compared poly-energetic X-ray spectra against estimated equivalent (effective) mono-energetic beams with the same number of simulated photons for small animal CT imaging and dosimetry applications. Two poly-energetic X-ray spectra were generated from a tungsten anode at 50 and 120 kVp. The corresponding effective mono-energetic beams were established as 36 keV for the 50 kVp spectrum and 49.5 keV for the 120 kVp spectrum. To assess imaging applications, we investigated the spatial resolution by a tungsten wire, and the contrast-to-noise ratio in a reference phantom and in a realistic mouse phantom. For dosimetry investigation, we calculated the absorbed dose in a segmented digital mouse atlas in the skin, fat, heart and bone tissues. Differences of 2.1 and 2.6% in spatial resolution were respectively obtained between the 50 and 120 kVp poly-energetic spectra and their respective 36 and 49.5 keV mono-energetic beams. The differences in contrast-to-noise ratio between the poly-energetic 50 kVp spectrum and its corresponding mono-energetic 36 keV beam for air, fat, brain and bone were respectively -2.9, -0.2, 11.2 and -4.8%, and similarly between the 120 kVp and its effective energy 49.5 keV: -11.3, -20.2, -4.2 and -13.5%. Concerning the absorbed dose, for the lower X-ray beam energies, 50 kVp against 36 keV, the poly-energetic radiation doses were higher than the mono-energetic doses. Instead, for the higher X-ray beam energies, 120 kVp and 49.5 keV, the absorbed dose to the bones and lungs were higher for the mono-energetic 49.5 keV. The intensity and energy of the X-ray beam spectrum have an impact on both imaging and dosimetry in small animal studies. Simulations with mono-energetic beams should take into account these differences in order to study biological effects or to be compared to

  15. In vitro dosimetry modeling will be a critical step toward ...

    EPA Pesticide Factsheets

    Presentation Description: The development and application of engineered nanomaterials (ENM) into commercial and consumer products is far outpacing the ability of traditional approaches to evaluate the potential implications for environmental health and safety. This problem recently prompted the National Nanotechnology Initiative (NNI) to issue a grand challenge to the research and development community to develop the ability to "determine the environmental, health, and safety characteristics of a nanomaterial in a month". This presentation will consider a general framework in which to consider potential for ENM release, environmental fate, transformations, exposures and effects. Within this framework ,the role of in vitro dosimetry modeling will be illustrated experimentally with examples comparing applied, measured and modeled tissue dose levels of silver and titanium dioxide ENM to cells in vitro. To meet the NNI grand challenge will be difficult, and likely require a combination of targeted rapid screening approaches and predictive modeling. A key step will be the ability to understand the dose of ENM delivered to cells in test systems, along with the use of other modeling approaches to rapidly estimate both levels of exposure and hazardwithin bounds of uncertainty acceptable for the applications being considered Will be presented at the Society of Toxicology Annual Meeting March 13-17, 2015, New Orleans, LA.

  16. 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.

  17. 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.

  18. 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...

  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. [Psoriasis in the animal model].

    PubMed

    Boehncke, W H

    1997-10-01

    Co-existing inflammation and epidermal hyperproliferation characteristic for psoriasis have been shown to be reproducible in several animal models utilizing a variety of different strategies. These models highlight some points of the multicausal pathogenesis of psoriasis. Based on observations made in the animal models, a hypothesis is proposed for the pathogenesis of psoriasis, the elements of which can be tested in a recently established xenogeneic transplantation model.

  1. Use of Physiologically Based Kinetic Modeling-Based Reverse Dosimetry to Predict in Vivo Toxicity from in Vitro Data.

    PubMed

    Louisse, Jochem; Beekmann, Karsten; Rietjens, Ivonne M C M

    2017-01-17

    The development of reliable nonanimal based testing strategies, such as in vitro bioassays, is the holy grail in current human safety testing of chemicals. However, the use of in vitro toxicity data in risk assessment is not straightforward. One of the main issues is that concentration-response curves from in vitro models need to be converted to in vivo dose-response curves. These dose-response curves are needed in toxicological risk assessment to obtain a point of departure to determine safe exposure levels for humans. Recent scientific developments enable this translation of in vitro concentration-response curves to in vivo dose-response curves using physiologically based kinetic (PBK) modeling-based reverse dosimetry. The present review provides an overview of the examples available in the literature on the prediction of in vivo toxicity using PBK modeling-based reverse dosimetry of in vitro toxicity data, showing that proofs-of-principle are available for toxicity end points ranging from developmental toxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity to DNA adduct formation. This review also discusses the promises and pitfalls, and the future perspectives of the approach. Since proofs-of-principle available so far have been provided for the prediction of toxicity in experimental animals, future research should focus on the use of in vitro toxicity data obtained in human models to predict the human situation using human PBK models. This would facilitate human- instead of experimental animal-based approaches in risk assessment.

  2. Inhalation dosimetry modeling provides insights into regional respiratory tract toxicity of inhaled diacetyl.

    PubMed

    Cichocki, Joseph A; Morris, John B

    2016-11-13

    Vapor dosimetry models provide a means of assessing the role of delivered dose in determining the regional airway response to inspired vapors. A validated hybrid computational fluid dynamics physiologically based pharmacokinetic model for inhaled diacetyl has been developed to describe inhaled diacetyl dosimetry in both the rat and human respiratory tracts. Comparison of the distribution of respiratory tract injury with dosimetry estimates provides strong evidence that regional delivered dose rather than regional airway tissue sensitivity to diacetyl-induced injury is the critical determinant of the regional respiratory tract response to this water soluble reactive vapor. In the rat, inhalation exposure to diacetyl causes much lesser injury in the distal bronchiolar airways compared to nose and large tracheobronchial airways. The degree of injury correlates very strongly to model based estimates of local airway diacetyl concentrations. According to the model, regional dosimetry patterns of diacetyl in the human differ greatly from those in the rat with much greater penetration of diacetyl to the bronchiolar airways in the lightly exercising mouth breathing human compared to the rat, providing evidence that rat inhalation toxicity studies underpredict the risk of bronchiolar injury in the human. For example, repeated exposure of the rat to 200ppm diacetyl results in bronchiolar injury; the estimated bronchiolar tissue concentration in rats exposed to 200ppm diacetyl would occur in lightly exercising mouth breathing humans exposed to 12ppm. Consideration of airway dosimetry patterns of inspired diacetyl is critical to the proper evaluation of rodent toxicity data and its relevance for predicting human risk.

  3. Animal models of erectile dysfunction.

    PubMed

    Kapoor, Mandeep Singh; Khan, Samsroz Ahmad; Gupta, Sanjay Kumar; Choudhary, Rajesh; Bodakhe, Surendra H

    2015-01-01

    Erectile dysfunction (ED) is a prevalent male sexual dysfunction with profound adverse effects on the physical and the psychosocial health of men and, subsequently, on their partners. The expanded use of various types of rodent models has produced some advances in the study of ED, and neurophysiological studies using various animal models have provided important insights into human sexual dysfunction. At present, animal models play a key role in exploring and screening novel drugs designed to treat ED.

  4. 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.

  5. 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

  6. Animal Models for Candidiasis

    PubMed Central

    Conti, Heather R.; Huppler, Anna R.; Whibley, Natasha; Gaffen, Sarah L.

    2014-01-01

    Multiple forms of candidiasis are clinically important in humans. Established murine models of disseminated, oropharyngeal, vaginal, and cutaneous candidiasis caused by Candida albicans are described in this unit. Detailed materials and methods for C. albicans growth and detection are also described. PMID:24700323

  7. 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

  8. 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

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

    PubMed

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

    2014-03-01

    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.

  10. 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

  11. Animal models of chronic migraine.

    PubMed

    Storer, Robin James; Supronsinchai, Weera; Srikiatkhachorn, Anan

    2015-01-01

    Many animal models of migraine have been described. Some of them have been useful in the development of new therapies. All of them have their shortcomings. Animal models of chronic migraine have been relatively less frequently described. Whether a rigid distinction between episodic and chronic migraine is useful when their underlying pathophysiology is likely to be the same and that migraine frequency probably depends on complex polygenic influences remains to be determined. Any model of chronic migraine must reflect the chronicity of the disorder and be reliable and validated with pharmacological interventions. Future animal models of chronic migraine are likely to involve recurrent activation of the trigeminal nociceptive system. Valid models would provide a means for investigating pathophysiological mechanism of the transformation from episodic to chronic migraine and may also be used to test the efficacy of potential preventive medications.

  12. 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

  13. Animal welfare and use of silkworm as a model animal.

    PubMed

    Sekimizu, N; Paudel, A; Hamamoto, H

    2012-08-01

    Sacrificing model animals is required for developing effective drugs before being used in human beings. In Japan today, at least 4,210,000 mice and other mammals are sacrificed to a total of 6,140,000 per year for the purpose of medical studies. All the animals treated in Japan, including test animals, are managed under control of "Act on Welfare and Management of Animals". Under the principle of this Act, no person shall kill, injure, or inflict cruelty on animals without due cause. "Animal" addressed in the Act can be defined as a "vertebrate animal". If we can make use of invertebrate animals in testing instead of vertebrate ones, that would be a remarkable solution for the issue of animal welfare. Furthermore, there are numerous advantages of using invertebrate animal models: less space and small equipment are enough for taking care of a large number of animals and thus are cost-effective, they can be easily handled, and many biological processes and genes are conserved between mammals and invertebrates. Today, many invertebrates have been used as animal models, but silkworms have many beneficial traits compared to mammals as well as other insects. In a Genome Pharmaceutical Institute's study, we were able to achieve a lot making use of silkworms as model animals. We would like to suggest that pharmaceutical companies and institutes consider the use of the silkworm as a model animal which is efficacious both for financial value by cost cutting and ethical aspects in animals' welfare.

  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.

  15. 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

  16. Small animal models of xenotransplantation.

    PubMed

    Wang, Hao

    2012-01-01

    Organ transplantation has become a successful and acceptable treatment for end-stage organ failure. Such success has allowed transplant patients to resume a normal lifestyle. The demands for transplantation have been steadily increasing, as more patients and new diseases are being deemed eligible for treatment via transplantation. However, it is clear that human organs will never meet the increasing demand of transplantation. Therefore, scientists must continue to pursue alternative therapies and explore new treatments to meet the growing demand for the limited number of organs available. Transplanting organs from animals into humans (xenotransplantation) is one such therapy. The observed enthusiasm for xenotransplantation, irrespective of the severe shortage of human organs and tissues available for transplantation, can be said to stem from at least two factors. First, there is the possibility that animal organs and tissues might be less susceptible than those of humans to the recurrence of disease processes. Second, a xenograft might be used as a vehicle for introducing novel genes or biochemical processes which could be of therapeutic value for the transplant recipient.To date, millions of lives have been saved by organ transplantation. These remarkable achievements would have been impossible without experimental transplantation research in animal models. Presently, more than 95% of organ transplantation research projects are carried out using rodents, such as rats and mice. The key factor to ensure the success of these experiments lies in state-of-the art experimental surgery. Small animal models offer unique advantages for the mechanistic study of xenotransplantation rejection. Currently, multiple models have been developed for investigating the different stages of immunological barriers in xenotransplantation. In this chapter, we describe six valuable small animal models that have been used in xenotransplantation research. The methodology for the small animal

  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. Numerical modeling and dosimetry of the 35 mm Petri dish under 46 GHz millimeter wave exposure.

    PubMed

    Zhao, Jianxun; Wei, Zhenggang

    2005-09-01

    Experimental studies on effects of millimeter wave (MMW) exposure on cells cultured in Petri dishes have attracted interest in recent decades. To improve the quantification of the biological responses toward the MMW energy, an accurate and precise MMW dosimetry is to be provided. By using the finite difference time domain (FDTD) method, the numerical dosimetry is performed for a typical 35 mm Petri dish under 46 GHz continuous MMW exposure from an irradiator of a specified power pattern. With the aim of building a precise model, the meniscus at the interface between the culture solution and the Petri dish sidewall is taken into account, followed by the modeling of smooth edges of the Petri dish. The trilinear interpolation is introduced to assist the FDTD method to obtain a more precise dosimetric assessment. The specific absorption rate (SAR) distributions in the cornea cells covered by culture solution in the Petri dish are calculated and compared to display the effects of using Petri dish models of various precision and the trilinear interpolation on dosimetry results. In addition, the SAR distribution in the cells is analyzed to study its homogeneity. The results indicate that the precise Petri dish model and the application of the trilinear interpolation are helpful in improving the precision of numerical dosimetry. It is also revealed that the inhomogeneity of the SAR distribution is well beyond neglect, which deserves cautious consideration in experiments investigating MMW effects on cells in vitro.

  19. 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...

  20. Partition Model-Based 99mTc-MAA SPECT/CT Predictive Dosimetry Compared with 90Y TOF PET/CT Posttreatment Dosimetry in Radioembolization of Hepatocellular Carcinoma: A Quantitative Agreement Comparison.

    PubMed

    Gnesin, Silvano; Canetti, Laurent; Adib, Salim; Cherbuin, Nicolas; Silva Monteiro, Marina; Bize, Pierre; Denys, Alban; Prior, John O; Baechler, Sebastien; Boubaker, Ariane

    2016-11-01

    (90)Y-microsphere selective internal radiation therapy (SIRT) is a valuable treatment in unresectable hepatocellular carcinoma (HCC). Partition-model predictive dosimetry relies on differential tumor-to-nontumor perfusion evaluated on pretreatment (99m)Tc-macroaggregated albumin (MAA) SPECT/CT. The aim of this study was to evaluate agreement between the predictive dosimetry of (99m)Tc-MAA SPECT/CT and posttreatment dosimetry based on (90)Y time-of-flight (TOF) PET/CT.

  1. Stochastic modelling of animal movement

    PubMed Central

    Smouse, Peter E.; Focardi, Stefano; Moorcroft, Paul R.; Kie, John G.; Forester, James D.; Morales, Juan M.

    2010-01-01

    Modern animal movement modelling derives from two traditions. Lagrangian models, based on random walk behaviour, are useful for multi-step trajectories of single animals. Continuous Eulerian models describe expected behaviour, averaged over stochastic realizations, and are usefully applied to ensembles of individuals. We illustrate three modern research arenas. (i) Models of home-range formation describe the process of an animal ‘settling down’, accomplished by including one or more focal points that attract the animal's movements. (ii) Memory-based models are used to predict how accumulated experience translates into biased movement choices, employing reinforced random walk behaviour, with previous visitation increasing or decreasing the probability of repetition. (iii) Lévy movement involves a step-length distribution that is over-dispersed, relative to standard probability distributions, and adaptive in exploring new environments or searching for rare targets. Each of these modelling arenas implies more detail in the movement pattern than general models of movement can accommodate, but realistic empiric evaluation of their predictions requires dense locational data, both in time and space, only available with modern GPS telemetry. PMID:20566497

  2. Animal models of Alzheimer disease.

    PubMed

    LaFerla, Frank M; Green, Kim N

    2012-11-01

    Significant insights into the function of genes associated with Alzheimer disease and related dementias have occurred through studying genetically modified animals. Although none of the existing models fully reproduces the complete spectrum of this insidious human disease, critical aspects of Alzheimer pathology and disease processes can be experimentally recapitulated. Genetically modified animal models have helped advance our understanding of the underlying mechanisms of disease and have proven to be invaluable in the preclinical evaluation of potential therapeutic interventions. Continuing refinement and evolution to yield the next generation of animal models will facilitate successes in producing greater translational concordance between preclinical studies and human clinical trials and eventually lead to the introduction of novel therapies into clinical practice.

  3. 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.

  4. Animal models of cardiovascular diseases.

    PubMed

    Zaragoza, Carlos; Gomez-Guerrero, Carmen; Martin-Ventura, Jose Luis; Blanco-Colio, Luis; Lavin, Begoña; Mallavia, Beñat; Tarin, Carlos; Mas, Sebastian; Ortiz, Alberto; Egido, Jesus

    2011-01-01

    Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology, making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available, models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against human cardiovascular diseases.

  5. Animal Models of Zika Virus.

    PubMed

    P Bradley And Claude M Nagamine, Michael

    2017-03-07

    Zika virus has garnered great attention over the last several years, as outbreaks of the disease have emerged throughout the Western Hemisphere. Until quite recently Zika virus was considered a fairly benign virus, with limited clinical severity in both people and animals. The size and scope of the outbreak in the Western Hemisphere has allowed for the identification of severe clinical disease that is associated with Zika virus infection, most notably microcephaly among newborns, and an association with Guillian-Barré syndrome in adults. This recent association with severe clinical disease, of which further analysis strongly suggested causation by Zika virus, has resulted in a massive increase in the amount of both basic and applied research of this virus. Both small and large animal models are being used to uncover the pathogenesis of this emerging disease and to develop vaccine and therapeutic strategies. Here we review the animal-model-based Zika virus research that has been performed to date.

  6. Animal models for auditory streaming.

    PubMed

    Itatani, Naoya; Klump, Georg M

    2017-02-19

    Sounds in the natural environment need to be assigned to acoustic sources to evaluate complex auditory scenes. Separating sources will affect the analysis of auditory features of sounds. As the benefits of assigning sounds to specific sources accrue to all species communicating acoustically, the ability for auditory scene analysis is widespread among different animals. Animal studies allow for a deeper insight into the neuronal mechanisms underlying auditory scene analysis. Here, we will review the paradigms applied in the study of auditory scene analysis and streaming of sequential sounds in animal models. We will compare the psychophysical results from the animal studies to the evidence obtained in human psychophysics of auditory streaming, i.e. in a task commonly used for measuring the capability for auditory scene analysis. Furthermore, the neuronal correlates of auditory streaming will be reviewed in different animal models and the observations of the neurons' response measures will be related to perception. The across-species comparison will reveal whether similar demands in the analysis of acoustic scenes have resulted in similar perceptual and neuronal processing mechanisms in the wide range of species being capable of auditory scene analysis.This article is part of the themed issue 'Auditory and visual scene analysis'.

  7. 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

  8. Animal models of papillomavirus pathogenesis.

    PubMed

    Campo, M Saveria

    2002-11-01

    Tumorigenesis due to papillomavirus (PV) infection was first demonstrated in rabbits and cattle early last century. Despite the evidence obtained in animals, the role of viruses in human cancer was dismissed as irrelevant. It took a paradigm shift in the late 1970s for some viruses to be recognised as 'tumour viruses' in humans, and in 1995, more than 60 years after Rous's first demonstration of CRPV oncogenicity, WHO officially declared that 'HPV-16 and HPV-18 are carcinogenic to humans'. Experimental studies with animal PVs have been a determining factor in this decision. Animal PVs have been studied both as agents of disease in animals and as models of human PV infection. In addition to the study of PV infection in whole animals, in vitro studies with animal PV proteins have contributed greatly to the understanding of the mechanisms of cell transformation. Animal PVs cause distressing diseases in both farm and companion animals, such as teat papillomatosis in cattle, equine sarcoids and canine oral papillomatosis and there is an urgent need to understand the pathogenesis of these problematic infections. Persistent and florid teat papillomatosis in cows can lead to mastitis, prevent the suckling of calves and make milking impossible; heavily affected animals are culled and so occasionally are whole herds. Equine sarcoids are often recurrent and untreatable and lead to loss of valuable animals. Canine oral papillomatosis can be very extensive and persistent and lead to great distress. Thus the continuing research in the biology of animal PVs is amply justified. BPVs and CRPV have been for many years the model systems with which to study the biology of HPV. Induction of papillomas and their neoplastic progression has been experimentally demonstrated and reproduced in cattle and rabbits, and virus-cofactor interactions have been elucidated in these systems. With the advancements in molecular and cell culture techniques, the direct study of HPV has become less

  9. Dosimetry Formalism and Implementation of a Homogenous Irradiation Protocol to Improve the Accuracy of Small Animal Whole-Body Irradiation Using a 137Cs Irradiator.

    PubMed

    Brodin, N Patrik; Chen, Yong; Yaparpalvi, Ravindra; Guha, Chandan; Tomé, Wolfgang A

    2016-02-01

    Shielded Cs irradiators are routinely used in pre-clinical radiation research to perform in vitro or in vivo investigations. Without appropriate dosimetry and irradiation protocols in place, there can be large uncertainty in the delivered dose of radiation between irradiated subjects that could lead to inaccurate and possibly misleading results. Here, a dosimetric evaluation of the JL Shepard Mark I-68A Cs irradiator and an irradiation technique for whole-body irradiation of small animals that allows one to limit the between subject variation in delivered dose to ±3% are provided. Mathematical simulation techniques and Gafchromic EBT film were used to describe the region within the irradiation cavity with homogeneous dose distribution (100% ± 5%), the dosimetric impact of varying source-to-subject distance, and the variation in attenuation thickness due to turntable rotation. Furthermore, an irradiation protocol and dosimetry formalism that allows calculation of irradiation time for whole-body irradiation of small animals is proposed that is designed to ensure a more consistent dose delivery between irradiated subjects. To compare this protocol with the conventional irradiation protocol suggested by the vendor, high-resolution film dosimetry measurements evaluating the dose difference between irradiation subjects and the dose distribution throughout subjects was performed using phantoms resembling small animals. Based on these results, there can be considerable variation in the delivered dose of > ± 5% using the conventional irradiation protocol for whole-body irradiation doses below 5 Gy. Using the proposed irradiation protocol this variability can be reduced to within ±3% and the dosimetry formalism allows for more accurate calculation of the irradiation time in relation to the intended prescription dose.

  10. 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.

  11. Animal models of drug addiction.

    PubMed

    García Pardo, María Pilar; Roger Sánchez, Concepción; De la Rubia Ortí, José Enrique; Aguilar Calpe, María Asunción

    2017-01-12

    The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction.

  12. Animal models of cognitive dysfunction.

    PubMed

    Tayebati, Seyed Khosrow

    2006-02-01

    The increased life expectancy in industrialised countries in the last half century has also brought to a greater incidence of neurological disorders, including neurodegenerative diseases and developing in a rather long time. In this respect, Alzheimer's disease (AD), for the large incidence, and the dramatic loss of autonomy caused by its cognitive and behavioural symptoms represents one of the main challenges of modern medicine. Although AD is a typical human disease and probably includes several nosographic entities, the use of animal models may contribute to understand specific aspects of pathophysiology of the disease. The most widely used animal models are rodents and non-human primates. In this review different animal models characterised by impaired cognitive functions are analysed. None of the models available mimics exactly cognitive, behavioural, biochemical and histopathological abnormalities observed in neurological disorders characterised by cognitive impairment. However, partial reproduction of neuropathology and/or cognitive deficits of Alzheimer's disease (AD), vascular dementia and dementia occurring in Huntington's and Parkinson's diseases, or in other neurodegenerative disorders may represent a basis for understanding pathophysiological traits of these diseases and for contributing to their treatments.

  13. Resin versus Glass Microspheres for Yttrium-90 Transarterial Radioembolization: Comparing Survival in Unresectable Hepatocellular Carcinoma using Pretreatment Partition Model Dosimetry.

    PubMed

    VAN DER Gucht, Axel; Jreige, Mario; Denys, Alban; Blanc-Durand, Paul; Boubaker, Ariane; Pomoni, Anastasia; Mitsakis, Periklis; Silva-Monteiro, Marina; Gnesin, Silvano; Nicod-Lalonde, Marie; Duran, Rafael; Prior, John; Schaefer, Niklaus

    2017-01-12

    The aim of this study was to compare survival of patients treated for unresectable hepatocellular carcinoma (uHCC) with Yttrium-90 ((90)Y) transarterial radioembolization (TARE) using pretreatment partition model dosimetry (PMD).

  14. Development of computational small animal models and their applications in preclinical imaging and therapy research.

    PubMed

    Xie, Tianwu; Zaidi, Habib

    2016-01-01

    The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

  15. Development of computational small animal models and their applications in preclinical imaging and therapy research

    SciTech Connect

    Xie, Tianwu; Zaidi, Habib

    2016-01-15

    The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

  16. 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.

  17. [Animal models of cardiovascular disease].

    PubMed

    Chorro, Francisco J; Such-Belenguer, Luis; López-Merino, Vicente

    2009-01-01

    The use of animal models to study cardiovascular disease has made a substantial contribution to increasing our understanding of disease pathogenesis, has led to the development of diagnostic techniques, and has made it possible to verify the effectiveness of different preventative and therapeutic approaches, whether pharmacological or interventional. The main limitations stem from differences between human and experimentally induced pathology, in terms of both genetic regulatory mechanisms and factors that influence cardiovascular function. The experimental models and preparations used in cardiovascular research include those based on isolated cells or tissues or structures immersed in organ baths. The Langendorff system enables isolated perfused hearts to be studied directly under conditions of either no load or controlled loading. In small mammals, a number of models have been developed of cardiovascular conditions that result from spontaneous genetic mutations or, alternatively, that may be induced by specific genomic modification. One of the techniques employed is gene transfer, which can involve the controlled induction of mutations that result in the expression of abnormalities associated with the development of a broad range of different types of cardiovascular disease. Larger animals are used in experimental models in which it is important that physiological regulatory and homeostatic mechanisms are present.

  18. Animal models of RLS phenotypes.

    PubMed

    Allen, Richard P; Donelson, Nathan C; Jones, Byron C; Li, Yuqing; Manconi, Mauro; Rye, David B; Sanyal, Subhabrata; Winkelmann, Juliane

    2017-03-01

    Restless legs syndrome (RLS) is a complex disorder that involves sensory and motor systems. The major pathophysiology of RLS is low iron concentration in the substantia nigra containing the cell bodies of dopamine neurons that project to the striatum, an area that is crucial for modulating movement. People who have RLS often present with normal iron values outside the brain; recent studies implicate several genes are involved in the syndrome. Like most complex diseases, animal models usually do not faithfully capture the full phenotypic spectrum of "disease," which is a uniquely human construct. Nonetheless, animal models have proven useful in helping to unravel the complex pathophysiology of diseases such as RLS and suggesting novel treatment paradigms. For example, hypothesis-independent genome-wide association studies (GWAS) have identified several genes as increasing the risk for RLS, including BTBD9. Independently, the murine homolog Btbd9 was identified as a candidate gene for iron regulation in the midbrain in mice. The relevance of the phenotype of another of the GWAS identified genes, MEIS1, has also been explored. The role of Btbd9 in iron regulation and RLS-like behaviors has been further evaluated in mice carrying a null mutation of the gene and in fruit flies when the BTBD9 protein is degraded. The BTBD9 and MEIS1 stories originate from human GWAS research, supported by work in a genetic reference population of mice (forward genetics) and further verified in mice, fish flies, and worms. Finally, the role of genetics is further supported by an inbred mouse strain that displays many of the phenotypic characteristics of RLS. The role of animal models of RLS phenotypes is also extended to include periodic limb movements.

  19. 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

  20. A model-based comparison of implicit and direct dosimetry for ALA-PDT of skin

    NASA Astrophysics Data System (ADS)

    Liu, Baochang; Farrell, Thomas J.; Patterson, Michael S.

    2011-07-01

    Photosensitizer fluorescence photobleaching and Singlet Oxygen (1O2) Luminescence Dosimetry (SOLD) are being studied as potential dosimetric tools for ALA-PDT of skin diseases. However, the correlation of both SOLD data and PpIX fluorescence to 1O2 distribution is difficult to interpret because of the temporal and spatial variations of the PDT parameters (light fluence rate, photosensitizer concentration and oxygen concentration). This work used our dynamic model to investigate both dosimetry approaches for varied PpIX concentration and distribution, and three commonly used treatment wavelengths. The results show that SOLD is much less dependent upon the treatment parameters, which implies it has better potential as a "gold standard" dosimetric tool for clinical PDT.

  1. 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.

  2. 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

  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. 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

  5. Animal models of recurrent or bipolar depression.

    PubMed

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

    2016-05-03

    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.

  6. 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...

  7. Companion animals symposium: humanized animal models of the microbiome.

    PubMed

    Gootenberg, D B; Turnbaugh, P J

    2011-05-01

    Humans and other mammals are colonized by trillions of microorganisms, most of which reside in the gastrointestinal tract, that provide key metabolic capabilities, such as the biosynthesis of vitamins and AA, the degradation of dietary plant polysaccharides, and the metabolism of orally administered therapeutics. Although much progress has been made by studying the human microbiome directly, comparing the human microbiome with that of other animals, and constructing in vitro models of the human gut, there remains a need to develop in vivo models where host, microbial, and environmental parameters can be manipulated. Here, we discuss some of the initial results from a promising method that enables the direct manipulation of microbial community structure, environmental exposures, host genotype, and other factors: the colonization of germ-free animals with complex microbial communities, including those from humans or other animal donors. Analyses of these resulting "humanized" gut microbiomes have begun to reveal 1) that key microbial activities can be transferred from the donor to the recipient animal (e.g., microbial reduction of cholesterol and production of equol), 2) that dietary shifts can affect the composition, gene abundance, and gene expression of the gut microbiome, 3) the succession of the microbial community in infants and ex-germ-free adult animals, and 4) the biogeography of these microbes across the length of gastrointestinal tract. Continued studies of humanized and other intentionally colonized animal models stand to provide new insight into not only the human microbiome, but also the microbiomes of our animal companions.

  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. Theoretical modelling of experimental diagnostic procedures employed during pre-dose dosimetry of quartz.

    PubMed

    Pagonis, Vasilis; Chen, Reuven; Kitis, George

    2006-01-01

    The pre-dose technique in thermoluminescence (TL) is used for dating archaeological ceramics and for accident dosimetry. During routine applications of this technique, the sensitisation of the quartz samples is measured as a function of the annealing temperature, yielding the so-called thermal activation characteristic (TAC). The measurement of multiple TACs and the study of the effect of UV-radiation on the TL sensitivity of quartz are important analytical and diagnostic tools. In this paper, it is shown that a modified Zimmerman model for quartz can successfully model the experimental steps undertaken during a measurement of multiple TACs.

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

    2016-06-07

    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.

  16. 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.

  17. Chronobiology of ethanol: animal models.

    PubMed

    Rosenwasser, Alan M

    2015-06-01

    Clinical and epidemiological observations have revealed that alcohol abuse and alcoholism are associated with widespread disruptions in sleep and other circadian biological rhythms. As with other psychiatric disorders, animal models have been very useful in efforts to better understand the cause and effect relationships underlying the largely correlative human data. This review summarizes the experimental findings indicating bidirectional interactions between alcohol (ethanol) consumption and the circadian timing system, emphasizing behavioral studies conducted in the author's laboratory. Together with convergent evidence from multiple laboratories, the work summarized here establishes that ethanol intake (or administration) alters fundamental properties of the underlying circadian pacemaker. In turn, circadian disruption induced by either environmental or genetic manipulations can alter voluntary ethanol intake. These reciprocal interactions may create a vicious cycle that contributes to the downward spiral of alcohol and drug addiction. In the future, such studies may lead to the development of chronobiologically based interventions to prevent relapse and effectively mitigate some of the societal burden associated with such disorders.

  18. New concept of light dosimetry in photodynamic therapy: the control by using an ARX modeling

    NASA Astrophysics Data System (ADS)

    Muller, Laure; Abdul-Nour, Charles; Granjon, Yves; Guillemin, Francois H.; Yvroud, Edouard

    1995-01-01

    The control of light dosimetry during photodynamic therapy requires the knowledge of all the optical coefficient in situ. Therefore, a sensor based upon the backscattering phenomenon has been conceived. It is described in the first part. The second part of the paper shows how the combination of the Kubelka and Munk's theory and an ARX modeling of light gives access to the required values. In the last part the results obtained in vitro on optical phantoms and in vivo on nude mice are analyzed.

  19. Solar particle events observed at Mars: dosimetry measurements and model calculations

    NASA Astrophysics Data System (ADS)

    Cleghorn, T.; Saganti, P.; Zeitlin, C.; Cucinotta, F.

    The first solar particle events from a Martian orbit are observed with the MARIE (Martian Radiation Environment Experiment) on the 2001 Mars Odyssey space -craft that is currently in orbit and collecting the mapping data of the red planet. These solar particle events observed at Mars during March and April 2002, are correlated with the GOES-8 and ACE satellite data from the same time period at Earth orbits. Dosimetry measurements for the Mars orbit from the period of March 13t h through April 29t h . Particle count rate and the corresponding dose rate enhancements were observed on March 16t h through 20t h and on April 22n d corresponding to solar particle events that were observed at Earth orbit on March 16t h through 21s t and beginning on April 21s t respectively. The model calculations with the HZETRN (High Z=atomic number and high Energy Transport) code estimated the background GCR (Galactic Cosmic Rays) dose rates. The dose rates observed by the MARIE instrument are within 10% of the model calculations. Dosimetry measurements and model calculation will be presented.

  20. 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

  1. Internal dosimetry - a review.

    SciTech Connect

    Potter, Charles Augustus

    2004-06-01

    The field history and current status of internal dosimetry is reviewed in this article. Elements of the field that are reviewed include standards and models, derivation of dose coefficients and intake retention fractions, bioassay measurements, and intake and dose calculations. In addition, guidance is developed and provided as to the necessity of internal dosimetry for a particular facility or operation and methodology for implementing a program. A discussion of the purposes of internal dosimetry is included as well as recommendations for future development and direction.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Utero-fetal unit and pregnant woman modeling using a computer graphics approach for dosimetry studies.

    PubMed

    Anquez, Jérémie; Boubekeur, Tamy; Bibin, Lazar; Angelini, Elsa; Bloch, Isabelle

    2009-01-01

    Potential sanitary effects related to electromagnetic fields exposure raise public concerns, especially for fetuses during pregnancy. Human fetus exposure can only be assessed through simulated dosimetry studies, performed on anthropomorphic models of pregnant women. In this paper, we propose a new methodology to generate a set of detailed utero-fetal unit (UFU) 3D models during the first and third trimesters of pregnancy, based on segmented 3D ultrasound and MRI data. UFU models are built using recent geometry processing methods derived from mesh-based computer graphics techniques and embedded in a synthetic woman body. Nine pregnant woman models have been generated using this approach and validated by obstetricians, for anatomical accuracy and representativeness.

  8. 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

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

    PubMed

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

    2012-07-07

    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

  10. 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

  11. 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

  12. Animal model and neurobiology of suicide.

    PubMed

    Preti, Antonio

    2011-06-01

    Animal models are formidable tools to investigate the etiology, the course and the potential treatment of an illness. No convincing animal model of suicide has been produced to date, and despite the intensive study of thousands of animal species naturalists have not identified suicide in nonhuman species in field situations. When modeling suicidal behavior in the animal, the greatest challenge is reproducing the role of will and intention in suicide mechanics. To overcome this limitation, current investigations on animals focus on every single step leading to suicide in humans. The most promising endophenotypes worth investigating in animals are the cortisol social-stress response and the aggression/impulsivity trait, involving the serotonergic system. Astroglia, neurotrophic factors and neurotrophins are implied in suicide, too. The prevention of suicide rests on the identification and treatment of every element increasing the risk.

  13. Animal models for the study of tendinopathy.

    PubMed

    Warden, S J

    2007-04-01

    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.

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

    PubMed Central

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

    2016-01-01

    Abstract 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

  15. 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

  16. Animal Models in Studying Cerebral Arteriovenous Malformation.

    PubMed

    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.

  17. 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

  18. Overview of Animal Models of Obesity

    PubMed Central

    Lutz, Thomas A.; Woods, Stephen C.

    2012-01-01

    This is a review of animal models of obesity currently used in research. We have focused upon more commonly utilized models since there are far too many newly created models to consider, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, we will not discuss the generation and use of inducible transgenic animals (induced knock-out or knock-in) even though they often bear significant advantages compared to traditional transgenic animals; influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this chapter. PMID:22948848

  19. 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

  20. 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.

  1. 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

  2. Animal Models for Cartilage Regeneration and Repair

    PubMed Central

    Szczodry, Michal; Bruno, Stephen

    2010-01-01

    Articular cartilage injury and degeneration are leading causes of disability. Animal studies are critically important to developing effective treatments for cartilage injuries. This review focuses on the use of animal models for the study of the repair and regeneration of focal cartilage defects. Animals commonly used in cartilage repair studies include murine, lapine, canine, caprine, porcine, and equine models. There are advantages and disadvantages to each model. Small animal rodent and lapine models are cost effective, easy to house, and useful for pilot and proof-of-concept studies. The availability of transgenic and knockout mice provide opportunities for mechanistic in vivo study. Athymic mice and rats are additionally useful for evaluating the cartilage repair potential of human cells and tissues. Their small joint size, thin cartilage, and greater potential for intrinsic healing than humans, however, limit the translational value of small animal models. Large animal models with thicker articular cartilage permit study of both partial thickness and full thickness chondral repair, as well as osteochondral repair. Joint size and cartilage thickness for canine, caprine, and mini-pig models remain significantly smaller than that of humans. The repair and regeneration of chondral and osteochondral defects of size and volume comparable to that of clinically significant human lesions can be reliably studied primarily in equine models. While larger animals may more closely approximate the human clinical situation, they carry greater logistical, financial, and ethical considerations. A multifactorial analysis of each animal model should be carried out when planning in vivo studies. Ultimately, the scientific goals of the study will be critical in determining the appropriate animal model. PMID:19831641

  3. Modeling the impact of prostate edema on LDR brachytherapy: a Monte Carlo dosimetry study based on a 3D biphasic finite element biomechanical model

    NASA Astrophysics Data System (ADS)

    Mountris, K. A.; Bert, J.; Noailly, J.; Rodriguez Aguilera, A.; Valeri, A.; Pradier, O.; Schick, U.; Promayon, E.; Gonzalez Ballester, M. A.; Troccaz, J.; Visvikis, D.

    2017-03-01

    Prostate volume changes due to edema occurrence during transperineal permanent brachytherapy should be taken under consideration to ensure optimal dose delivery. Available edema models, based on prostate volume observations, face several limitations. Therefore, patient-specific models need to be developed to accurately account for the impact of edema. In this study we present a biomechanical model developed to reproduce edema resolution patterns documented in the literature. Using the biphasic mixture theory and finite element analysis, the proposed model takes into consideration the mechanical properties of the pubic area tissues in the evolution of prostate edema. The model’s computed deformations are incorporated in a Monte Carlo simulation to investigate their effect on post-operative dosimetry. The comparison of Day1 and Day30 dosimetry results demonstrates the capability of the proposed model for patient-specific dosimetry improvements, considering the edema dynamics. The proposed model shows excellent ability to reproduce previously described edema resolution patterns and was validated based on previous findings. According to our results, for a prostate volume increase of 10–20% the Day30 urethra D10 dose metric is higher by 4.2%–10.5% compared to the Day1 value. The introduction of the edema dynamics in Day30 dosimetry shows a significant global dose overestimation identified on the conventional static Day30 dosimetry. In conclusion, the proposed edema biomechanical model can improve the treatment planning of transperineal permanent brachytherapy accounting for post-implant dose alterations during the planning procedure.

  4. Animal models for simulating weightlessness

    NASA Technical Reports Server (NTRS)

    Morey-Holton, E.; Wronski, T. J.

    1982-01-01

    NASA has developed a rat model to simulate on earth some aspects of the weightlessness alterations experienced in space, i.e., unloading and fluid shifts. Comparison of data collected from space flight and from the head-down rat suspension model suggests that this model system reproduces many of the physiological alterations induced by space flight. Data from various versions of the rat model are virtually identical for the same parameters; thus, modifications of the model for acute, chronic, or metabolic studies do not alter the results as long as the critical components of the model are maintained, i.e., a cephalad shift of fluids and/or unloading of the rear limbs.

  5. 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

  6. A comprehensive tool for image-based generation of fetus and pregnant women mesh models for numerical dosimetry studies

    NASA Astrophysics Data System (ADS)

    Dahdouh, S.; Varsier, N.; Serrurier, A.; De la Plata, J.-P.; Anquez, J.; Angelini, E. D.; Wiart, J.; Bloch, I.

    2014-08-01

    Fetal dosimetry studies require the development of accurate numerical 3D models of the pregnant woman and the fetus. This paper proposes a 3D articulated fetal growth model covering the main phases of pregnancy and a pregnant woman model combining the utero-fetal structures and a deformable non-pregnant woman body envelope. The structures of interest were automatically or semi-automatically (depending on the stage of pregnancy) segmented from a database of images and surface meshes were generated. By interpolating linearly between fetal structures, each one can be generated at any age and in any position. A method is also described to insert the utero-fetal structures in the maternal body. A validation of the fetal models is proposed, comparing a set of biometric measurements to medical reference charts. The usability of the pregnant woman model in dosimetry studies is also investigated, with respect to the influence of the abdominal fat layer.

  7. Animal Models of Tuberculosis: Zebrafish

    PubMed Central

    van Leeuwen, Lisanne M.; van der Sar, Astrid M.; Bitter, Wilbert

    2015-01-01

    Over the past decade the zebrafish (Danio rerio) has become an attractive new vertebrate model organism for studying mycobacterial pathogenesis. The combination of medium-throughput screening and real-time in vivo visualization has allowed new ways to dissect host pathogenic interaction in a vertebrate host. Furthermore, genetic screens on the host and bacterial sides have elucidated new mechanisms involved in the initiation of granuloma formation and the importance of a balanced immune response for control of mycobacterial pathogens. This article will highlight the unique features of the zebrafish–Mycobacterium marinum infection model and its added value for tuberculosis research. PMID:25414379

  8. Animal models of orofacial pain.

    PubMed

    Khan, Asma; Hargreaves, Kenneth M

    2010-01-01

    Pain is one of the most common reasons for which patients seek dental and medical care. Orofacial pain conditions consist of a wide range of disorders including odontalgia (toothache), temporomandibular disorders, trigeminal neuralgia and others. Most of these conditions are either inflammatory or neuropathic in nature. This chapter provides an overview of the commonly used models to study inflammatory and neuropathic orofacial pain.

  9. The relevance of animal models in osteoarthritis.

    PubMed

    Moskowitz, R W

    1990-01-01

    Studies of osteoarthritis (OA) in humans are restricted by the slow rate at which the disease progresses, and the limited opportunity for study of the tissue changes over time. A range of animal models of OA have been developed which demonstrate histopathological and gross features typical of OA in humans. Animal models can be used to study OA, and to investigate the effects of a variety of agents, including so-called chondroprotective agents, on the progression of the disease.

  10. Radioactive Waste Management: Study of Spent Fuel Dissolution Rates in Geological Storage Using Dosimetry Modeling and Experimental Verification

    SciTech Connect

    Hansen, Brady; Miller, William

    2011-10-28

    This research will provide improved predictions into the mechanisms and effects of radiolysis on spent nuclear fuel dissolution in a geological respository through accurate dosimetry modeling of the dose to water, mechanistic chemistry modeling of the resulting radiolytic reactions and confirmatory experimental measurements. This work will combine effort by the Nuclear Science and Engineering Institute (NSEI) and the Missouri University Research Reactor (MURR) at the University of Missouri-Columbia, and the expertise and facilities at the Pacific Northwest National Laboratory (PNNL).

  11. 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

  12. Animal models of orthopedic implant infection.

    PubMed

    An, Y H; Friedman, R J

    1998-01-01

    Prosthetic infection following total joint replacement can have catastrophic results both physically and psychologically for patients, leading to complete failure of the arthroplasty, possible amputation, prolonged hospitalization, and even death. Although with the use of prophylactic antibiotics and greatly improved operating room techniques the infection rate has decreased markedly during the years, challenges still remain for better preventive and therapeutic measures. In this review the in vivo experimental methods for studies of prosthetic infection are discussed, concentrating on (1) the animal models that have been established and the use of these animal models for studies of pathogenesis of bacteria, behavior of biofilm, effect of biomaterials on prosthetic infection rate, and the effect of infection on biomaterial surfaces, and (2) how to design and conduct an animal model of orthopedic prosthetic infection including animal selection, implant fabrication, bacterial inoculation, surgical technique, and the methods for evaluating the results.

  13. Animal models for SARS and MERS coronaviruses.

    PubMed

    Gretebeck, Lisa M; Subbarao, Kanta

    2015-08-01

    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.

  14. Application of a canine 238Pu biokinetics/dosimetry model to human bioassay data.

    PubMed

    Hickman, A W; Griffith, W C; Roessler, G S; Guilmette, R A

    1995-03-01

    Associated with the use of 238Pu in thermoelectric power sources for space probes is the potential for human exposure, primarily by inhalation and most likely as 238PuO2. Several models have been developed for assessing the level of intake and predicting the resulting radiation dose following human exposure to 239Pu. However, there are indications that existing models do not adequately describe the disposition and dosimetry of 238Pu following human exposure. In this study, a canine model that accounts for these differences has been adapted for use with human excretion data. The model is based on existing knowledge about organ retention of plutonium. An analysis of the sensitivity of the model to changes in aerosol-associated properties indicated that predictions of urinary excretion are most sensitive to changes in particle solubility and diameter and in the ratio of fragment:particle surface area. Application of the model to urinary excretion data from seven workers exposed to a 238Pu ceramic aerosol gave estimated intakes of 390-8,200 Bq and associated initial pulmonary burdens of 80-1,700 Bq. The resulting 50-y dose commitments to critical organs per Bq of 238Pu intake were estimated to be 0.5 mSv for the thoracic region, 0.2 mSv for the liver, and 1 mSv for the bone surfaces.

  15. Modeling physicochemical interactions affecting in vitro cellular dosimetry of engineered nanomaterials: application to nanosilver

    NASA Astrophysics Data System (ADS)

    Mukherjee, Dwaipayan; Leo, Bey Fen; Royce, Steven G.; Porter, Alexandra E.; Ryan, Mary P.; Schwander, Stephan; Chung, Kian Fan; Tetley, Teresa D.; Zhang, Junfeng; Georgopoulos, Panos G.

    2014-10-01

    Engineered nanomaterials (ENMs) possess unique characteristics affecting their interactions in biological media and biological tissues. Systematic investigation of the effects of particle properties on biological toxicity requires a comprehensive modeling framework which can be used to predict ENM particokinetics in a variety of media. The Agglomeration-diffusion-sedimentation-reaction model (ADSRM) described here is stochastic, using a direct simulation Monte Carlo method to study the evolution of nanoparticles in biological media, as they interact with each other and with the media over time. Nanoparticle diffusion, gravitational settling, agglomeration, and dissolution are treated in a mechanistic manner with focus on silver ENMs (AgNPs). The ADSRM model utilizes particle properties such as size, density, zeta potential, and coating material, along with medium properties like density, viscosity, ionic strength, and pH, to model evolving patterns in a population of ENMs along with their interaction with associated ions and molecules. The model predictions for agglomeration and dissolution are compared with in vitro measurements for various types of ENMs, coating materials, and incubation media, and are found to be overall consistent with measurements. The model has been implemented for an in vitro case in cell culture systems to inform in vitro dosimetry for toxicology studies, and can be directly extended to other biological systems, including in vivo tissue sub-systems by suitably modifying system geometry.

  16. Building models of animals from video.

    PubMed

    Ramanan, Deva; Forsyth, David A; Barnard, Kobus

    2006-08-01

    This paper argues that tracking, object detection, and model building are all similar activities. We describe a fully automatic system that builds 2D articulated models known as pictorial structures from videos of animals. The learned model can be used to detect the animal in the original video--in this sense, the system can be viewed as a generalized tracker (one that is capable of modeling objects while tracking them). The learned model can be matched to a visual library; here, the system can be viewed as a video recognition algorithm. The learned model can also be used to detect the animal in novel images--in this case, the system can be seen as a method for learning models for object recognition. We find that we can significantly improve the pictorial structures by augmenting them with a discriminative texture model learned from a texture library. We develop a novel texture descriptor that outperforms the state-of-the-art for animal textures. We demonstrate the entire system on real video sequences of three different animals. We show that we can automatically track and identify the given animal. We use the learned models to recognize animals from two data sets; images taken by professional photographers from the Corel collection, and assorted images from the Web returned by Google. We demonstrate quite good performance on both data sets. Comparing our results with simple baselines, we show that, for the Google set, we can detect, localize, and recover part articulations from a collection demonstrably hard for object recognition.

  17. 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.

  18. Composite Mandibulectomy: A Novel Animal Model

    PubMed Central

    Sidell, Douglas R.; Aghaloo, Tara; Tetradis, Sotirios; Lee, Min; Bezouglaia, Olga; DeConde, Adam; St. John, Maie A.

    2012-01-01

    Objectives Segmental mandibular defects can result after the treatment of various pathologic processes, including osteoradionecrosis, tumor resection, or fracture nonunion with sequestration. The variety of etiologies and the frequency of occurrence make the reconstruction of segmental mandibular defects a topic of significant interest. Despite these incentives, a well-established small-animal model of the segmental mandibulectomy, including composite resection, does not exist. The objective of this study is the creation of a reliable animal model that can be used to study the reconstruction of en bloc mandibular defects. Surgical techniques and an array of reconstructive options are described. Study design Description of an animal model. Setting Animal laboratory at a quaternary care university medical center. Methods We present an Animal Research Oversight Committee–approved prospective analysis of survival operations in the rat model. A detailed, stepwise description of surgical technique and relevant intraoperative anatomy is presented. Postoperative management, early pitfalls, surgical complications, and future applications are discussed. Results A total of 72 operations were performed by a single individual between July and October 2010. Two intraoperative and 9 postoperative complications were recognized. There were 6 orocutaneous fistulas, 2 abscesses, and 1 seroma. There were 4 fatalities, which were attributed to anesthetic complications (2, intraoperative), hematoma formation (1, postoperative), and foreign-body aspiration (1, postoperative). Conclusion This novel animal model reliably replicates the en bloc segmental mandibular defects seen in our patient population and can be manipulated to achieve a wide variety of research objectives. PMID:22282867

  19. MODELING VOLATILE ORGANIC COMPOUND PHARMACOKINETICS IN RAT PUPS

    EPA Science Inventory

    PBPK model predictions of internal dosimetry in young rats were compared to adult animals for benzene, chloroform (CHL), methylene chloride, methyl ethly ketone (MEK), perchloroethylene, and trichloroethylene.

  20. 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.

  1. 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.

  2. A novel homogenization procedure to model the skin layers in LF numerical dosimetry

    NASA Astrophysics Data System (ADS)

    De Santis, Valerio; Chen, Xi Lin; Cruciani, Silvano; Campi, Tommaso; Feliziani, Mauro

    2016-06-01

    In this study we focus on the validity of the skin layer currently implemented in up-to-date human-body anatomical models employed in low frequency (LF) numerical dosimetry. Indeed, the several layers of the skin structure, i.e. the stratum corneum (SC), dermis, and epidermis are in these models embedded into a unique fairly-thick (2-3 mm) layer encompassing all of them. While a previous work from the authors showed that for normal-standing (or limb-non-touching) postures a single-layer skin model could conservatively estimate the peak electric field induced in the skin, at least a two-layer skin model comprising of the SC and the remaining skin layers should be used for limb-touching exposure scenarios. This implies notable efforts to discretize the tiny SC layer questioning the validity of current anatomical models. A novel strategy based on the homogenization of the several skin layers has been therefore proposed in order to eliminate the SC from the computational domain opening the doors to future LF magnetic applications even for limb-touching scenarios.

  3. Uncertainty in spatially explicit animal dispersal models

    USGS Publications Warehouse

    Mooij, Wolf M.; DeAngelis, Donald L.

    2003-01-01

    Uncertainty in estimates of survival of dispersing animals is a vexing difficulty in conservation biology. The current notion is that this uncertainty decreases the usefulness of spatially explicit population models in particular. We examined this problem by comparing dispersal models of three levels of complexity: (1) an event-based binomial model that considers only the occurrence of mortality or arrival, (2) a temporally explicit exponential model that employs mortality and arrival rates, and (3) a spatially explicit grid-walk model that simulates the movement of animals through an artificial landscape. Each model was fitted to the same set of field data. A first objective of the paper is to illustrate how the maximum-likelihood method can be used in all three cases to estimate the means and confidence limits for the relevant model parameters, given a particular set of data on dispersal survival. Using this framework we show that the structure of the uncertainty for all three models is strikingly similar. In fact, the results of our unified approach imply that spatially explicit dispersal models, which take advantage of information on landscape details, suffer less from uncertainly than do simpler models. Moreover, we show that the proposed strategy of model development safeguards one from error propagation in these more complex models. Finally, our approach shows that all models related to animal dispersal, ranging from simple to complex, can be related in a hierarchical fashion, so that the various approaches to modeling such dispersal can be viewed from a unified perspective.

  4. 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

  5. Animal models of idiosyncratic drug reactions.

    PubMed

    Ng, Winnie; Lobach, Alexandra R M; Zhu, Xu; Chen, Xin; Liu, Feng; Metushi, Imir G; Sharma, Amy; Li, Jinze; Cai, Ping; Ip, Julia; Novalen, Maria; Popovic, Marija; Zhang, Xiaochu; Tanino, Tadatoshi; Nakagawa, Tetsuya; Li, Yan; Uetrecht, Jack

    2012-01-01

    If we could predict and prevent idiosyncratic drug reactions (IDRs) it would have a profound effect on drug development and therapy. Given our present lack of mechanistic understanding, this goal remains elusive. Hypothesis testing requires valid animal models with characteristics similar to the idiosyncratic reactions that occur in patients. Although it has not been conclusively demonstrated, it appears that almost all IDRs are immune-mediated, and a dominant characteristic is a delay between starting the drug and the onset of the adverse reaction. In contrast, most animal models are acute and therefore involve a different mechanism than idiosyncratic reactions. There are, however, a few animal models such as the nevirapine-induced skin rash in rats that have characteristics very similar to the idiosyncratic reaction that occurs in humans and presumably have a very similar mechanism. These models have allowed testing hypotheses that would be impossible to test in any other way. In addition there are models in which there is a delayed onset of mild hepatic injury that resolves despite continued treatment similar to the "adaptation" reactions that are more common than severe idiosyncratic hepatotoxicity in humans. This probably represents the development of immune tolerance. However, most attempts to develop animal models by stimulating the immune system have been failures. A specific combination of MHC and T cell receptor may be required, but it is likely more complex. Animal studies that determine the requirements for an immune response would provide vital clues about risk factors for IDRs in patients.

  6. Large Animal Models of Huntington's Disease.

    PubMed

    Li, Xiao-Jiang; Li, Shihua

    2015-01-01

    Huntington's disease is caused by the expansion of a polyglutamine repeat (>37 glutamines) in the disease protein huntingtin, which results in preferential neuronal loss in distinct brain regions. Mutant huntingtin causes late-onset neurological symptoms in patients in middle life, though the expression of mutant huntingtin is ubiquitous from early life. Thus, it is important to understand why mutant huntingtin selectively causes neuronal loss in an age-dependent manner. Transgenic animal models have been essential tools for uncovering the pathogenesis and therapeutic targets of neurodegenerative diseases. Genetic mouse models have been investigated extensively and have revealed the common pathological hallmark of age-dependent formation of aggregates or inclusions consisting of misfolded proteins. However, most genetic mouse models lack striking neurodegeneration that has been found in patient brains. Since there are considerable species differences between small and large animals, large animal models of Huntington's disease may allow one to identify the pathological features that are more similar to those in patients and also help uncover more effective therapeutic targets. This chapter will focus on the important findings from large animal models of Huntington's disease and discusses the use of large animal models to investigate the pathogenesis of Huntington's disease and develop new therapeutic strategies.

  7. Dosimetry study of PHOTOFRIN-mediated photodynamic therapy in a mouse tumor model

    NASA Astrophysics Data System (ADS)

    Qiu, Haixia; Kim, Michele M.; Penjweini, Rozhin; Zhu, Timothy C.

    2016-03-01

    It is well known in photodynamic therapy (PDT) that there is a large variability between PDT light dose and therapeutic outcomes. An explicit dosimetry model using apparent reacted 1O2 concentration [1O2]rx has been developed as a PDT dosimetric quantity to improve the accuracy of the predicted ability of therapeutic efficacy. In this study, this explicit macroscopic singlet oxygen model was adopted to establish the correlation between calculated reacted [1O2]rx and the tumor growth using Photofrin-mediated PDT in a mouse tumor model. Mice with radiation-induced fibrosarcoma (RIF) tumors were injected with Photofrin at a dose of 5 mg/kg. PDT was performed 24h later with different fluence rates (50, 75 and 150 mW/cm2) and different fluences (50 and 135 J/cm2) using a collimated light applicator coupled to a 630nm laser. The tumor volume was monitored daily after PDT and correlated with the total light fluence and [1O2]rx. Photophysical parameters as well as the singlet oxygen threshold dose for this sensitizer and the RIF tumor model were determined previously. The result showed that tumor growth rate varied greatly with light fluence for different fluence rates while [1O2]rx had a good correlation with the PDT-induced tumor growth rate. This preliminary study indicated that [1O2]rx could serve as a better dosimetric predictor for predicting PDT outcome than PDT light dose.

  8. Realistic multi-cellular dosimetry for 177Lu-labelled antibodies: model and application

    NASA Astrophysics Data System (ADS)

    Marcatili, S.; Pichard, A.; Courteau, A.; Ladjohounlou, R.; Navarro-Teulon, I.; Repetto-Llamazares, A.; Heyerdahl, H.; Dahle, J.; Pouget, J. P.; Bardiès, M.

    2016-10-01

    Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General-purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin®, a novel 177Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of 177Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions.

  9. 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.

  10. 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.

  11. An image-based skeletal dosimetry model for the ICRP reference adult female—internal electron sources

    NASA Astrophysics Data System (ADS)

    O'Reilly, Shannon E.; DeWeese, Lindsay S.; Maynard, Matthew R.; Rajon, Didier A.; Wayson, Michael B.; Marshall, Emily L.; Bolch, Wesley E.

    2016-12-01

    An image-based skeletal dosimetry model for internal electron sources was created for the ICRP-defined reference adult female. Many previous skeletal dosimetry models, which are still employed in commonly used internal dosimetry software, do not properly account for electron escape from trabecular spongiosa, electron cross-fire from cortical bone, and the impact of marrow cellularity on active marrow self-irradiation. Furthermore, these existing models do not employ the current ICRP definition of a 50 µm bone endosteum (or shallow marrow). Each of these limitations was addressed in the present study. Electron transport was completed to determine specific absorbed fractions to both active and shallow marrow of the skeletal regions of the University of Florida reference adult female. The skeletal macrostructure and microstructure were modeled separately. The bone macrostructure was based on the whole-body hybrid computational phantom of the UF series of reference models, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 years-old female cadaver. The active and shallow marrow are typically adopted as surrogate tissue regions for the hematopoietic stem cells and osteoprogenitor cells, respectively. Source tissues included active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume, and cortical bone surfaces. Marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. All other sources were run at the defined ICRP Publication 70 cellularity for each bone site. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or analytically modeled. The method of combining skeletal macrostructure and microstructure absorbed fractions assessed using MCNPX electron transport was found to yield results similar to those determined with the PIRT model applied to the UF adult male skeletal dosimetry model. Calculated

  12. An image-based skeletal dosimetry model for the ICRP reference adult female-internal electron sources.

    PubMed

    O'Reilly, Shannon E; DeWeese, Lindsay S; Maynard, Matthew R; Rajon, Didier A; Wayson, Michael B; Marshall, Emily L; Bolch, Wesley E

    2016-12-21

    An image-based skeletal dosimetry model for internal electron sources was created for the ICRP-defined reference adult female. Many previous skeletal dosimetry models, which are still employed in commonly used internal dosimetry software, do not properly account for electron escape from trabecular spongiosa, electron cross-fire from cortical bone, and the impact of marrow cellularity on active marrow self-irradiation. Furthermore, these existing models do not employ the current ICRP definition of a 50 µm bone endosteum (or shallow marrow). Each of these limitations was addressed in the present study. Electron transport was completed to determine specific absorbed fractions to both active and shallow marrow of the skeletal regions of the University of Florida reference adult female. The skeletal macrostructure and microstructure were modeled separately. The bone macrostructure was based on the whole-body hybrid computational phantom of the UF series of reference models, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 years-old female cadaver. The active and shallow marrow are typically adopted as surrogate tissue regions for the hematopoietic stem cells and osteoprogenitor cells, respectively. Source tissues included active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume, and cortical bone surfaces. Marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. All other sources were run at the defined ICRP Publication 70 cellularity for each bone site. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or analytically modeled. The method of combining skeletal macrostructure and microstructure absorbed fractions assessed using MCNPX electron transport was found to yield results similar to those determined with the PIRT model applied to the UF adult male skeletal dosimetry model. Calculated

  13. 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.

  14. 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.

  15. Large animal models for stem cell therapy.

    PubMed

    Harding, John; Roberts, R Michael; Mirochnitchenko, Oleg

    2013-03-28

    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

  16. Model-based versus specific dosimetry in diagnostic context: Comparison of three dosimetric approaches

    SciTech Connect

    Marcatili, S. Villoing, D.; Mauxion, T.; Bardiès, M.; McParland, B. J.

    2015-03-15

    Purpose: The dosimetric assessment of novel radiotracers represents a legal requirement in most countries. While the techniques for the computation of internal absorbed dose in a therapeutic context have made huge progresses in recent years, in a diagnostic scenario the absorbed dose is usually extracted from model-based lookup tables, most often derived from International Commission on Radiological Protection (ICRP) or Medical Internal Radiation Dose (MIRD) Committee models. The level of approximation introduced by these models may impact the resulting dosimetry. The aim of this work is to establish whether a more refined approach to dosimetry can be implemented in nuclear medicine diagnostics, by analyzing a specific case. Methods: The authors calculated absorbed doses to various organs in six healthy volunteers administered with flutemetamol ({sup 18}F) injection. Each patient underwent from 8 to 10 whole body 3D PET/CT scans. This dataset was analyzed using a Monte Carlo (MC) application developed in-house using the toolkit GATE that is capable to take into account patient-specific anatomy and radiotracer distribution at the voxel level. They compared the absorbed doses obtained with GATE to those calculated with two commercially available software: OLINDA/EXM and STRATOS implementing a dose voxel kernel convolution approach. Results: Absorbed doses calculated with GATE were higher than those calculated with OLINDA. The average ratio between GATE absorbed doses and OLINDA’s was 1.38 ± 0.34 σ (from 0.93 to 2.23). The discrepancy was particularly high for the thyroid, with an average GATE/OLINDA ratio of 1.97 ± 0.83 σ for the six patients. Differences between STRATOS and GATE were found to be higher. The average ratio between GATE and STRATOS absorbed doses was 2.51 ± 1.21 σ (from 1.09 to 6.06). Conclusions: This study demonstrates how the choice of the absorbed dose calculation algorithm may introduce a bias when gamma radiations are of importance, as is

  17. Mathematical modelling of scanner-specific bowtie filters for Monte Carlo CT dosimetry.

    PubMed

    Kramer, R; Cassola, V F; Andrade, M E A; de Araújo, M W C; Brenner, D J; Khoury, H J

    2017-02-07

    The purpose of bowtie filters in CT scanners is to homogenize the x-ray intensity measured by the detectors in order to improve the image quality and at the same time to reduce the dose to the patient because of the preferential filtering near the periphery of the fan beam. For CT dosimetry, especially for Monte Carlo calculations of organ and tissue absorbed doses to patients, it is important to take the effect of bowtie filters into account. However, material composition and dimensions of these filters are proprietary. Consequently, a method for bowtie filter simulation independent of access to proprietary data and/or to a specific scanner would be of interest to many researchers involved in CT dosimetry. This study presents such a method based on the weighted computer tomography dose index, CTDIw, defined in two cylindrical PMMA phantoms of 16 cm and 32 cm diameter. With an EGSnrc-based Monte Carlo (MC) code, ratios CTDIw/CTDI100,a were calculated for a specific CT scanner using PMMA bowtie filter models based on sigmoid Boltzmann functions combined with a scanner filter factor (SFF) which is modified during calculations until the calculated MC CTDIw/CTDI100,a matches ratios CTDIw/CTDI100,a, determined by measurements or found in publications for that specific scanner. Once the scanner-specific value for an SFF has been found, the bowtie filter algorithm can be used in any MC code to perform CT dosimetry for that specific scanner. The bowtie filter model proposed here was validated for CTDIw/CTDI100,a considering 11 different CT scanners and for CTDI100,c, CTDI100,p and their ratio considering 4 different CT scanners. Additionally, comparisons were made for lateral dose profiles free in air and using computational anthropomorphic phantoms. CTDIw/CTDI100,a determined with this new method agreed on average within 0.89% (max. 3.4%) and 1.64% (max. 4.5%) with corresponding data published by CTDosimetry (www.impactscan.org) for the CTDI HEAD and BODY phantoms

  18. Mathematical modelling of scanner-specific bowtie filters for Monte Carlo CT dosimetry

    NASA Astrophysics Data System (ADS)

    Kramer, R.; Cassola, V. F.; Andrade, M. E. A.; de Araújo, M. W. C.; Brenner, D. J.; Khoury, H. J.

    2017-02-01

    The purpose of bowtie filters in CT scanners is to homogenize the x-ray intensity measured by the detectors in order to improve the image quality and at the same time to reduce the dose to the patient because of the preferential filtering near the periphery of the fan beam. For CT dosimetry, especially for Monte Carlo calculations of organ and tissue absorbed doses to patients, it is important to take the effect of bowtie filters into account. However, material composition and dimensions of these filters are proprietary. Consequently, a method for bowtie filter simulation independent of access to proprietary data and/or to a specific scanner would be of interest to many researchers involved in CT dosimetry. This study presents such a method based on the weighted computer tomography dose index, CTDIw, defined in two cylindrical PMMA phantoms of 16 cm and 32 cm diameter. With an EGSnrc-based Monte Carlo (MC) code, ratios CTDIw/CTDI100,a were calculated for a specific CT scanner using PMMA bowtie filter models based on sigmoid Boltzmann functions combined with a scanner filter factor (SFF) which is modified during calculations until the calculated MC CTDIw/CTDI100,a matches ratios CTDIw/CTDI100,a, determined by measurements or found in publications for that specific scanner. Once the scanner-specific value for an SFF has been found, the bowtie filter algorithm can be used in any MC code to perform CT dosimetry for that specific scanner. The bowtie filter model proposed here was validated for CTDIw/CTDI100,a considering 11 different CT scanners and for CTDI100,c, CTDI100,p and their ratio considering 4 different CT scanners. Additionally, comparisons were made for lateral dose profiles free in air and using computational anthropomorphic phantoms. CTDIw/CTDI100,a determined with this new method agreed on average within 0.89% (max. 3.4%) and 1.64% (max. 4.5%) with corresponding data published by CTDosimetry (www.impactscan.org) for the CTDI HEAD and BODY phantoms

  19. Food allergy animal models: an overview.

    PubMed

    Helm, Ricki M

    2002-05-01

    Specific food allergy is characterized by sensitization to innocuous food proteins with production of allergen-specific IgE that binds to receptors on basophils and mast cells. Upon recurrent exposure to the same allergen, an allergic response is induced by mediator release following cross-linking of cell-bound allergen-specific IgE. The determination of what makes an innocuous food protein an allergen in predisposed individuals is unknown; however, mechanistic and protein allergen predictive models are being actively investigated in a number of animal models. Currently, there is no animal model that will actively profile known food allergens, predict the allergic potential of novel food proteins, or demonstrate clinically the human food allergic sensitization/allergic response. Animal models under investigation include mice, rats, the guinea pig, atopic dog, and neonatal swine. These models are being assessed for production of IgE, clinical responses to re-exposure, and a ranking of food allergens (based on potency) including a nonfood allergen protein source. A selection of animal models actively being investigated that will contribute to our understanding of what makes a protein an allergen and future predictive models for assessing the allergenicity of novel proteins is presented in this review.

  20. Standardization of A Physiologic Hypoparathyroidism Animal Model

    PubMed Central

    Jung, Soo Yeon; Kim, Ha Yeong; Park, Hae Sang; Yin, Xiang Yun; Chung, Sung Min; Kim, Han Su

    2016-01-01

    Ideal hypoparathyroidism animal models are a prerequisite to developing new treatment modalities for this disorder. The purpose of this study was to evaluate the feasibility of a model whereby rats were parathyroidectomized (PTX) using a fluorescent-identification method and the ideal calcium content of the diet was determined. Thirty male rats were divided into surgical sham (SHAM, n = 5) and PTX plus 0, 0.5, and 2% calcium diet groups (PTX-FC (n = 5), PTX-NC (n = 10), and PTX-HC (n = 10), respectively). Serum parathyroid hormone levels decreased to non-detectable levels in all PTX groups. All animals in the PTX—FC group died within 4 days after the operation. All animals survived when supplied calcium in the diet. However, serum calcium levels were higher in the PTX-HC than the SHAM group. The PTX-NC group demonstrated the most representative modeling of primary hypothyroidism. Serum calcium levels decreased and phosphorus levels increased, and bone volume was increased. All animals survived without further treatment and did not show nephrotoxicity including calcium deposits. These findings demonstrate that PTX animal models produced by using the fluorescent-identification method, and fed a 0.5% calcium diet, are appropriate for hypoparathyroidism treatment studies. PMID:27695051

  1. Animal models of traumatic brain injury

    PubMed Central

    Xiong, Ye; Mahmood, Asim; Chopp, Michael

    2014-01-01

    Traumatic brain injury (TBI) is a leading cause of mortality and morbidity in both civilian life and the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs, which were identified to be effective in animal TBI models, have all failed in phase II or phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies. PMID:23329160

  2. Evaluation of absorbed doses in voxel-based and simplified models for small animals.

    PubMed

    Mohammadi, Akram; Kinase, Sakae; Saito, Kimiaki

    2012-07-01

    Internal dosimetry in non-human biota is desirable from the viewpoint of radiation protection of the environment. The International Commission on Radiological Protection (ICRP) proposed Reference Animals and Plants using simplified models, such as ellipsoids and spheres and calculated absorbed fractions (AFs) for whole bodies. In this study, photon and electron AFs in whole bodies of voxel-based rat and frog models have been calculated and compared with AFs in the reference models. It was found that the voxel-based and the reference frog (or rat) models can be consistent for the whole-body AFs within a discrepancy of 25%, as the source was uniformly distributed in the whole body. The specific absorbed fractions (SAFs) and S values were also evaluated in whole bodies and all organs of the voxel-based frog and rat models as the source was distributed in the whole body or skeleton. The results demonstrated that the whole-body SAFs reflect SAFs of all individual organs as the source was uniformly distributed per mass within the whole body by about 30% uncertainties with exceptions for body contour (up to -40%) for both electrons and photons due to enhanced radiation leakages, and for the skeleton for photons only (up to +185%) due to differences in the mass attenuation coefficients. For nuclides such as (90)Y and (90)Sr, which were concentrated in the skeleton, there were large differences between S values in the whole body and those in individual organs, however the whole-body S values for the reference models with the whole body as the source were remarkably similar to those for the voxel-based models with the skeleton as the source, within about 4 and 0.3%, respectively. It can be stated that whole-body SAFs or S values in simplified models without internal organs are not sufficient for accurate internal dosimetry because they do not reflect SAFs or S values of all individual organs as the source was not distributed uniformly in whole body. Thus, voxel-based models

  3. 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?

  4. 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.

  5. An ecologist's guide to the animal model.

    PubMed

    Wilson, Alastair J; Réale, Denis; Clements, Michelle N; Morrissey, Michael M; Postma, Erik; Walling, Craig A; Kruuk, Loeske E B; Nussey, Daniel H

    2010-01-01

    1. Efforts to understand the links between evolutionary and ecological dynamics hinge on our ability to measure and understand how genes influence phenotypes, fitness and population dynamics. Quantitative genetics provides a range of theoretical and empirical tools with which to achieve this when the relatedness between individuals within a population is known. 2. A number of recent studies have used a type of mixed-effects model, known as the animal model, to estimate the genetic component of phenotypic variation using data collected in the field. Here, we provide a practical guide for ecologists interested in exploring the potential to apply this quantitative genetic method in their research. 3. We begin by outlining, in simple terms, key concepts in quantitative genetics and how an animal model estimates relevant quantitative genetic parameters, such as heritabilities or genetic correlations. 4. We then provide three detailed example tutorials, for implementation in a variety of software packages, for some basic applications of the animal model. We discuss several important statistical issues relating to best practice when fitting different kinds of mixed models. 5. We conclude by briefly summarizing more complex applications of the animal model, and by highlighting key pitfalls and dangers for the researcher wanting to begin using quantitative genetic tools to address ecological and evolutionary questions.

  6. Neutron beam measurement dosimetry

    SciTech Connect

    Amaro, C.R.

    1995-11-01

    This report describes animal dosimetry studies and phantom measurements. During 1994, 12 dogs were irradiated at BMRR as part of a 4 fraction dose tolerance study. The animals were first infused with BSH and irradiated daily for 4 consecutive days. BNL irradiated 2 beagles as part of their dose tolerance study using BPA fructose. In addition, a dog at WSU was irradiated at BMRR after an infusion of BPA fructose. During 1994, the INEL BNCT dosimetry team measured neutron flux and gamma dose profiles in two phantoms exposed to the epithermal neutron beam at the BMRR. These measurements were performed as a preparatory step to the commencement of human clinical trials in progress at the BMRR.

  7. Pathophysiology and animal modeling of underactive bladder.

    PubMed

    Tyagi, Pradeep; Smith, Phillip P; Kuchel, George A; de Groat, William C; Birder, Lori A; Chermansky, Christopher J; Adam, Rosalyn M; Tse, Vincent; Chancellor, Michael B; Yoshimura, Naoki

    2014-09-01

    While the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB.

  8. Animal models of mucositis: implications for therapy.

    PubMed

    Bowen, Joanne M; Gibson, Rachel J; Keefe, Dorothy M K

    2011-01-01

    Alimentary mucositis is a major acute complication in the clinical setting, occurring in a large percentage of patients undergoing cytotoxic therapy. One of the major problems with alimentary mucositis is that the underlying mechanisms behind its development are not entirely understood, which makes it extremely difficult to develop effective interventions. Animal models provide a critical source of knowledge when sampling from patients is unavailable or interventions are yet to be fully tested. This review focuses on the animal models used to increase our understanding of the mechanisms of mucositis and translate new antimucotoxic agents into clinical trials.

  9. Laboratory animal models for esophageal cancer

    PubMed Central

    Nair, Dhanya Venugopalan; Reddy, A. Gopala

    2016-01-01

    The incidence of esophageal cancer is rapidly increasing especially in developing countries. The major risk factors include unhealthy lifestyle practices such as alcohol consumption, smoking, and chewing tobacco to name a few. Diagnosis at an advanced stage and poor prognosis make esophageal cancer one of the most lethal diseases. These factors have urged further research in understanding the pathophysiology of the disease. Animal models not only aid in understanding the molecular pathogenesis of esophageal cancer but also help in developing therapeutic interventions for the disease. This review throws light on the various recent laboratory animal models for esophageal cancer. PMID:27956773

  10. Animal models of focal brain ischemia

    PubMed Central

    2009-01-01

    Stroke is a leading cause of disability and death in many countries. Understanding the pathophysiology of ischemic injury and developing therapies is an important endeavor that requires much additional research. Animal stroke models provide an important mechanism for these activities. A large number of stroke models have been developed and are currently used in laboratories around the world. These models are overviewed as are approaches for measuring infarct size and functional outcome. PMID:20150985

  11. Animal models of soft-tissue sarcoma

    PubMed Central

    Dodd, Rebecca D.; Mito, Jeffery K.; Kirsch, David G.

    2010-01-01

    Soft-tissue sarcomas (STSs) are rare mesenchymal tumors that arise from muscle, fat and connective tissue. Currently, over 75 subtypes of STS are recognized. The rarity and heterogeneity of patient samples complicate clinical investigations into sarcoma biology. Model organisms might provide traction to our understanding and treatment of the disease. Over the past 10 years, many successful animal models of STS have been developed, primarily genetically engineered mice and zebrafish. These models are useful for studying the relevant oncogenes, signaling pathways and other cell changes involved in generating STSs. Recently, these model systems have become preclinical platforms in which to evaluate new drugs and treatment regimens. Thus, animal models are useful surrogates for understanding STS disease susceptibility and pathogenesis as well as for testing potential therapeutic strategies. PMID:20713645

  12. [Laboratory animal infection in modeling intestinal schistosomiasis].

    PubMed

    Zelia, O P

    1984-01-01

    A comparative efficiency of different regimes for infecting laboratory animals has been determined in order to find out optimal conditions under which an experimental model of intestinal schistosomiasis (infection with Schistosoma mansoni) can be maintained. When evaluating the results of laboratory definitive hosts infection we took into account the character of Schistosoma distribution in animals, which with high probability rate was modelled by means of negative binomial distribution. The main parameters of this distribution were used for determination of effective doses and methods of animals infection alongside with generally accepted indices of infection rate and intensiveness. Analysis of the data obtained has shown that the infection of 150 cercarians per mouse and 200 cercarians per golden and striped hairy-footed hamster by their subcutaneous administration creates optimal density of parasites in the host. Results of investigations have shown that striped hairy-footed hamsters can be used as definitive hosts of Schistosoma.

  13. 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

  14. Respiratory Tract Lung Geometry and Dosimetry Model for Male Sprague-Dawley Rats

    SciTech Connect

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.; Price, Owen; Corley, Richard A.; Einstein, Daniel R.; Jacob, Rick E.; Cox, Timothy C.; Kabilan, Senthil; Bentley, Timothy

    2015-07-24

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract model for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague-Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.

  15. Respiratory tract lung geometry and dosimetry model for male Sprague-Dawley rats.

    SciTech Connect

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.; Price, Owen; Corley, Richard A.; Einstein, Daniel R.; Jacob, Rick E.; Cox, Timothy C.; Kabilan, Senthil; Bentley, Timothy

    2014-08-26

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract model for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague- Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.

  16. Comparative biology of cystic fibrosis animal models.

    PubMed

    Fisher, John T; Zhang, Yulong; Engelhardt, John F

    2011-01-01

    Animal models of human diseases are critical for dissecting mechanisms of pathophysiology and developing therapies. In the context of cystic fibrosis (CF), mouse models have been the dominant species by which to study CF disease processes in vivo for the past two decades. Although much has been learned through these CF mouse models, limitations in the ability of this species to recapitulate spontaneous lung disease and several other organ abnormalities seen in CF humans have created a need for additional species on which to study CF. To this end, pig and ferret CF models have been generated by somatic cell nuclear transfer and are currently being characterized. These new larger animal models have phenotypes that appear to closely resemble human CF disease seen in newborns, and efforts to characterize their adult phenotypes are ongoing. This chapter will review current knowledge about comparative lung cell biology and cystic fibrosis transmembrane conductance regulator (CFTR) biology among mice, pigs, and ferrets that has implications for CF disease modeling in these species. We will focus on methods used to compare the biology and function of CFTR between these species and their relevance to phenotypes seen in the animal models. These cross-species comparisons and the development of both the pig and the ferret CF models may help elucidate pathophysiologic mechanisms of CF lung disease and lead to new therapeutic approaches.

  17. 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.

  18. Transgenic Animal Models of Huntington's Disease.

    PubMed

    Yang, Shang-Hsun; Chan, Anthony W S

    2011-01-01

    Huntington's disease (HD) is a devastating neurodegenerative disorder that currently has no cure. In order to develop effective treatment, an understanding of HD pathogenesis and the evaluation of therapeutic efficacy of novel medications with the aid of animal models are critical steps. Transgenic animals sharing similar genetic defects that lead to HD have provided important discoveries in HD mechanisms that cell models are not able to replicate, which include psychiatric impairment, cognitive behavioral impact, and motor functions. Although transgenic HD rodent models have been widely used in HD research, it is clear that an animal model with comparable physiology to man, similar genetic defects that lead to HD, and the ability to develop similar cognitive and behavioral impairments is critical for explaining HD pathogenesis and the development of cures. Compared to HD rodents, HD transgenic nonhuman primates have not only developed comparable neuropathology but also present HD clinical features such as rigidity, seizure, dystonia, bradykinesia, and chorea that no other animal model has been able to replicate. Distinctive degenerating neurons and the accumulation of neuropil aggregates observed in HD monkey brain strongly support the hypothesis that the unique neuropathogenic events seen in HD monkey brain recapitulate HD in man. The latest development of transgenic HD primates has opened a new era of animal modeling that better represents human genetic disorders such as HD, which will accelerate the development of diagnostic tools and identifying novel biomarkers through longitudinal studies including gene expression and metabolite profiling, and noninvasive imaging. Furthermore, novel treatments with predictable efficacy in human patients can be developed using HD monkeys because of comparable neuropathology and clinical features.

  19. 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

  20. Henipavirus infections: lessons from animal models.

    PubMed

    Dhondt, Kévin P; Horvat, Branka

    2013-04-09

    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.

  1. Henipavirus Infections: Lessons from Animal Models

    PubMed Central

    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

  2. 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

  3. Development of a geometry-based respiratory motion–simulating patient model for radiation treatment dosimetry

    PubMed Central

    Zhang, Juying; Xu, X. George; Shi, Chengyu; Fuss, Martin

    2009-01-01

    Temporal and spatial anatomic changes caused by respiration during radiation treatment delivery can lead to discrepancies between prescribed and actual radiation doses. The present paper documents a study to construct a respiratory-motion-simulating, four-dimensional (4D) anatomic and dosimetry model for the study of the dosimetric effects of organ motion for various radiation treatment plans and delivery strategies. The non-uniform rational B-splines (NURBS) method has already been used to reconstruct a three-dimensional (3D) VIP-Man (“visible photographic man”) model that can reflect the deformation of organs during respiration by using time-dependent equations to manipulate surface control points. The EGS4 (Electron Gamma Shower, version 4) Monte Carlo code is then used to apply the 4D model to dose simulation. We simulated two radiation therapy delivery scenarios: gating treatment and 4D image-guided treatment. For each delivery scenario, we developed one conformal plan and one intensity-modulated radiation therapy plan. A lesion in the left lung was modeled to investigate the effect of respiratory motion on radiation dose distributions. Based on target dose–volume histograms, the importance of using accurate gating to improve the dose distribution is demonstrated. The results also suggest that, during 4D image-guided treatment delivery, monitoring of the patient’s breathing pattern is critical. This study demonstrates the potential of using a “standard” motion-simulating patient model for 4D treatment planning and motion management. PMID:18449164

  4. DOSIMETRY MODELING FOR PREDICTING RADIOLYTIC PRODUCTION AT THE SPENT FUEL-WATER INTERFACE

    SciTech Connect

    W.H. Miller

    2006-03-03

    The radiolysis of water in contact with spent nuclear fuel (SNF) will produce oxidants and reductants that can affect the dissolution of the fuel in a geologic disposal site. These products are created by initial radiolytic species which are a function of the type of radiation being emitted by the SNF, i.e. alpha, beta and/or gamma, as well as the energy of this radiation, the fuel grain size (and resulting surface-to-volume ratio) and the fuel-to-water ratio. These products interact with the surface of the fuel, creating new species and ultimately affecting the dissolution rate. The objective of the work reported here is to develop a systematic dosimetry model to determine the dose to water from the SNF as a function of these variables. This dose is calculated for different radiation types as a function of decay for the average fuel composition expected at Yucca Mountain. From these dose calculations the production rate of initial radiolytic products can be estimated. This data provides the basis for subsequent determination of the resulting chemical interactions at the fuel/water interface predicted by published theoretical and experimental data.

  5. 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.

  6. Animal models of trauma-induced coagulopathy.

    PubMed

    Frith, Daniel; Cohen, Mitchell J; Brohi, Karim

    2012-05-01

    Resurgent study of trauma-induced coagulopathy (TIC) has delivered considerable improvements in survival after injury. Robust, valid and clinically relevant experimental models of TIC are essential to support the evolution of our knowledge and management of this condition. The aims of this study were to identify and analyze contemporary animal models of TIC with regard to their ability to accurately characterize known mechanisms of coagulopathy and/or to test the efficacy of therapeutic agents. A literature review was performed. Structured search of the indexed online database MEDLINE/PubMed in July 2010 identified 43 relevant articles containing 23 distinct animal models of TIC. The main aim of 26 studies was to test a therapeutic and the other 17 were conducted to investigate pathophysiology. A preponderance of porcine models was identified. Three new models demonstrating an endogenous acute traumatic coagulopathy (ATC) have offered new insights into the pathophysiology of TIC. Independent or combined effects of induced hypothermia and metabolic acidosis have been extensively evaluated. Recently, a pig model of TIC has been developed that features all major etiologies of TIC, although not in correct chronological order. This review identifies a general lack of experimental research to keep pace with clinical developments. Tissue injury and hemorrhagic shock are fundamental initiating events that prime the hemostatic system for subsequent iatrogenic insults. New animal models utilizing a variety of species that accurately simulate the natural clinical trajectory of trauma are urgently needed.

  7. Small mammalian animal models of heart disease

    PubMed Central

    Camacho, Paula; Fan, Huimin; Liu, Zhongmin; He, Jia-Qiang

    2016-01-01

    There is an urgent clinical need to develop new therapeutic approaches for treating cardiovascular disease, but the biology of cardiovascular regeneration is complex. Model systems are required to advance our understanding of the pathogenesis, progression, and mechanisms underlying cardiovascular disease as well as to test therapeutic approaches to regenerate tissue and restore cardiac function following injury. An ideal model system should be inexpensive, easily manipulated, reproducible, physiologically representative of human disease, and ethically sound. The choice of animal model needs to be considered carefully since it affects experimental outcomes and whether findings of the study can be reasonably translated to humans. This review presents a guideline for the commonly used small animal models (mice, rats, rabbits, and cats) used in cardiac research as an effort to standardize the most relevant procedures and obtain translatable and reproducible results. PMID:27679742

  8. The modelling cycle for collective animal behaviour.

    PubMed

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

    2012-12-06

    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.

  9. (Biological dosimetry)

    SciTech Connect

    Sega, G.A.

    1990-11-06

    The traveler participated in an International Symposium on Trends in Biological Dosimetry and presented an invited paper entitled, Adducts in sperm protamine and DNA vs mutation frequency.'' The purpose of the Symposium was to examine the applicability of new methods to study quantitatively the effects of xenobiotic agents (radiation and chemicals) on molecular, cellular and organ systems, with special emphasis on human biological dosimetry. The general areas covered at the meeting included studies on parent compounds and metabolites; protein adducts; DNA adducts; gene mutations; cytogenetic end-points and reproductive methods.

  10. Cholestasis: human disease and experimental animal models.

    PubMed

    Rodríguez-Garay, Emilio Alberto

    2003-01-01

    Cholestasis may result from a failure in bile secretion in hepatocytes or ductular cells, or from a blockade to the free bile flow. Human cholestasis may be induced by many drugs, being antibiotics the more common. Other types of cholestasis seen in humans are a group of familial cholestatic disorders, obstructive cholestasis, primary biliary cirrhosis, extrahepatic biliary atresia, primary sclerosing cholangitis, cholestasis of pregnancy, oral contraceptive-induced cholestasis, and sepsis-induced cholestasis. Experimental animal models allow the understanding of pathophysiological mechanisms involved and their clinical correlates. The most common experimental models of intrahepatic cholestasis are estrogen-induced, endotoxin-induced and drug-induced cholestasis. A well known model of extrahepatic biliary obstruction is common bile duct ligation. Drug-induced cholestasis were described using different drugs. On this regard, alpha naphthylisothiocyanate treatment has been extensively used, permitting to describe not only cholestatic alterations but also compensatory mechanisms. Congenital defficiency of transport proteins also were studied in natural rat models of cholestasis. The experimental animal models allow to define down-regulated alterations of hepatocyte transport proteins, and up-regulated ones acting as compensatory mechanisms. In conclusion, animal model and transport protein studies are necessary for the progressive understanding of congenital and acquired human cholestasis, and regulatory mechanisms that operate on liver cells.

  11. 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

  12. Animal models of psoriasis and pustular psoriasis.

    PubMed

    Mizutani, Hitoshi; Yamanaka, Keiichi; Konishi, Hiroshi; Murakami, Takaaki

    2003-04-01

    Investigation of psoriasis and pustular psoriasis is presently hampered by the lack of appropriate animal models. So far, more than ten models have been developed in mice by spontaneous gene mutations and by gene manipulation. However, none of them has satisfactorily reproduced the clinicopathological and immunopathological phenotypes of these diseases. Xenotransplantation techniques have been used for designing models of psoriasis vulgaris, in which CD4(+) T cells have been shown to play an important role. An ideal model for pustular psoriasis should have an immunological background and fulfill the diagnostic criteria of psoriasis.

  13. Nonmurine animal models of food allergy.

    PubMed

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

    2003-02-01

    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.

  14. Potential animal models of seasonal affective disorder.

    PubMed

    Workman, Joanna L; Nelson, Randy J

    2011-01-01

    Seasonal affective disorder (SAD) is characterized by depressive episodes during winter that are alleviated during summer and by morning bright light treatment. Currently, there is no animal model of SAD. However, it may be possible to use rodents that respond to day length (photoperiod) to understand how photoperiod can shape the brain and behavior in humans. As nights lengthen in the autumn, the duration of the nightly elevation of melatonin increase; seasonally breeding animals use this information to orchestrate seasonal changes in physiology and behavior. SAD may originate from the extended duration of nightly melatonin secretion during fall and winter. These similarities between humans and rodents in melatonin secretion allows for comparisons with rodents that express more depressive-like responses when exposed to short day lengths. For instance, Siberian hamsters, fat sand rats, Nile grass rats, and Wistar rats display a depressive-like phenotype when exposed to short days. Current research in depression and animal models of depression suggests that hippocampal plasticity may underlie the symptoms of depression and depressive-like behaviors, respectively. It is also possible that day length induces structural changes in human brains. Many seasonally breeding rodents undergo changes in whole brain and hippocampal volume in short days. Based on strict validity criteria, there is no animal model of SAD, but rodents that respond to reduced day lengths may be useful to approximate the neurobiological phenomena that occur in people with SAD, leading to greater understanding of the etiology of the disorder as well as novel therapeutic interventions.

  15. Large genetic animal models of Huntington's Disease.

    PubMed

    Morton, A Jennifer; Howland, David S

    2013-01-01

    The dominant nature of the Huntington's disease gene mutation has allowed genetic models to be developed in multiple species, with the mutation causing an abnormal neurological phenotype in all animals in which it is expressed. Many different rodent models have been generated. The most widely used of these, the transgenic R6/2 mouse, carries the mutation in a fragment of the human huntingtin gene and has a rapidly progressive and fatal neurological phenotype with many relevant pathological changes. Nevertheless, their rapid decline has been frequently questioned in the context of a disease that takes years to manifest in humans, and strenuous efforts have been made to make rodent models that are genetically more 'relevant' to the human condition, including full length huntingtin gene transgenic and knock-in mice. While there is no doubt that we have learned, and continue to learn much from rodent models, their usefulness is limited by two species constraints. First, the brains of rodents differ significantly from humans in both their small size and their neuroanatomical organization. Second, rodents have much shorter lifespans than humans. Here, we review new approaches taken to these challenges in the development of models of Huntington's disease in large brained, long-lived animals. We discuss the need for such models, and how they might be used to fill specific niches in preclinical Huntington's disease research, particularly in testing gene-based therapeutics. We discuss the advantages and disadvantages of animals in which the prodromal period of disease extends over a long time span. We suggest that there is considerable 'value added' for large animal models in preclinical Huntington's disease research.

  16. 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

  17. Animal models of enteroaggregative Escherichia coli infection

    PubMed Central

    Philipson, Casandra W.; Bassaganya-Riera, Josep; Hontecillas, Raquel

    2013-01-01

    Enteroaggregative Escherichia coli (EAEC) has been acknowledged as an emerging cause of gastroenteritis worldwide for over two decades. Epidemiologists are revealing the role of EAEC in diarrheal outbreaks as a more common occurrence than ever suggested before. EAEC induced diarrhea is most commonly associated with travelers, children and immunocompromised individuals however its afflictions are not limited to any particular demographic. Many attributes have been discovered and characterized surrounding the capability of EAEC to provoke a potent pro-inflammatory immune response, however cellular and molecular mechanisms underlying initiation, progression and outcomes are largely unknown. This limited understanding can be attributed to heterogeneity in strains and the lack of adequate animal models. This review aims to summarize current knowledge about EAEC etiology, pathogenesis and clinical manifestation. Additionally, current animal models and their limitations will be discussed along with the value of applying systems-wide approaches such as computational modeling to study host-EAEC interactions. PMID:23680797

  18. 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

  19. Animal models of coronary heart disease.

    PubMed

    Liao, Jiawei; Huang, Wei; Liu, George

    2015-08-20

    Cardiovascular disease, predominantly coronary heart disease and stroke, leads to high morbidity and mortality not only in developed worlds but also in underdeveloped regions. The dominant pathologic foundation for cardiovascular disease is atherosclerosis and as to coronary heart disease, coronary atherosclerosis and resulting lumen stenosis, even total occlusions. In translational research, several animals, such as mice, rabbits and pigs, have been used as disease models of human atherosclerosis and related cardiovascular disorders. However, coronary lesions are either naturally rare or hard to be fast induced in these models, hence, coronary heart disease induction mostly relies on surgical or pharmaceutical interventions with no or limited primary coronary lesions, thus unrepresentative of human coronary heart disease progression and pathology. In this review, we will describe the progress of animal models of coronary heart disease following either spontaneous or diet-accelerated coronary lesions.

  20. Animal models of insulin resistance: A review.

    PubMed

    Sah, Sangeeta Pilkhwal; Singh, Barinder; Choudhary, Supriti; Kumar, Anil

    2016-12-01

    Insulin resistance can be seen as a molecular and genetic mystery, with a role in the pathophysiology of type 2 diabetes mellitus. It is a basis for a number of chronic diseases like hypertension, dyslipidemia, glucose intolerance, coronary heart disease, cerebral vascular disease along with T2DM, thus the key is to cure and prevent insulin resistance. Critical perspicacity into the etiology of insulin resistance have been gained by the use of animal models where insulin action has been modulated by various transgenic and non-transgenic models which is not possible in human studies. The following review comprises the pathophysiology involved in insulin resistance, various factors causing insulin resistance, their screening and various genetic and non-genetic animal models highlighting the pathological and metabolic characteristics of each.

  1. Animal models of acute renal failure.

    PubMed

    Singh, Amrit Pal; Junemann, Anselm; Muthuraman, Arunachalam; Jaggi, Amteshwar Singh; Singh, Nirmal; Grover, Kuldeep; Dhawan, Ravi

    2012-01-01

    The animal models are pivotal for understanding the characteristics of acute renal failure (ARF) and development of effective therapy for its optimal management. Since the etiology for induction of renal failure is multifold, therefore, a large number of animal models have been developed to mimic the clinical conditions of renal failure. Glycerol-induced renal failure closely mimics the rhabdomyolysis; ischemia-reperfusion-induced ARF simulate the hemodynamic changes-induced changes in renal functioning; drug-induced such as gentamicin, cisplatin, NSAID, ifosfamide-induced ARF mimics the renal failure due to clinical administration of respective drugs; uranium, potassium dichromate-induced ARF mimics the occupational hazard; S-(1,2-dichlorovinyl)-L-cysteine-induced ARF simulate contaminated water-induced renal dysfunction; sepsis-induced ARF mimics the infection-induced renal failure and radiocontrast-induced ARF mimics renal failure in patients during use of radiocontrast media at the time of cardiac catheterization. Since each animal model has been created with specific methodology, therefore, it is essential to describe the model in detail and consequently interpret the results in the context of a specific model.

  2. An image-based skeletal dosimetry model for the ICRP reference newborn--internal electron sources.

    PubMed

    Pafundi, Deanna; Rajon, Didier; Jokisch, Derek; Lee, Choonsik; Bolch, Wesley

    2010-04-07

    In this study, a comprehensive electron dosimetry model of newborn skeletal tissues is presented. The model is constructed using the University of Florida newborn hybrid phantom of Lee et al (2007 Phys. Med. Biol. 52 3309-33), the newborn skeletal tissue model of Pafundi et al (2009 Phys. Med. Biol. 54 4497-531) and the EGSnrc-based Paired Image Radiation Transport code of Shah et al (2005 J. Nucl. Med. 46 344-53). Target tissues include the active bone marrow (surrogate tissue for hematopoietic stem cells), shallow marrow (surrogate tissue for osteoprogenitor cells) and unossified cartilage (surrogate tissue for chondrocytes). Monoenergetic electron emissions are considered over the energy range 1 keV to 10 MeV for the following source tissues: active marrow, trabecular bone (surfaces and volumes), cortical bone (surfaces and volumes) and cartilage. Transport results are reported as specific absorbed fractions according to the MIRD schema and are given as skeletal-averaged values in the paper with bone-specific values reported in both tabular and graphic format as electronic annexes (supplementary data). The method utilized in this work uniquely includes (1) explicit accounting for the finite size and shape of newborn ossification centers (spongiosa regions), (2) explicit accounting for active and shallow marrow dose from electron emissions in cortical bone as well as sites of unossified cartilage, (3) proper accounting of the distribution of trabecular and cortical volumes and surfaces in the newborn skeleton when considering mineral bone sources and (4) explicit consideration of the marrow cellularity changes for active marrow self-irradiation as applicable to radionuclide therapy of diseased marrow in the newborn child.

  3. 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

  4. Animal models of viral hemorrhagic fever.

    PubMed

    Smith, Darci R; Holbrook, Michael R; Gowen, Brian B

    2014-12-01

    The term "viral hemorrhagic fever" (VHF) designates a syndrome of acute febrile illness, increased vascular permeability and coagulation defects which often progresses to bleeding and shock and may be fatal in a significant percentage of cases. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae, which are maintained in a variety of animal species and are transferred to humans through direct or indirect contact or by an arthropod vector. Except for dengue, which is transmitted among humans by mosquitoes, the geographic distribution of each type of VHF is determined by the range of its animal reservoir. Treatments are available for Argentine HF and Lassa fever, but no approved countermeasures have been developed against other types of VHF. The development of effective interventions is hindered by the sporadic nature of most infections and their occurrence in geographic regions with limited medical resources. Laboratory animal models that faithfully reproduce human disease are therefore essential for the evaluation of potential vaccines and therapeutics. The goal of this review is to highlight the current status of animal models that can be used to study the pathogenesis of VHF and test new countermeasures.

  5. 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

  6. (Biological dosimetry)

    SciTech Connect

    Preston, R.J.

    1990-12-17

    The traveler attended the 1st International Conference on Biological Dosimetry in Madrid, Spain. This conference was organized to provide information to a general audience of biologists, physicists, radiotherapists, industrial hygiene personnel and individuals from related fields on the current ability of cytogenetic analysis to provide estimates of radiation dose in cases of occupational or environmental exposure. There is a growing interest in Spain in biological dosimetry because of the increased use of radiation sources for medical and occupational uses, and with this the anticipated and actual increase in numbers of overexposure. The traveler delivered the introductory lecture on Biological Dosimetry: Mechanistic Concepts'' that was intended to provide a framework by which the more applied lectures could be interpreted in a mechanistic way. A second component of the trip was to provide advice with regard to several recent cases of overexposure that had been or were being assessed by the Radiopathology and Radiotherapy Department of the Hospital General Gregorio Maranon'' in Madrid. The traveler had provided information on several of these, and had analyzed cells from some exposed or purportedly exposed individuals. The members of the biological dosimetry group were referred to individuals at REACTS at Oak Ridge Associated Universities for advice on follow-up treatment.

  7. ROPES eye plaque brachytherapy dosimetry for two models of (103)Pd seeds.

    PubMed

    Saidi, Pooneh; Sadeghi, Mahdi; Shirazi, Alireza; Tenreiro, Claudio

    2011-06-01

    Brachytherapy dose distributions are calculated for 15 mm ROPES eye plaque loaded with model Theragenics200 and IR06-(103)Pd seeds. The effects of stainless steel backing and Acrylic insert on dose distribution along the central axis of the eye plaque and at critical ocular structure are investigated. Monte Carlo simulation was carried out with the Version 5 of the MCNP. The dose at critical ocular structure by considering the eye composition was calculated. Results are compared with the calculated data for COMS eye plaque loaded with Theragenics200 palladium-103 seeds and model 6711 iodine-125 seed. The air kerma strength of the IR06-(103)Pd seed to deliver 85 Gy in apex of tumor in water medium was calculated to be 4.10 U/seed. Along the central axis of stainless steel plaque loaded with new (103)Pd seeds in Acrylic insert, the dose reduction relative to water is 6.9% at 5 mm (apex). Removal of the Acrylic insert from the plaque (replacing with water) did not make significantly difference in dose reduction results (~0.2%). The presence of the stainless steel backing results in dose enhancement near the plaque relative to water. Doses at points of interest are higher for ROPES eye plaque when compared to COMS eye plaque. The dosimetric parameters calculated in this work for the new palladium seed, showed that in dosimetry point of view, the IR06-(103)Pd seed is suitable for use in brachytherapy. The effect of Acrylic insert on dose distribution is negligible and the main effect on dose reduction is due to the presence of stainless steel plaque backing.

  8. 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

  9. Models of GH deficiency in animal studies.

    PubMed

    Gahete, Manuel D; Luque, Raul M; Castaño, Justo P

    2016-12-01

    Growth hormone (GH) is a peptide hormone released from pituitary somatotrope cells that promotes growth, cell division and regeneration by acting directly through the GH receptor (GHR), or indirectly via hepatic insulin-like growth factor 1 (IGF1) production. GH deficiency (GHD) can cause severe consequences, such as growth failure, changes in body composition and altered insulin sensitivity, depending of the origin, time of onset (childhood or adulthood) or duration of GHD. The highly variable clinical phenotypes of GHD can now be better understood through research on transgenic and naturally-occurring animal models, which are widely employed to investigate the origin, phenotype, and consequences of GHD, and particularly the underlying mechanisms of metabolic disorders associated to GHD. Here, we reviewed the most salient aspects of GH biology, from somatotrope development to GH actions, linked to certain GHD types, as well as the animal models employed to reproduce these GHD-associated alterations.

  10. Animal models of age related macular degeneration.

    PubMed

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

    2012-08-01

    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.

  11. 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

  12. Animal models of ANCA associated vasculitis

    PubMed Central

    Salama, Alan D.; Little, Mark A

    2012-01-01

    This review seeks to provide an update on the experimental models that have been developed recapitulating clinical ANCA associated vasculitis. The recent insights regarding the application of the models in the study of pathogenesis, and the therapeutic implications of this, are covered in the article by van Timmeren and Heeringa in this issue. Recent findings Rodent models of both MPO- and PR3 ANCA associated vasculitis have been developed, which have provided important insights into the pathogenesis of ANCA associated pulmonary and renal disease. The vast majority of in vivo work in this field has concerned MPO-ANCA associated disease, although the last year has seen some advances in modelling of anti-PR3 disease. As with all experimental animal models they are flawed in one way or another, by virtue of the means by which they are induced, but they have already provided novel directions for future intervention in these complex diseases. To date there are no good models that replicate the granulomatous lesions found in granulomatosis with polyangiitis (GPA, formerly Wegener’s), or the development of vasculitis lesions in organs other than the lungs or kidneys. However, use of a combination of the available models should allow greater understanding of the critical requirements for disease and how these may be potentially monitored and modified in patients. Summary ANCA associated vasculitis can be induced in various forms in susceptible rodents. Further refinements are required for the full spectrum of disease phenotype to be replicated in animals, but critical new targets have been proposed based on use of molecular blocking agents and transgenic animals to elucidate disease pathways. PMID:22089094

  13. 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

  14. Animal models of compulsive eating behavior.

    PubMed

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

    2014-10-22

    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.

  15. Neutron personnel dosimetry

    SciTech Connect

    Griffith, R.V.

    1981-06-16

    The current state-of-the-art in neutron personnel dosimetry is reviewed. Topics covered include dosimetry needs and alternatives, current dosimetry approaches, personnel monitoring devices, calibration strategies, and future developments. (ACR)

  16. Online dosimetry for temoporfin-mediated interstitial photodynamic therapy using the canine prostate as model.

    PubMed

    Swartling, Johannes; Höglund, Odd V; Hansson, Kerstin; Södersten, Fredrik; Axelsson, Johan; Lagerstedt, Anne-Sofie

    2016-02-01

    Online light dosimetry with real-time feedback was applied for temoporfin-mediated interstitial photodynamic therapy (PDT) of dog prostate. The aim was to investigate the performance of online dosimetry by studying the correlation between light dose plans and the tissue response, i.e., extent of induced tissue necrosis and damage to surrounding organs at risk. Light-dose planning software provided dose plans, including light source positions and light doses, based on ultrasound images. A laser instrument provided therapeutic light and dosimetric measurements. The procedure was designed to closely emulate the procedure for whole-prostate PDT in humans with prostate cancer. Nine healthy dogs were subjected to the procedure according to a light-dose escalation plan. About 0.15 mg/kg temoporfin was administered 72 h before the procedure. The results of the procedure were assessed by magnetic resonance imaging, and gross pathology and histopathology of excised tissue. Light dose planning and online dosimetry clearly resulted in more focused effect and less damage to surrounding tissue than interstitial PDT without dosimetry. A light energy dose-response relationship was established where the threshold dose to induce prostate gland necrosis was estimated from 20 to 30  J/cm2.

  17. Online dosimetry for temoporfin-mediated interstitial photodynamic therapy using the canine prostate as model

    NASA Astrophysics Data System (ADS)

    Swartling, Johannes; Höglund, Odd V.; Hansson, Kerstin; Södersten, Fredrik; Axelsson, Johan; Lagerstedt, Anne-Sofie

    2016-02-01

    Online light dosimetry with real-time feedback was applied for temoporfin-mediated interstitial photodynamic therapy (PDT) of dog prostate. The aim was to investigate the performance of online dosimetry by studying the correlation between light dose plans and the tissue response, i.e., extent of induced tissue necrosis and damage to surrounding organs at risk. Light-dose planning software provided dose plans, including light source positions and light doses, based on ultrasound images. A laser instrument provided therapeutic light and dosimetric measurements. The procedure was designed to closely emulate the procedure for whole-prostate PDT in humans with prostate cancer. Nine healthy dogs were subjected to the procedure according to a light-dose escalation plan. About 0.15 mg/kg temoporfin was administered 72 h before the procedure. The results of the procedure were assessed by magnetic resonance imaging, and gross pathology and histopathology of excised tissue. Light dose planning and online dosimetry clearly resulted in more focused effect and less damage to surrounding tissue than interstitial PDT without dosimetry. A light energy dose-response relationship was established where the threshold dose to induce prostate gland necrosis was estimated from 20 to 30 J/cm2.

  18. Correction of confidence intervals in excess relative risk models using Monte Carlo dosimetry systems with shared errors

    PubMed Central

    Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce A.; Degteva, Marina; Moroz, Brian; Vostrotin, Vadim; Shiskina, Elena; Birchall, Alan; Stram, Daniel O.

    2017-01-01

    In epidemiological studies, exposures of interest are often measured with uncertainties, which may be independent or correlated. Independent errors can often be characterized relatively easily while correlated measurement errors have shared and hierarchical components that complicate the description of their structure. For some important studies, Monte Carlo dosimetry systems that provide multiple realizations of exposure estimates have been used to represent such complex error structures. While the effects of independent measurement errors on parameter estimation and methods to correct these effects have been studied comprehensively in the epidemiological literature, the literature on the effects of correlated errors, and associated correction methods is much more sparse. In this paper, we implement a novel method that calculates corrected confidence intervals based on the approximate asymptotic distribution of parameter estimates in linear excess relative risk (ERR) models. These models are widely used in survival analysis, particularly in radiation epidemiology. Specifically, for the dose effect estimate of interest (increase in relative risk per unit dose), a mixture distribution consisting of a normal and a lognormal component is applied. This choice of asymptotic approximation guarantees that corrected confidence intervals will always be bounded, a result which does not hold under a normal approximation. A simulation study was conducted to evaluate the proposed method in survival analysis using a realistic ERR model. We used both simulated Monte Carlo dosimetry systems (MCDS) and actual dose histories from the Mayak Worker Dosimetry System 2013, a MCDS for plutonium exposures in the Mayak Worker Cohort. Results show our proposed methods provide much improved coverage probabilities for the dose effect parameter, and noticeable improvements for other model parameters. PMID:28369141

  19. Animal Models Utilized in HTLV-1 Research.

    PubMed

    Panfil, Amanda R; Al-Saleem, Jacob J; Green, Patrick L

    2013-01-01

    Since the isolation and discovery of human T-cell leukemia virus type 1 (HTLV-1) over 30 years ago, researchers have utilized animal models to study HTLV-1 transmission, viral persistence, virus-elicited immune responses, and HTLV-1-associated disease development (ATL, HAM/TSP). Non-human primates, rabbits, rats, and mice have all been used to help understand HTLV-1 biology and disease progression. Non-human primates offer a model system that is phylogenetically similar to humans for examining viral persistence. Viral transmission, persistence, and immune responses have been widely studied using New Zealand White rabbits. The advent of molecular clones of HTLV-1 has offered the opportunity to assess the importance of various viral genes in rabbits, non-human primates, and mice. Additionally, over-expression of viral genes using transgenic mice has helped uncover the importance of Tax and Hbz in the induction of lymphoma and other lymphocyte-mediated diseases. HTLV-1 inoculation of certain strains of rats results in histopathological features and clinical symptoms similar to that of humans with HAM/TSP. Transplantation of certain types of ATL cell lines in immunocompromised mice results in lymphoma. Recently, "humanized" mice have been used to model ATL development for the first time. Not all HTLV-1 animal models develop disease and those that do vary in consistency depending on the type of monkey, strain of rat, or even type of ATL cell line used. However, the progress made using animal models cannot be understated as it has led to insights into the mechanisms regulating viral replication, viral persistence, disease development, and, most importantly, model systems to test disease treatments.

  20. 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

  1. 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.

  2. COMPUTATIONAL LYMPHATIC NODE MODELS IN PEDIATRIC AND ADULT HYBRID PHANTOMS FOR RADIATION DOSIMETRY

    PubMed Central

    Lee, Choonsik; Lamart, Stephanie; Moroz, Brian E.

    2013-01-01

    We developed models of lymphatic nodes for 6 pediatric and 2 adult hybrid computational phantoms to calculate the lymphatic node dose estimates from external and internal radiation exposures. We derived the number of lymphatic nodes from the recommendations in International Commission on Radiological Protection (ICRP) Publications 23 and 89 at 16 cluster locations for the lymphatic nodes: extrathoracic, cervical, thoracic (upper and lower), breast (left and right), mesentery (left and right), axillary (left and right), cubital (left and right), inguinal (left and right), and popliteal (left and right), for different ages (newborn, 1-, 5-, 10-, 15-year-old, and adult). We modeled each lymphatic node within the voxel format of the hybrid phantoms by assuming that all nodes have identical size derived from published data except narrow cluster sites. The lymph nodes were generated by the following algorithm: (1) selection of the lymph node site among the 16 cluster sites; (2) random sampling of the location of the lymph node within a spherical space centered at the chosen cluster site; (3) creation of the sphere or ovoid of tissue representing the node based on lymphatic node characteristics defined in ICRP Publications 23 and 89. We created lymph nodes until the pre-defined number of lymphatic nodes at the selected cluster site was reached. This algorithm was applied to pediatric (newborn, 1-, 5-, and 10-year-old male, and 15-year-old males) and adult male and female ICRP-compliant hybrid phantoms after voxelization. To assess the performance of our models for internal dosimetry, we calculated dose conversion coefficients, called S values, for selected organs and tissues with Iodine-131 distributed in 6 lymphatic node cluster sites using MCNPX2.6, a well validated Monte Carlo radiation transport code. Our analysis of the calculations indicates that the S values were significantly affected by the location of the lymph node clusters and that the values increased for

  3. Computational lymphatic node models in pediatric and adult hybrid phantoms for radiation dosimetry

    NASA Astrophysics Data System (ADS)

    Lee, Choonsik; Lamart, Stephanie; Moroz, Brian E.

    2013-03-01

    We developed models of lymphatic nodes for six pediatric and two adult hybrid computational phantoms to calculate the lymphatic node dose estimates from external and internal radiation exposures. We derived the number of lymphatic nodes from the recommendations in International Commission on Radiological Protection (ICRP) Publications 23 and 89 at 16 cluster locations for the lymphatic nodes: extrathoracic, cervical, thoracic (upper and lower), breast (left and right), mesentery (left and right), axillary (left and right), cubital (left and right), inguinal (left and right) and popliteal (left and right), for different ages (newborn, 1-, 5-, 10-, 15-year-old and adult). We modeled each lymphatic node within the voxel format of the hybrid phantoms by assuming that all nodes have identical size derived from published data except narrow cluster sites. The lymph nodes were generated by the following algorithm: (1) selection of the lymph node site among the 16 cluster sites; (2) random sampling of the location of the lymph node within a spherical space centered at the chosen cluster site; (3) creation of the sphere or ovoid of tissue representing the node based on lymphatic node characteristics defined in ICRP Publications 23 and 89. We created lymph nodes until the pre-defined number of lymphatic nodes at the selected cluster site was reached. This algorithm was applied to pediatric (newborn, 1-, 5-and 10-year-old male, and 15-year-old males) and adult male and female ICRP-compliant hybrid phantoms after voxelization. To assess the performance of our models for internal dosimetry, we calculated dose conversion coefficients, called S values, for selected organs and tissues with Iodine-131 distributed in six lymphatic node cluster sites using MCNPX2.6, a well validated Monte Carlo radiation transport code. Our analysis of the calculations indicates that the S values were significantly affected by the location of the lymph node clusters and that the values increased for

  4. Animal modelling for inherited central vision loss.

    PubMed

    Kostic, Corinne; Arsenijevic, Yvan

    2016-01-01

    Disease-causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale-up of new therapies. Examples of innovative approaches will be presented such as lentiviral-based transgenesis in pigs and adeno-associated virus (AAV)-gene transfer into the monkey eye to investigate the neural circuitry plasticity of the visual system. The models reported herein permit the exploration of common mechanisms that exist between different species and the identification and highlighting of pathways that may be specific to primates, including humans.

  5. 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

  6. Fifth international radiopharmaceutical dosimetry symposium

    SciTech Connect

    Watson, E.E.; Schlafke-Stelson, A.T.

    1992-05-01

    This meeting was held to exchange information on how to get better estimates of the radiation absorbed dose. There seems to be a high interest of late in patient dosimetry; discussions were held in the light of revised risk estimates for radiation. Topics included: Strategies of Dose Assessment; Dose Estimation for Radioimmunotherapy; Dose Calculation Techniques and Models; Dose Estimation for Positron Emission Tomography (PET); Kinetics for Dose Estimation; and Small Scale Dosimetry and Microdosimetry. (VC)

  7. Hanford internal dosimetry program manual

    SciTech Connect

    Carbaugh, E.H.; Sula, M.J.; Bihl, D.E.; Aldridge, T.L.

    1989-10-01

    This document describes the Hanford Internal Dosimetry program. Program Services include administrating the bioassay monitoring program, evaluating and documenting assessments of internal exposure and dose, ensuring that analytical laboratories conform to requirements, selecting and applying appropriate models and procedures for evaluating internal radionuclide deposition and the resulting dose, and technically guiding and supporting Hanford contractors in matters regarding internal dosimetry. 13 refs., 16 figs., 42 tabs.

  8. Methods to estimate solar radiation dosimetry in coral reefs using remote sensed, modeled, and in situ data.

    PubMed

    Barron, Mace G; Vivian, Deborah N; Yee, Susan H; Santavy, Deborah L

    2009-04-01

    Solar irradiance has been increasingly recognized as an important determinant of bleaching in coral reefs, but measurements of solar radiation exposure within coral reefs have been relatively limited. Solar radiation dosimetry within multiple coral reef areas of South Florida was assessed using remote sensed, modeled, and measured values during a minor bleaching event during August 2005. Coral reefs in the Dry Tortugas and Upper Keys had similar diffuse downwelling attenuation coefficients (Kd, m(-1)), whereas Kd values were significantly greater in the Middle and Lower Keys. Mean 1% attenuation depths varied by reef region for ultraviolet B (UVB; 9.7 to 20 m), ultraviolet A (UVA; 22 to 40 m) and visible (27 to 43 m) solar radiation. Solar irradiances determined from remote sensed data were significantly correlated with measured values, but were generally overestimated at the depth of corals. Solar irradiances modeled using an atmospheric radiative transfer model parameterized with site specific approximations of cloud cover showed close agreement with measured values. Estimated daily doses (W h/m(2)) of UVB (0.01-19), UVA (2-360) and visible (29-1,653) solar radiation varied with coral depth (2 to 24 m) and meteorological conditions. These results indicate large variation in solar radiation dosimetry within coral reefs that may be estimated with reasonable accuracy using regional Kd measurements and radiative transfer modeling.

  9. Radiation dosimetry.

    PubMed Central

    Cameron, J

    1991-01-01

    This article summarizes the basic facts about the measurement of ionizing radiation, usually referred to as radiation dosimetry. The article defines the common radiation quantities and units; gives typical levels of natural radiation and medical exposures; and describes the most important biological effects of radiation and the methods used to measure radiation. Finally, a proposal is made for a new radiation risk unit to make radiation risks more understandable to nonspecialists. PMID:2040250

  10. Experimental Oral Candidiasis in Animal Models

    PubMed Central

    Samaranayake, Yuthika H.; Samaranayake, Lakshman P.

    2001-01-01

    Oral candidiasis is as much the final outcome of the vulnerability of the host as of the virulence of the invading organism. We review here the extensive literature on animal experiments mainly appertaining to the host predisposing factors that initiate and perpetuate these infections. The monkey, rat, and mouse are the choice models for investigating oral candidiasis, but comparisons between the same or different models appear difficult, because of variables such as the study design, the number of animals used, their diet, the differences in Candida strains, and the duration of the studies. These variables notwithstanding, the following could be concluded. (i) The primate model is ideal for investigating Candida-associated denture stomatitis since both erythematous and pseudomembranous lesions have been produced in monkeys with prosthetic plates; they are, however, expensive and difficult to obtain and maintain. (ii) The rat model (both Sprague-Dawley and Wistar) is well proven for observing chronic oral candidal colonization and infection, due to the ease of breeding and handling and their ready availability. (iii) Mice are similar, but in addition there are well characterized variants simulating immunologic and genetic abnormalities (e.g., athymic, euthymic, murine-acquired immune deficiency syndrome, and severe combined immunodeficient models) and hence are used for short-term studies relating the host immune response and oral candidiasis. Nonetheless, an ideal, relatively inexpensive model representative of the human oral environment in ecological and microbiological terms is yet to be described. Until such a model is developed, researchers should pay attention to standardization of the experimental protocols described here to obtain broadly comparable and meaningful data. PMID:11292645

  11. Animal models of respiratory syncytial virus infection.

    PubMed

    Taylor, Geraldine

    2017-01-11

    Human respiratory syncytial virus (hRSV) is a major cause of respiratory disease and hospitalisation of infants, worldwide, and is also responsible for significant morbidity in adults and excess deaths in the elderly. There is no licensed hRSV vaccine or effective therapeutic agent. However, there are a growing number of hRSV vaccine candidates that have been developed targeting different populations at risk of hRSV infection. Animal models of hRSV play an important role in the preclinical testing of hRSV vaccine candidates and although many have shown efficacy in preclinical studies, few have progressed to clinical trials or they have had only limited success. This is, at least in part, due to the lack of animal models that fully recapitulate the pathogenesis of hRSV infection in humans. This review summarises the strengths and limitations of animal models of hRSV, which include those in which hRSV is used to infect non-human mammalian hosts, and those in which non-human pneumoviruses, such as bovine (b)RSV and pneumonia virus of mice (PVM) are studied in their natural host. Apart from chimpanzees, other non-human primates (NHP) are only semi-permissive for hRSV replication and experimental infection with large doses of virus result in little or no clinical signs of disease, and generally only mild pulmonary pathology. Other animal models such as cotton rats, mice, ferrets, guinea pigs, hamsters, chinchillas, and neonatal lambs are also only semi-permissive for hRSV. Nevertheless, mice and cotton rats have been of value in the development of monoclonal antibody prophylaxis for infants at high risk of severe hRSV infection and have provided insights into mechanisms of immunity to and pathogenesis of hRSV. However, the extent to which they predict hRSV vaccine efficacy and safety is unclear and several hRSV vaccine candidates that are completely protective in rodent models are poorly effective in chimpanzees and other NHP, such as African Green monkeys. Furthermore

  12. 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

  13. Domestic animals as models for biomedical research.

    PubMed

    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.

  14. Animal models of glucocorticoid-induced glaucoma.

    PubMed

    Overby, Darryl R; Clark, Abbot F

    2015-12-01

    Glucocorticoid (GC) therapy is widely used to treat a variety of inflammatory diseases and conditions. While unmatched in their anti-inflammatory and immunosuppressive activities, GC therapy is often associated with the significant ocular side effect of GC-induced ocular hypertension (OHT) and iatrogenic open-angle glaucoma. Investigators have generated GC-induced OHT and glaucoma in at least 8 different species besides man. These models mimic many features of this condition in man and provide morphologic and molecular insights into the pathogenesis of GC-OHT. In addition, there are many clinical, morphological, and molecular similarities between GC-induced glaucoma and primary open-angle glaucoma (POAG), making animals models of GC-induced OHT and glaucoma attractive models in which to study specific aspects of POAG.

  15. 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.

  16. Animal Models of Glucocorticoid-Induced Glaucoma

    PubMed Central

    Overby, Darryl R.; Clark, Abbot F.

    2015-01-01

    Glucocorticoid (GC) therapy is widely used to treat a variety of inflammatory diseases and conditions. While unmatched in their anti-inflammatory and immunosuppressive activities, GC therapy is often associated with the significant ocular side effect of GC-induced ocular hypertension (OHT) and iatrogenic open-angle glaucoma. Investigators have generated GC-induced OHT and glaucoma in at least 8 different species besides man. These models mimic many features of this condition in man and provide morphologic and molecular insights into the pathogenesis of GC-OHT. In addition, there are many clinical, morphological, and molecular similarities between GC-induced glaucoma and primary open-angle glaucoma (POAG), making animals models of GC-induced OHT and glaucoma attractive models in which to study specific aspects of POAG. PMID:26051991

  17. An animal model for progressive multifocal leukoencephalopathy.

    PubMed

    Haley, Sheila A; Atwood, Walter J

    2014-12-01

    JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease in humans. The disease, once considered fatal, is now managed with immune reconstitution therapy; however, surviving patients remain severely debilitated. Until now, there has been no animal model to study JCV in the brain, and research into treatment has relied on cell culture systems. In this issue of the JCI, Kondo and colleagues developed a mouse model in which human glial cells are engrafted into neonatal mice that are both immunodeficient and deficient for myelin basic protein. When challenged intracerebrally with JCV, these mice exhibit some of the characteristics of PML. The establishment of this chimeric mouse model is a significant advance toward understanding the mechanism of JCV pathogenesis and the identification of drugs to treat or prevent the disease.

  18. Animal models of premature and retarded ejaculation.

    PubMed

    Waldinger, Marcel D; Olivier, Berend

    2005-06-01

    Most of our current understanding of the neurobiology of sexual behavior and ejaculatory function has been derived from animal studies using rats with normal sexual behaviour. However, none of these proposed models adequately represents human ejaculatory disorders. Based on the "ejaculation distribution theory", which postulates that the intravaginal ejaculation latency time in men is represented by a biological continuum, we have developed an animal model for the research of premature and delayed ejaculation. In this model, a large number of male Wistar rats are investigated during 4-6 weekly sexual behavioural tests. Based on the number of ejaculations during 30 min tests, rapid and sluggish ejaculating rats are distinguished, each representing approximately 10% at both ends of a Gaussian distribution. Together with other parameters, such as ejaculation latency time, these rats at either side of the spectrum resemble men with premature and delayed ejaculation, respectively. Comparable to the human situation, in a normal population of rats, endophenotypes exist with regard to basal sexual (ejaculatory) performance.

  19. 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

  20. Estimating Effective Dose from Phantom Dose Measurements in Atrial Fibrillation Ablation Procedures and Comparison of MOSFET and TLD Detectors in a Small Animal Dosimetry Setting

    NASA Astrophysics Data System (ADS)

    Anderson-Evans, Colin David

    Two different studies will be presented in this work. The first involves the calculation of effective dose from a phantom study which simulates an atrial fibrillation (AF) ablation procedure. The second involves the validation of metal-oxide semiconducting field effect transistors (MOSFET) for small animal dosimetry applications as well as improved characterization of the animal irradiators on Duke University's campus. Atrial Fibrillation is an ever increasing health risk in the United States. The most common type of cardiac arrhythmia, AF is associated with increased mortality and ischemic cerebrovascular events. Managing AF can include, among other treatments, an interventional procedure called catheter ablation. The procedure involves the use of biplane fluoroscopy during which a patient can be exposed to radiation for as much as two hours or more. The deleterious effects of radiation become a concern when dealing with long fluoroscopy times, and because the AF ablation procedure is elective, it makes relating the risks of radiation ever more essential. This study hopes to quantify the risk through the derivation of dose conversion coefficients (DCCs) from the dose-area product (DAP) with the intent that DCCs can be used to provide estimates of effective dose (ED) for typical AF ablation procedures. A bi-plane fluoroscopic and angiographic system was used for the simulated AF ablation procedures. For acquisition of organ dose measurements, 20 diagnostic MOSFET detectors were placed at selected organs in a male anthropomorphic phantom, and these detectors were attached to 4 bias supplies to obtain organ dose readings. The DAP was recorded from the system console and independently validated with an ionization chamber and radiochromic film. Bi-plane fluoroscopy was performed on the phantom for 10 minutes to acquire the dose rate for each organ, and the average clinical procedure time was multiplied by each organ dose rate to obtain individual organ doses. The

  1. Internal dosimetry with the Monte Carlo code GATE: validation using the ICRP/ICRU female reference computational model

    NASA Astrophysics Data System (ADS)

    Villoing, Daphnée; Marcatili, Sara; Garcia, Marie-Paule; Bardiès, Manuel

    2017-03-01

    The purpose of this work was to validate GATE-based clinical scale absorbed dose calculations in nuclear medicine dosimetry. GATE (version 6.2) and MCNPX (version 2.7.a) were used to derive dosimetric parameters (absorbed fractions, specific absorbed fractions and S-values) for the reference female computational model proposed by the International Commission on Radiological Protection in ICRP report 110. Monoenergetic photons and electrons (from 50 keV to 2 MeV) and four isotopes currently used in nuclear medicine (fluorine-18, lutetium-177, iodine-131 and yttrium-90) were investigated. Absorbed fractions, specific absorbed fractions and S-values were generated with GATE and MCNPX for 12 regions of interest in the ICRP 110 female computational model, thereby leading to 144 source/target pair configurations. Relative differences between GATE and MCNPX obtained in specific configurations (self-irradiation or cross-irradiation) are presented. Relative differences in absorbed fractions, specific absorbed fractions or S-values are below 10%, and in most cases less than 5%. Dosimetric results generated with GATE for the 12 volumes of interest are available as supplemental data. GATE can be safely used for radiopharmaceutical dosimetry at the clinical scale. This makes GATE a viable option for Monte Carlo modelling of both imaging and absorbed dose in nuclear medicine.

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

    SciTech Connect

    Carbaugh, Eugene H.; Bihl, Donald E.; Maclellan, Jay A.; Antonio, Cheryl L.; Hill, Robin L.

    2009-09-30

    The Hanford Internal Dosimetry Program (HIDP) provides internal dosimetry support services for operations at the Hanford Site. The HIDP is staffed and managed by the Radiation and Health Technology group, within the Pacific Northwest National Laboratory (PNNL). Operations supported by the HIDP include research and development, the decontamination and decommissioning of facilities formerly used to produce and purify plutonium, and waste management activities. Radioelements of particular interest are plutonium, uranium, americium, tritium, and the fission and activation product radionuclides 137Cs, 90Sr, and 60Co. This manual describes the technical basis for the design of the routine bioassay monitoring program and for assessment of internal dose. The purposes of the manual are as follows: • Provide assurance that the HIDP derives from a sound technical base. • Promote the consistency and continuity of routine program activities. • Provide a historical record. • Serve as a technical reference for radiation protection personnel. • Aid in identifying and planning for future needs.

  3. 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.

  4. Monte Carlo modelling of angular radiance in tissue phantoms and human prostate: PDT light dosimetry.

    PubMed

    Barajas, O; Ballangrud, A M; Miller, G G; Moore, R B; Tulip, J

    1997-09-01

    Photodynamic therapy (PDT) is a promising technique for destroying tumours. Photosensitizing drugs presently available are not sufficiently tumour specific; hence, light dosimetry is required in order to control light exposure and thereby restrict cell kill to the target tissue to avoid damage to healthy tissue. Current light dosimetry methods rely on tissue optical characterization by fluence measurements at several points. Fluence-based tissue characterization is impractical for tumours in organs such as prostate where access by optical probes is limited and the tumours are highly optically inhomogeneous. This paper explores the potential of radiance-based light dosimetry as an alternative. Correlation is found between Monte Carlo simulation of radiance in a tissue phantom and radiance measurements made using a new radiance probe. Radiance is sensitive to variations in the tissue optical parameters, absorption coefficient mu(a), scattering coefficient mu(s), and anisotropy factor g, and therefore is potentially useful for tissue characterization. Radiance measurements have several advantages over fluence measurements. Radiance measurements provide more information from a single location, better spatial resolution of the tissue optical parameters, and higher sensitivity in discriminating between different media. However, the Monte Carlo method is too slow to be of practical value for tissue characterization by correlation of measured and simulated radiance. An analytical solution to the transport equation for radiance would be desirable as this would facilitate and increase the speed of tissue characterization.

  5. Neuropsychiatric SLE: from animal model to human.

    PubMed

    Pikman, R; Kivity, S; Levy, Y; Arango, M-T; Chapman, J; Yonath, H; Shoenfeld, Y; Gofrit, S G

    2017-04-01

    Animal models are a key element in disease research and treatment. In the field of neuropsychiatric lupus research, inbred, transgenic and disease-induced mice provide an opportunity to study the pathogenic routes of this multifactorial illness. In addition to achieving a better understanding of the immune mechanisms underlying the disease onset, supplementary metabolic and endocrine influences have been discovered and investigated. The ever-expanding knowledge about the pathologic events that occur at disease inception enables us to explore new drugs and therapeutic approaches further and to test them using the same animal models. Discovery of the molecular targets that constitute the pathogenic basis of the disease along with scientific advancements allow us to target these molecules with monoclonal antibodies and other specific approaches directly. This novel therapy, termed "targeted biological medication" is a promising endeavor towards producing drugs that are more effective and less toxic. Further work to discover additional molecular targets in lupus' pathogenic mechanism and to produce drugs that neutralize their activity is needed to provide patients with safe and efficient methods of controlling and treating the disease.

  6. Animal models of primary biliary cirrhosis.

    PubMed

    Wang, Jinjun; Yang, Guo-Xiang; Tsuneyama, Koichi; Gershwin, M Eric; Ridgway, William M; Leung, Patrick S C

    2014-08-01

    Within the last decade, several mouse models that manifest characteristic features of primary biliary cirrhosis (PBC) with antimitochondrial antibodies (AMAs) and immune-mediated biliary duct pathology have been reported. Here, the authors discuss the current findings on two spontaneous (nonobese diabetic autoimmune biliary disease [NOD.ABD] and dominant negative transforming growth factor-β receptor II [dnTGFβRII]) and two induced (chemical xenobiotics and microbial immunization) models of PBC. These models exhibit the serological, immunological, and histopathological features of human PBC. From these animal models, it is evident that the etiology of PBC is multifactorial and requires both specific genetic predispositions and environmental insults (either xenobiotic chemicals or microbial), which lead to the breaking of tolerance and eventually liver pathology. Human PBC is likely orchestrated by multiple factors and hence no single model can fully mimic the immunopathophysiology of human PBC. Nevertheless, knowledge gained from these models has greatly advanced our understanding of the major immunological pathways as well as the etiology of PBC.

  7. 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

  8. Animal Models of Fibrotic Lung Disease

    PubMed Central

    Lawson, William E.; Oury, Tim D.; Sisson, Thomas H.; Raghavendran, Krishnan; Hogaboam, Cory M.

    2013-01-01

    Interstitial lung fibrosis can develop as a consequence of occupational or medical exposure, as a result of genetic defects, and after trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome, or it can develop in an idiopathic manner. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes the common and emerging models of lung fibrosis to highlight their usefulness in understanding the cell–cell and soluble mediator interactions that drive fibrotic responses. Recent advances have allowed for the development of models to study targeted injuries of Type II alveolar epithelial cells, fibroblastic autonomous effects, and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung has increased susceptibility to fibrosis. Each of the models reviewed in this report offers a powerful tool for studying some aspect of fibrotic lung disease. PMID:23526222

  9. Dosimetry for Radiopharmaceutical Therapy

    PubMed Central

    Sgouros, George; Hobbs, Robert F.

    2014-01-01

    Radiopharmaceutical therapy (RPT) involves the use of radionuclides that are either conjugated to tumor-targeting agents (eg, nanoscale constructs, antibodies, peptides, and small molecules) or concentrated in tissue through natural physiological mechanisms that occur predominantly in neoplastic or otherwise targeted cells (eg, Graves disease). The ability to collect pharmacokinetic data by imaging and use this to perform dosimetry calculations for treatment planning distinguishes RPT from other systemic treatment modalities. Treatment planning has not been widely adopted, in part, because early attempts to relate dosimetry to outcome were not successful. This was partially because a dosimetry methodology appropriate to risk evaluation rather than efficacy and toxicity was being applied to RPT. The weakest links in both diagnostic and therapeutic dosimetry are the accuracy of the input and the reliability of the radiobiological models used to convert dosimetric data to the relevant biologic end points. Dosimetry for RPT places a greater demand on both of these weak links. To date, most dosimetric studies have been retrospective, with a focus on tumor dose-response correlations rather than prospective treatment planning. In this regard, transarterial radioembolization also known as intra-arterial radiation therapy, which uses radiolabeled (90Y) microspheres of glass or resin to treat lesions in the liver holds much promise for more widespread dosimetric treatment planning. The recent interest in RPT with alpha-particle emitters has highlighted the need to adopt a dosimetry methodology that specifically accounts for the unique aspects of alpha particles. The short range of alpha-particle emitters means that in cases in which the distribution of activity is localized to specific functional components or cell types of an organ, the absorbed dose will be equally localized and dosimetric calculations on the scale of organs or even voxels (~5 mm) are no longer sufficient

  10. Vaccines and animal models for arboviral encephalitides.

    PubMed

    Nalca, Aysegul; Fellows, Patricia F; Whitehouse, Chris A

    2003-11-01

    Arthropod-borne viruses ("arboviruses") cause significant human illness ranging from mild, asymptomatic infection to fatal encephalitis or hemorrhagic fever. The most significant arboviruses causing human illness belong to genera in three viral families, Togaviridae, Flaviviridae, and Bunyaviridae. These viruses represent a significant public health threat to many parts of the world, and, as evidenced by the recent introduction of the West Nile virus (WNV) to the Western Hemisphere, they can no longer be considered specific to any one country or region of the world. Like most viral diseases, there are no specific therapies for the arboviral encephalitides; therefore, effective vaccines remain the front line of defense for these diseases. With this in mind, the development of new, more effective vaccines and the appropriate animal models in which to test them become paramount. In fact, for many important arboviruses (e.g. California serogroup and St. Louis encephalitis viruses), there are currently no approved vaccines available for human use. For others, such as the alphaviruses, human vaccines are available only as Investigational New Drugs, and thus are not in widespread use. On the other hand, safe and effective vaccines against tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JEV) have been in use for decades. New challenges in vaccine development have been met with new technologies in vaccine research. Many of the newer vaccines are now being developed by recombinant DNA technology. For example, chimeric virus vaccines have been developed using infectious clone technology for many of the arboviruses including, WNV, JEV, and TBEV. Other successful approaches have involved the use of naked DNA encoding and subsequently expressing the desired protective epitopes. Naked DNA vaccines have been used for TBEV and JEV and are currently under development for use against WNV. The development of less expensive, more authentic animal models to

  11. [Analysis of dalbavancin in animal models].

    PubMed

    Murillo, Óscar; El-Haj, Cristina

    2017-01-01

    Multiresistant Gram-positive infections continue to pose a major clinical challenge and the development of new antibiotics is always desirable. Dalbavancin is a lipoglycopeptide with a prolonged half-life that allows long dosing intervals. In experimental models, its activity has been evaluated in distinct models and microorganisms, which limits the conclusions that can be drawn; however, the largest number of studies have been conducted in Staphylococcus aureus infection. Overall, dalbavancin has shown concentration-dependent efficacy and the parameters best explaining its activity are maximal pharmacodynamic concentration/minimal inhibitory concentration and the area under the curve/minimal inhibitory concentration. In these experimental models, dalbavancin has shown good distribution, a prolonged half-life in all animal species and efficacy that is mostly similar to that of previous glycopeptides but with lower doses and with longer dosing intervals. Of note, the efficacy of dalbavancin is not altered by methicillin resistance or the glycopeptide sensitivity of S. aureus. In the case of difficult-to-treat staphylococcal infections (eg, endocarditis, foreign body infections), an adequate dosing interval and high dosage seem to play an important role in the efficacy of the drug. All in all, experimental models can still provide greater knowledge of this new antibiotic to guide clinical research and determine its role in the treatment of distinct infections produced by Gram-positive microorganisms.

  12. Fetal akinesia deformation sequence: an animal model.

    PubMed

    Moessinger, A C

    1983-12-01

    Rat fetuses were paralyzed by daily transuterine injections of curare from day 18 of gestation until term (day 21). The following anomalies were noted at the time of delivery: multiple joint contractures, pulmonary hypoplasia, micrognathia, fetal growth retardation, short umbilical cords, and polyhydramnios. Neither sham-operated nor untouched littermate control fetuses had any of these anomalies. The group of anomalies (or deformation sequence) obtained with this animal model is presumed to result from the paralytic effect of curare. This phenotype bears a striking resemblance to the syndrome of ankyloses, facial anomalies, and pulmonary hypoplasia (also known as Pena and Shokeir I), presumably inherited in an autosomal recessive manner. It is suggested that this phenotype is not specific but, rather, represents a deformation sequence which results from fetal immobilization or akinesia. Diagnostic evaluation of patients with this group of anomalies should include the identification of the underlying pathologic process (etiology of the akinesia) to allow for proper classification and genetic counseling.

  13. A computational tool for patient specific dosimetry and radiobiological modeling of selective internal radiation therapy with (90)Y microspheres.

    PubMed

    Kalantzis, Georgios; Leventouri, Theodora; Apte, Aditiya; Shang, Charles

    2015-11-01

    In recent years we have witnessed tremendous progress in selective internal radiation therapy. In clinical practice, quite often, radionuclide therapy is planned using simple models based on standard activity values or activity administered per unit body weight or surface area in spite of the admission that radiation-dose methods provide more accurate dosimetric results. To address that issue, the authors developed a Matlab-based computational software, named Patient Specific Yttrium-90 Dosimetry Toolkit (PSYDT). PSYDT was designed for patient specific voxel-based dosimetric calculations and radiobiological modeling of selective internal radiation therapy with (90)Y microspheres. The developed toolkit is composed of three dimensional dose calculations for both bremsstrahlung and beta emissions. Subsequently, radiobiological modeling is performed on a per-voxel basis and cumulative dose volume histograms (DVHs) are generated. In this report we describe the functionality and visualization features of PSYDT.

  14. Ethical guidelines, animal profile, various animal models used in periodontal research with alternatives and future perspectives

    PubMed Central

    Pasupuleti, Mohan Kumar; Molahally, Subramanya Shetty; Salwaji, Supraja

    2016-01-01

    Laboratory animal models serve as a facilitator to investigate the etiopathogenesis of periodontal disease, are used to know the efficacy of reconstructive and regenerative procedures, and are also helpful in evaluation of newer therapeutic techniques including laser and implant therapies prior to application in the human beings. The aim of this review is to know the different animal models used in various specialties of dental research and to know the ethical guidelines prior to the usage of experimental models with main emphasis on how to refine, replace, and reduce the number of animal models usage in the laboratory. An online search for experimental animal models used in dental research was performed using MEDLINE/PubMed database. Publications from 2009 to May 2013 in the specialty of periodontics were included in writing this review. A total of 652 references were published in PubMed/MEDLINE databases based on the search terms used. Out of 245 studies, 241 were related to the periodontal research published in English from 2009 to 2013. Relevant papers were chosen according to the inclusion and exclusion criteria. After extensive electronic and hand search on animal models, it has been observed that various animal models were used in dental research. Search on animal models used for dental research purpose revealed that various animals such as rats, mice, guinea pigs, rabbit, beagle dogs, goats, and nonhuman primates were extensively used. However, with the new advancement of ex vivo animal models, it has become easy to investigate disease pathogenesis and to test the efficacy of newer therapeutic modalities with the reduced usage of animal models. This review summarized the large amount of literature on animal models used in periodontal research with main emphasis on ethical guidelines and on reducing the animal model usage in future perspective. PMID:28298815

  15. Three dosimetry models of lipoma arborescens treated by {sup 90}Y synovectomy

    SciTech Connect

    O’Doherty, Jim; Clauss, Ralf; Scuffham, James; Khan, Aman; Petitguillaume, Alice; Desbrée, Aurélie

    2014-05-15

    Purpose: Lipoma arborescens (LA) is a benign intra-articular lipomatous proliferation of the synovial membrane. This extremely rare condition has previously been treated by intra-articular{sup 90}Y radiosynoviorthesis but dosimetry literature on this form of radionuclide therapy is nonexistent. The authors detail methodology for successful treatment of LA and provide for the first time estimates of radiation dosimetry. The authors also analyze the biodistribution of the radiopharmaceutical over the course of the patient's treatment through sequential imaging. Methods: A patient with bilateral LA underwent intracavity injection of{sup 90}Y citrate colloid to the right and left knee joint spaces (181 and 198 MBq, respectively). SPECT/CT datasets were acquired over 9 days to quantify the biodistribution and kinetics of the radiopharmaceutical. Radiation dosimetry was performed using the MIRD schema (through OLINDA software), a custom voxel-based method, and a direct Monte Carlo calculation (OEDIPE). Results: Follow-up MRI showed marked reduction in LA size in both knees. Mean absorbed doses to the LA were 21.2 ± 0.8 and 42.9 ± 2.3 Gy using OLINDA, 8.1 ± 0.3 and 16.7 ± 0.5 Gy using voxel based methodology, and 8.2 ± 0.3 and 15.7 ± 0.5 Gy for OEDIPE in the right and left LA, respectively. Distribution of the radiopharmaceutical within the joint space alters over the imaging period, with less than 1% of the remaining activity having moved posteriorly in the knee cavity. No uptake was detected outside of the joint space after assessment with whole-body scintigraphy. Conclusions: An activity of approximately 185 MBq successfully relieved clinical symptoms of LA. There was good correlation between direct Monte Carlo and voxel based techniques, but OLINDA was shown to overestimate the absorbed dose to the tumor. Accurate dosimetry may help select an activity more tailored to the specific size and location of the LA.

  16. 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

  17. Biologically-based modeling insights in inhaled vapor absorption and dosimetry.

    PubMed

    Morris, John B

    2012-12-01

    The lung is a route of entry and also a target site for inhaled vapors, therefore, knowledge of the total absorbed dose and/or the dose absorbed in each airway during inhalation exposure is essential. Vapor absorption characteristics result primarily from the fact that vapors demonstrate equilibrium/saturation behavior in fluids. Thus, during inhalation exposures blood and airway tissue vapor concentrations increase to a steady state value and increase no further no matter how long the exposure. High tissue concentrations can be obtained with highly soluble vapors, thus solubility, as measured by blood:air partition coefficient, is a fundamentally important physical/chemical characteristic of vapors. While it is classically thought that vapor absorption occurs only in the alveoli it is now understood that this is not the case. Soluble vapors can be efficiently absorbed in the airways themselves and do not necessarily penetrate to the alveolar level. Such vapors are more likely to injure the proximal than distal airways because that is the site of the greatest delivered dose. There are substantial species differences in airway vapor absorption between laboratory animals and humans making interpretation of laboratory animal inhalation toxicity data difficult. Airway absorption is dependent on vapor solubility and is enhanced by local metabolism and/or direct reaction within airway tissues. Modern simulation models that incorporate terms for solubility, metabolism, and reaction rate accurately predict vapor absorption patterns in both animals and humans and have become essential tools for understanding the pharmacology and toxicology of airborne vapors.

  18. Goats as an osteopenic animal model.

    PubMed

    Leung, K S; Siu, W S; Cheung, N M; Lui, P Y; Chow, D H; James, A; Qin, L

    2001-12-01

    A large osteopenic animal model that resembles human osteoporotic changes is essential for osteoporosis research. This study aimed at establishing a large osteopenic animal model in goats. Twenty-five Chinese mountain goats were used in which they were either ovariectomized (OVX) and fed with a low-calcium diet (n = 16) or sham-operated (SHAM; n = 9). Monthly photodensitometric analysis on proximal tibial metaphysis and calcaneus was performed. Two iliac crest biopsy specimens obtained before and 6 months after OVX were used for bone mineral density (BMD) measurement with peripheral quantitative computed tomography (pQCT). Lumbar vertebrae (L2 and L7), humeral heads, and calcanei were collected for BMD measurement after euthanasia. The humeral heads and calcanei were used in biomechanical indentation test. BMD measurement showed a significant 25.0% (p = 0.006) decrease in BMD of the iliac crest biopsy specimens 6 months after OVX. It also was statistically significant when compared with the SHAM (p = 0.028). BMD at L2, L7, calcaneus, and humeral head reduced by 24-33% (p ranged from 0.001 to 0.011) when compared with the SHAM. Photodensitometry showed a continuous decrease in bone density after OVX. There were significant decreases of 18.9% in proximal tibial metaphysis (p = 0.003) and 21.8% in calcaneus (p = 0.023) in the OVX group 6 months postoperatively. Indentation test on the humeral head and calcaneus showed a significant decrease 52% (p = 0.006) and 54% (p = 0.001), respectively, in energy required for displacement of 3 mm in the OVX group compared with the SHAM group. The decreases correlated significantly to the decrease in BMD of the corresponding specimens (r2 = 0.439 and 0.581; p < 0.001 for both). In conclusion, this study showed that OVX plus a low-calcium diet could induce significant osteopenia and deterioration of mechanical properties of the cancellous bone in goats.

  19. Large animal model of chronic pulmonary hypertension.

    PubMed

    Sato, Hitoshi; Hall, Candice M; Griffith, Grant W; Johnson, Kent F; McGillicuddy, John W; Bartlett, Robert H; Cook, Keith E

    2008-01-01

    A large animal model is needed to study artificial lung attachment in a setting simulating chronic lung disease with significant pulmonary hypertension (PH). This study sought to create a sheep model that develops significant PH within 60 days with a low rate of mortality. Sephadex beads were injected in the pulmonary circulation of sheep every other day for 60 days at doses of 0.5, 0.75, and 1 g (n = 10, 10, 7). Mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were obtained every 2 weeks. In the 0.5, 0.75, and 1-g groups, 90, 70, and 14.3% of sheep completed the study, respectively, with the remainder experiencing heart failure. By the 60th day, pulmonary vascular resistance had increased (p < 0.01) from 0.89 +/- 0.3 to 3.2 +/- 0.9 mm Hg/(L/min) and from 0.9 +/- 0.3 to 4.3 +/- 3.2 mm Hg/(L/min) in the 0.5 and 0.75-g groups, respectively. Significant right ventricular hypertrophy was observed in the 0.75-g group but not in the 0.5-g group. Data from the 1-g group were insufficient for analysis due to high mortality. Thus, the 0.5 and 0.75-g groups generate significant PH, but the 0.75-g group is a better model of chronic PH in lung disease due to the development of right ventricular hypertrophy.

  20. 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

  1. 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.

  2. Radiation Dosimetry Experiment (RaD-X): High-Altitude Balloon Flight Mission for Improving the NAIRAS Model

    NASA Technical Reports Server (NTRS)

    Mertens, Christopher J.; Alston, Erica J.; Straume, Tore; Gersey, Brad; Lusby, Terry C.; Norman, Ryan B.; Gronoff, Guillaume P.; Tobiska, W. Kent; Wilkins, Rick

    2015-01-01

    The NASA Radiation Dosimetry Experiment (RaD-X) high-altitude balloon mission was successfully launched from Fort Sumner, New Mexico USA on 25 September, 2015. Over 15 hours of science data were obtained from four dosimeters at altitudes above about 25 km. One of the main goals of the RaD-X mission is to improve aviation radiation model characterization of cosmic ray primaries by taking dosimetric measurements above the Pfotzer maximum before the production of secondary particles occurs. The second goal of the RaD-X mission is to facilitate the pathway toward real-time, data assimilative predictions of atmospheric cosmic radiation exposure by identifying and characterizing low-cost radiation measurement solutions.

  3. Modelling the effective atomic number and the packing factor of polyatomic compounds: Applications to refractive index and dosimetry

    NASA Astrophysics Data System (ADS)

    Lima, H.; Couto dos Santos, M. A.

    2016-09-01

    In this work, based on fundamental physics and chemistry (charge distribution, electronegativity, induced dipole moment), we are introducing an analytical expression for Zeff and a general way of calculating the crystal packing factor, p, of any ionic material. By using the average separation between the atomic and crystal(ionic) radii of the interacting ions, we are postulating an effective distance(Rij) between the positive and the negative centre of charge. When compared to the available experimental data, predictions within 20% have been obtained to Zeff of materials applied to dosimetry. In photonics, the increasing behaviour of the refractive index with Zeff is confirmed. By combining crystal field and effective charge models, we have predicted Zeff of the Eu2O3 within the range of available experimental data.

  4. Multi-resolution voxel phantom modeling: a high-resolution eye model for computational dosimetry

    NASA Astrophysics Data System (ADS)

    Caracappa, Peter F.; Rhodes, Ashley; Fiedler, Derek

    2014-09-01

    Voxel models of the human body are commonly used for simulating radiation dose with a Monte Carlo radiation transport code. Due to memory limitations, the voxel resolution of these computational phantoms is typically too large to accurately represent the dimensions of small features such as the eye. Recently reduced recommended dose limits to the lens of the eye, which is a radiosensitive tissue with a significant concern for cataract formation, has lent increased importance to understanding the dose to this tissue. A high-resolution eye model is constructed using physiological data for the dimensions of radiosensitive tissues, and combined with an existing set of whole-body models to form a multi-resolution voxel phantom, which is used with the MCNPX code to calculate radiation dose from various exposure types. This phantom provides an accurate representation of the radiation transport through the structures of the eye. Two alternate methods of including a high-resolution eye model within an existing whole-body model are developed. The accuracy and performance of each method is compared against existing computational phantoms.

  5. Multi-resolution voxel phantom modeling: a high-resolution eye model for computational dosimetry.

    PubMed

    Caracappa, Peter F; Rhodes, Ashley; Fiedler, Derek

    2014-09-21

    Voxel models of the human body are commonly used for simulating radiation dose with a Monte Carlo radiation transport code. Due to memory limitations, the voxel resolution of these computational phantoms is typically too large to accurately represent the dimensions of small features such as the eye. Recently reduced recommended dose limits to the lens of the eye, which is a radiosensitive tissue with a significant concern for cataract formation, has lent increased importance to understanding the dose to this tissue. A high-resolution eye model is constructed using physiological data for the dimensions of radiosensitive tissues, and combined with an existing set of whole-body models to form a multi-resolution voxel phantom, which is used with the MCNPX code to calculate radiation dose from various exposure types. This phantom provides an accurate representation of the radiation transport through the structures of the eye. Two alternate methods of including a high-resolution eye model within an existing whole-body model are developed. The accuracy and performance of each method is compared against existing computational phantoms.

  6. 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.

  7. Animal models in virus research: their utility and limitations.

    PubMed

    Louz, Derrick; Bergmans, Hans E; Loos, Birgit P; Hoeben, Rob C

    2013-11-01

    Viral diseases are important threats to public health worldwide. With the number of emerging viral diseases increasing the last decades, there is a growing need for appropriate animal models for virus studies. The relevance of animal models can be limited in terms of mimicking human pathophysiology. In this review, we discuss the utility of animal models for studies of influenza A viruses, HIV and SARS-CoV in light of viral emergence, assessment of infection and transmission risks, and regulatory decision making. We address their relevance and limitations. The susceptibility, immune responses, pathogenesis, and pharmacokinetics may differ between the various animal models. These complexities may thwart translating results from animal experiments to the humans. Within these constraints, animal models are very informative for studying virus immunopathology and transmission modes and for translation of virus research into clinical benefit. Insight in the limitations of the various models may facilitate further improvements of the models.

  8. Modeling individual animal histories with multistate capture–recapture models

    USGS Publications Warehouse

    Lebreton, Jean-Dominique; Nichols, James D.; Barker, Richard J.; Pradel, Roger; Spendelow, Jeffrey A.

    2009-01-01

    Many fields of science begin with a phase of exploration and description, followed by investigations of the processes that account for observed patterns. The science of ecology is no exception, and recent decades have seen a focus on understanding key processes underlying the dynamics of ecological systems. In population ecology, emphasis has shifted from the state variable of population size to the demographic processes responsible for changes in this state variable: birth, death, immigration, and emigration. In evolutionary ecology, some of these same demographic processes, rates of birth and death, are also the determinants of fitness. In animal population ecology, the estimation of state variables and their associated vital rates is especially problematic because of the difficulties in sampling such populations and detecting individual animals. Indeed, early capture–recapture models were developed for the purpose of estimating population size, given the reality that all animals are not caught or detected at any sampling occasion. More recently, capture–recapture models for open populations were developed to draw inferences about survival in the face of these same sampling problems. The focus of this paper is on multi‐state mark–recapture models (MSMR), which first appeared in the 1970s but have undergone substantial development in the last 15 years. These models were developed to deal explicitly with biological variation, in that animals in different “states” (classes defined by location, physiology, behavior, reproductive status, etc.) may have different probabilities of survival and detection. Animal transitions between states are also stochastic and themselves of interest. These general models have proven to be extremely useful and provide a way of thinking about a remarkably wide range of important ecological processes. These methods are now at a stage of refinement and sophistication where they can readily be used by biologists to tackle a wide

  9. Animal models to study gluten sensitivity.

    PubMed

    Marietta, Eric V; Murray, Joseph A

    2012-07-01

    The initial development and maintenance of tolerance to dietary antigens is a complex process that, when prevented or interrupted, can lead to human disease. Understanding the mechanisms by which tolerance to specific dietary antigens is attained and maintained is crucial to our understanding of the pathogenesis of diseases related to intolerance of specific dietary antigens. Two diseases that are the result of intolerance to a dietary antigen are celiac disease (CD) and dermatitis herpetiformis (DH). Both of these diseases are dependent upon the ingestion of gluten (the protein fraction of wheat, rye, and barley) and manifest in the gastrointestinal tract and skin, respectively. These gluten-sensitive diseases are two examples of how devastating abnormal immune responses to a ubiquitous food can be. The well-recognized risk genotype for both is conferred by either of the HLA class II molecules DQ2 or DQ8. However, only a minority of individuals who carry these molecules will develop either disease. Also of interest is that the age at diagnosis can range from infancy to 70-80 years of age. This would indicate that intolerance to gluten may potentially be the result of two different phenomena. The first would be that, for various reasons, tolerance to gluten never developed in certain individuals, but that for other individuals, prior tolerance to gluten was lost at some point after childhood. Of recent interest is the concept of non-celiac gluten sensitivity, which manifests as chronic digestive or neurologic symptoms due to gluten, but through mechanisms that remain to be elucidated. This review will address how animal models of gluten-sensitive disorders have substantially contributed to a better understanding of how gluten intolerance can arise and cause disease.

  10. Animal models to evaluate anti-atherosclerotic drugs.

    PubMed

    Priyadharsini, Raman P

    2015-08-01

    Atherosclerosis is a multifactorial condition characterized by endothelial injury, fatty streak deposition, and stiffening of the blood vessels. The pathogenesis is complex and mediated by adhesion molecules, inflammatory cells, and smooth muscle cells. Statins have been the major drugs in treating hypercholesterolemia for the past two decades despite little efficacy. There is an urgent need for new drugs that can replace statins or combined with statins. The preclinical studies evaluating atherosclerosis require an ideal animal model which resembles the disease condition, but there is no single animal model which mimics the disease. The animal models used are rabbits, rats, mice, hamsters, mini pigs, etc. Each animal model has its own advantages and disadvantages. The method of induction of atherosclerosis includes diet, chemical induction, mechanically induced injuries, and genetically manipulated animal models. This review mainly focuses on the various animal models, method of induction, the advantages, disadvantages, and the current perspectives with regard to preclinical studies on atherosclerosis.

  11. WE-E-BRE-01: An Image-Based Skeletal Dosimetry Model for the ICRP Reference Adult Female - Internal Electron Sources

    SciTech Connect

    O'Reilly, S; Maynard, M; Marshall, E; Bolch, W; Sinclair, L; Rajon, D; Wayson, M

    2014-06-15

    Purpose: Limitations seen in previous skeletal dosimetry models, which are still employed in commonly used software today, include the lack of consideration of electron escape and cross-fire from cortical bone, the modeling of infinite spongiosa, the disregard of the effect of varying cellularity on active marrow self-irradiation, and the lack of use of the more recent ICRP definition of a 50 micron surrogate tissue region for the osteoprogenitor cells - shallow marrow. These limitations were addressed in the present dosimetry model. Methods: Electron transport was completed to determine specific absorbed fractions to active marrow and shallow marrow of the skeletal regions of the adult female. The bone macrostructure was obtained from the whole-body hybrid computational phantom of the UF series of reference phantoms, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 year-old female cadaver. The target tissue regions were active marrow and shallow marrow. The source tissues were active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume and cortical bone surfaces. The marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or modeled analytically. Results: The method of combining macro- and microstructure absorbed fractions calculated using MCNPX electron transport was found to yield results similar to those determined with the PIRT model for the UF adult male in the Hough et al. study. Conclusion: The calculated skeletal averaged absorbed fractions for each source-target combination were found to follow similar trends of more recent dosimetry models (image-based models) and did not follow current models used in nuclear medicine dosimetry at high energies (due to that models use of an infinite expanse of trabecular spongiosa)

  12. Cumulative permanent environmental effects for repeated records animal models.

    PubMed

    Schaeffer, L R

    2011-04-01

    The assumption of a single permanent environmental (PE) effect contributing to every record made by an animal is questioned. An alternative model where new PE effects accumulate with each record made by an animal is proposed. An example is used to illustrate the differences between the traditional model and the proposed model.

  13. Intraperitoneal chemotherapy (IPC) for peritoneal carcinomatosis: review of animal models.

    PubMed

    Gremonprez, Félix; Willaert, Wouter; Ceelen, Wim

    2014-02-01

    The development of suitable animal models is essential to experimental research on intraperitoneal chemotherapy (IPC). This review of the English literature (MEDLINE) presents a detailed analysis of current animal models and gives recommendations for future experimental research. Special consideration should be given to cytotoxic drug dose and concentration, tumor models, and outcome parameters.

  14. Animal models of leukemia: any closer to the real thing?

    PubMed

    Cook, Guerry J; Pardee, Timothy S

    2013-06-01

    Animal models have been invaluable in the efforts to better understand and ultimately treat patients suffering from leukemia. While important insights have been gleaned from these models, limitations must be acknowledged. In this review, we will highlight the various animal models of leukemia and describe their contributions to the improved understanding and treatment of these cancers.

  15. Animal Models of Leukemia: Any closer to the real thing?

    PubMed Central

    Cook, Guerry J; Pardee, Timothy S.

    2012-01-01

    Animal models have been invaluable in the efforts to better understand and ultimately treat patients suffering from leukemia. While important insights have been gleaned from these models, limitations must be acknowledged. In this review, we will highlight the various animal models of leukemia and describe their contributions to the improved understanding and treatment of these cancers. PMID:23081702

  16. ANIMAL MODELS OF CHRONIC PESTICIDE NEUROTOXICITY.

    EPA Science Inventory

    There is a wealth of literature on neurotoxicological outcomes of acute and short-term exposure to pesticides in laboratory animals, but there are relatively few reports of long-term exposure. Reports in the literature describing "chronic" exposures to pesticides are, in fact, a...

  17. ANIMAL MODELS OF CHRONIC PESTICIDE NEUROTOXICITY.

    EPA Science Inventory

    There is a wealth of literature on neurotoxicological outcomes of acute and short-term exposure to pesticides in laboratory animals, but there are relatively few studies of- long-term exposure. Many reports in the literature describing ;chronic' exposures to pesticides are, in fa...

  18. Institutional Animal Care and Use Committee Considerations for Animal Models of Peripheral Neuropathy

    PubMed Central

    Brabb, Thea; Carbone, Larry; Snyder, Jessica; Phillips, Nona

    2014-01-01

    Peripheral neuropathy and neuropathic pain are debilitating, life-altering conditions that affect a significant proportion of the human population. Animal models, used to study basic disease mechanisms and treatment modalities, are diverse and provide many challenges for institutional animal care and use committee (IACUC) review and postapproval monitoring. Items to consider include regulatory and ethical imperatives in animal models that may be designed to study pain, the basic mechanism of neurodegeneration, and different disease processes for which neuropathic pain is a side effect. Neuropathic pain can be difficult to detect or quantify in many models, and pain management is often unsuccessful in both humans and animals, inspiring the need for more research. Design of humane endpoints requires clear communication of potential adverse outcomes and solutions. Communication with the IACUC, researchers, and veterinary staff is also key for successful postapproval monitoring of these challenging models. PMID:24615447

  19. Hierarchical animal movement models for population-level inference

    USGS Publications Warehouse

    Hooten, Mevin B.; Buderman, Frances E.; Brost, Brian M.; Hanks, Ephraim M.; Ivans, Jacob S.

    2016-01-01

    New methods for modeling animal movement based on telemetry data are developed regularly. With advances in telemetry capabilities, animal movement models are becoming increasingly sophisticated. Despite a need for population-level inference, animal movement models are still predominantly developed for individual-level inference. Most efforts to upscale the inference to the population level are either post hoc or complicated enough that only the developer can implement the model. Hierarchical Bayesian models provide an ideal platform for the development of population-level animal movement models but can be challenging to fit due to computational limitations or extensive tuning required. We propose a two-stage procedure for fitting hierarchical animal movement models to telemetry data. The two-stage approach is statistically rigorous and allows one to fit individual-level movement models separately, then resample them using a secondary MCMC algorithm. The primary advantages of the two-stage approach are that the first stage is easily parallelizable and the second stage is completely unsupervised, allowing for an automated fitting procedure in many cases. We demonstrate the two-stage procedure with two applications of animal movement models. The first application involves a spatial point process approach to modeling telemetry data, and the second involves a more complicated continuous-time discrete-space animal movement model. We fit these models to simulated data and real telemetry data arising from a population of monitored Canada lynx in Colorado, USA.

  20. SU-E-T-05: A 2D EPID Transit Dosimetry Model Based On An Empirical Quadratic Formalism

    SciTech Connect

    Tan, Y; Metwaly, M; Glegg, M; Baggarley, S; Elliott, A

    2014-06-01

    Purpose: To describe a 2D electronic portal imaging device (EPID) transit dosimetry model, based on an empirical quadratic formalism, that can predict either EPID or in-phantom dose distribution for comparisons with EPID captured image or treatment planning system (TPS) dose respectively. Methods: A quadratic equation can be used to relate the reduction in intensity of an exit beam to the equivalent path length of the attenuator. The calibration involved deriving coefficients from a set of dose planes measured for homogeneous phantoms with known thicknesses under reference conditions. In this study, calibration dose planes were measured with EPID and ionisation chamber (IC) in water for the same reference beam (6MV, 100mu, 20×20cm{sup 2}) and set of thicknesses (0–30cm). Since the same calibration conditions were used, the EPID and IC measurements can be related through the quadratic equation. Consequently, EPID transit dose can be predicted from TPS exported dose planes and in-phantom dose can be predicted using EPID distribution captured during treatment as an input. The model was tested with 4 open fields, 6 wedge fields, and 7 IMRT fields on homogeneous and heterogeneous phantoms. Comparisons were done using 2D absolute gamma (3%/3mm) and results were validated against measurements with a commercial 2D array device. Results: The gamma pass rates for comparisons between EPID measured and predicted ranged from 93.6% to 100.0% for all fields and phantoms tested. Results from this study agreed with 2D array measurements to within 3.1%. Meanwhile, comparisons in-phantom between TPS computed and predicted ranged from 91.6% to 100.0%. Validation with 2D array device was not possible for inphantom comparisons. Conclusion: A 2D EPID transit dosimetry model for treatment verification was described and proven to be accurate. The model has the advantage of being generic and allows comparisons at the EPID plane as well as multiple planes in-phantom.

  1. Radiation dosimetry in radiotherapy: a model for an extrinsic optical fiber sensor

    NASA Astrophysics Data System (ADS)

    Mignani, Anna G.; Romano, Salvatore; Fusi, Franco; Mencaglia, Andrea A.

    1998-06-01

    The success of radiotherapy relies on the on-line monitoring of the dose of radiation to which the tumor and its adjacent tissues are exposed. Conventional thermoluminescence dosimeters provide only off-line monitoring, since they determine the radiation dosage after completion of the exposure. In order to overcome this limitation, optical fiber sensors have been proposed, which allow for a minimally invasive, real time and continuous monitoring of the delivered which allow for a minimally invasive, real time and continuous monitoring of the delivered dosage. These sensors make use of radio-transducers which are coupled at the end of a radiation-resistant fiber link, so as to obtain a radiation-induced intensity modulation. Typical radio-transducers are: (1) phosphors, which are stimulated to produce a visible luminescence linearly related to the radiation exposure; (2) heavy-metal-doped fiber sections, which undergo an intensity attenuation in the presence of radiation; (3) radiochromic dyes, which exhibit radiation-modulated optical absorption spectra. This paper presents preliminary test of radiation dosimetry performed by means of an extrinsic optical fiber sensor which makes use of a radiochromic film as radio-transducer. The spectral behavior of the transducer allows for two- wavelength differential measurements, so as to obtain a reference intensity-based sensor output.

  2. Are animal models as good as we think?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Models have been a tool of science at least since the 18th century and serve a variety of purposes from focusing abstract thoughts to representing scaled down version of things for study. Generally, animal models are needed when it is impractical or unethical to study the target animal. Biologists...

  3. The Various Roles of Animal Models in Understanding Human Development

    ERIC Educational Resources Information Center

    Gottlieb, Gilbert; Lickliter, Robert

    2004-01-01

    In this article, the authors take a very conservative view of the contribution of animal models to an understanding of human development. We do not think that homologies can be readily documented with even our most closely related relatives' behavior and psychological functioning. The major contribution of animal models is their provision of food…

  4. Overview of Vertebrate Animal Models of Fungal Infection

    PubMed Central

    Hohl, Tobias M.

    2014-01-01

    Fungi represent emerging infectious threats to human populations worldwide. Mice and other laboratory animals have proved invaluable in modeling clinical syndromes associated with superficial and life-threatening invasive mycoses. This review outlines salient features of common vertebrate animal model systems to study fungal pathogenesis, host antifungal immune responses, and antifungal compounds. PMID:24709390

  5. Technical intelligence in animals: the kea model.

    PubMed

    Huber, Ludwig; Gajdon, Gyula K

    2006-10-01

    The ability to act on information flexibly is one of the cornerstones of intelligent behavior. As particularly informative example, tool-oriented behavior has been investigated to determine to which extent nonhuman animals understand means-end relations, object affordances, and have specific motor skills. Even planning with foresight, goal-directed problem solving and immediate causal inference have been a focus of research. However, these cognitive abilities may not be restricted to tool-using animals but may be found also in animals that show high levels of curiosity, object exploration and manipulation, and extractive foraging behavior. The kea, a New Zealand parrot, is a particularly good example. We here review findings from laboratory experiments and field observations of keas revealing surprising cognitive capacities in the physical domain. In an experiment with captive keas, the success rate of individuals that were allowed to observe a trained conspecific was significantly higher than that of naive control subjects due to their acquisition of some functional understanding of the task through observation. In a further experiment using the string-pulling task, a well-probed test for means-end comprehension, we found the keas finding an immediate solution that could not be improved upon in nine further trials. We interpreted their performance as insightful in the sense of being sensitive of the relevant functional properties of the task and thereby producing a new adaptive response without trial-and-error learning. Together, these findings contribute to the ongoing debate on the distribution of higher cognitive skills in the animal kingdom by showing high levels of sensorimotor intelligence in animals that do not use tools. In conclusion, we suggest that the 'Technical intelligence hypothesis' (Byrne, Machiavellian intelligence II: extensions and evaluations, pp 289-211, 1997), which has been proposed to explain the origin of the ape/monkey grade-shift in

  6. An image-based skeletal dosimetry model for the ICRP reference adult male--internal electron sources.

    PubMed

    Hough, Matthew; Johnson, Perry; Rajon, Didier; Jokisch, Derek; Lee, Choonsik; Bolch, Wesley

    2011-04-21

    In this study, a comprehensive electron dosimetry model of the adult male skeletal tissues is presented. The model is constructed using the University of Florida adult male hybrid phantom of Lee et al (2010 Phys. Med. Biol. 55 339-63) and the EGSnrc-based Paired Image Radiation Transport code of Shah et al (2005 J. Nucl. Med. 46 344-53). Target tissues include the active bone marrow, associated with radiogenic leukemia, and total shallow marrow, associated with radiogenic bone cancer. Monoenergetic electron emissions are considered over the energy range 1 keV to 10 MeV for the following sources: bone marrow (active and inactive), trabecular bone (surfaces and volumes), and cortical bone (surfaces and volumes). Specific absorbed fractions are computed according to the MIRD schema, and are given as skeletal-averaged values in the paper with site-specific values reported in both tabular and graphical format in an electronic annex available from http://stacks.iop.org/0031-9155/56/2309/mmedia. The distribution of cortical bone and spongiosa at the macroscopic dimensions of the phantom, as well as the distribution of trabecular bone and marrow tissues at the microscopic dimensions of the phantom, is imposed through detailed analyses of whole-body ex vivo CT images (1 mm resolution) and spongiosa-specific ex vivo microCT images (30 µm resolution), respectively, taken from a 40 year male cadaver. The method utilized in this work includes: (1) explicit accounting for changes in marrow self-dose with variations in marrow cellularity, (2) explicit accounting for electron escape from spongiosa, (3) explicit consideration of spongiosa cross-fire from cortical bone, and (4) explicit consideration of the ICRP's change in the surrogate tissue region defining the location of the osteoprogenitor cells (from a 10 µm endosteal layer covering the trabecular and cortical surfaces to a 50 µm shallow marrow layer covering trabecular and medullary cavity surfaces). Skeletal

  7. An image-based skeletal dosimetry model for the ICRP reference adult male—internal electron sources

    NASA Astrophysics Data System (ADS)

    Hough, Matthew; Johnson, Perry; Rajon, Didier; Jokisch, Derek; Lee, Choonsik; Bolch, Wesley

    2011-04-01

    In this study, a comprehensive electron dosimetry model of the adult male skeletal tissues is presented. The model is constructed using the University of Florida adult male hybrid phantom of Lee et al (2010 Phys. Med. Biol. 55 339-63) and the EGSnrc-based Paired Image Radiation Transport code of Shah et al (2005 J. Nucl. Med. 46 344-53). Target tissues include the active bone marrow, associated with radiogenic leukemia, and total shallow marrow, associated with radiogenic bone cancer. Monoenergetic electron emissions are considered over the energy range 1 keV to 10 MeV for the following sources: bone marrow (active and inactive), trabecular bone (surfaces and volumes), and cortical bone (surfaces and volumes). Specific absorbed fractions are computed according to the MIRD schema, and are given as skeletal-averaged values in the paper with site-specific values reported in both tabular and graphical format in an electronic annex available from http://stacks.iop.org/0031-9155/56/2309/mmedia. The distribution of cortical bone and spongiosa at the macroscopic dimensions of the phantom, as well as the distribution of trabecular bone and marrow tissues at the microscopic dimensions of the phantom, is imposed through detailed analyses of whole-body ex vivo CT images (1 mm resolution) and spongiosa-specific ex vivo microCT images (30 µm resolution), respectively, taken from a 40 year male cadaver. The method utilized in this work includes: (1) explicit accounting for changes in marrow self-dose with variations in marrow cellularity, (2) explicit accounting for electron escape from spongiosa, (3) explicit consideration of spongiosa cross-fire from cortical bone, and (4) explicit consideration of the ICRP's change in the surrogate tissue region defining the location of the osteoprogenitor cells (from a 10 µm endosteal layer covering the trabecular and cortical surfaces to a 50 µm shallow marrow layer covering trabecular and medullary cavity surfaces). Skeletal

  8. Formal models in animal-metacognition research: the problem of interpreting animals' behavior.

    PubMed

    Smith, J David; Zakrzewski, Alexandria C; Church, Barbara A

    2016-10-01

    Ongoing research explores whether animals have precursors to metacognition-that is, the capacity to monitor mental states or cognitive processes. Comparative psychologists have tested apes, monkeys, rats, pigeons, and a dolphin using perceptual, memory, foraging, and information-seeking paradigms. The consensus is that some species have a functional analog to human metacognition. Recently, though, associative modelers have used formal-mathematical models hoping to describe animals' "metacognitive" performances in associative-behaviorist ways. We evaluate these attempts to reify formal models as proof of particular explanations of animal cognition. These attempts misunderstand the content and proper application of models. They embody mistakes of scientific reasoning. They blur fundamental distinctions in understanding animal cognition. They impede theoretical development. In contrast, an energetic empirical enterprise is achieving strong success in describing the psychology underlying animals' metacognitive performances. We argue that this careful empirical work is the clear path to useful theoretical development. The issues raised here about formal modeling-in the domain of animal metacognition-potentially extend to biobehavioral research more broadly.

  9. Explicit dosimetry for 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a-mediated photodynamic therapy: macroscopic singlet oxygen modeling

    PubMed Central

    Penjweini, Rozhin; Liu, Baochang; Kim, Michele M.; Zhu, Timothy C.

    2015-01-01

    Abstract. Type II photodynamic therapy (PDT) is based on the photochemical reactions mediated through an interaction between a photosensitizer, ground-state oxygen ([O32]), and light excitation at an appropriate wavelength, which results in production of reactive singlet oxygen ([O12]rx). We use an empirical macroscopic model based on four photochemical parameters for the calculation of [O12]rx threshold concentration ([O12]rx,sh) causing tissue necrosis in tumors after PDT. For this reason, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-mediated PDT was performed interstitially on mice with radiation-induced fibrosarcoma (RIF) tumors. A linear light source at 665 nm with total energy released per unit length of 12 to 100  J/cm and source power per unit length (LS) of 12 to 150  mW/cm was used to induce different radii of necrosis. Then the amount of [O12]rx calculated by the macroscopic model incorporating explicit PDT dosimetry of light fluence distribution, tissue optical properties, and HPPH concentration was correlated to the necrotic radius to obtain the model parameters and [O12]rx,sh. We provide evidence that [O12]rx is a better dosimetric quantity for predicting the treatment outcome than PDT dose, which is proportional to the time integral of the products of the photosensitizer concentration and light fluence rate. PMID:26720883

  10. Explicit dosimetry for 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a-mediated photodynamic therapy: macroscopic singlet oxygen modeling

    NASA Astrophysics Data System (ADS)

    Penjweini, Rozhin; Liu, Baochang; Kim, Michele M.; Zhu, Timothy C.

    2015-12-01

    Type II photodynamic therapy (PDT) is based on the photochemical reactions mediated through an interaction between a photosensitizer, ground-state oxygen ([O]), and light excitation at an appropriate wavelength, which results in production of reactive singlet oxygen ([]rx). We use an empirical macroscopic model based on four photochemical parameters for the calculation of []rx threshold concentration ([]rx,sh) causing tissue necrosis in tumors after PDT. For this reason, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-mediated PDT was performed interstitially on mice with radiation-induced fibrosarcoma (RIF) tumors. A linear light source at 665 nm with total energy released per unit length of 12 to 100 J/cm and source power per unit length (LS) of 12 to 150 mW/cm was used to induce different radii of necrosis. Then the amount of []rx calculated by the macroscopic model incorporating explicit PDT dosimetry of light fluence distribution, tissue optical properties, and HPPH concentration was correlated to the necrotic radius to obtain the model parameters and []rx,sh. We provide evidence that []rx is a better dosimetric quantity for predicting the treatment outcome than PDT dose, which is proportional to the time integral of the products of the photosensitizer concentration and light fluence rate.

  11. Animal models of human respiratory syncytial virus disease.

    PubMed

    Bem, Reinout A; Domachowske, Joseph B; Rosenberg, Helene F

    2011-08-01

    Infection with the human pneumovirus pathogen, respiratory syncytial virus (hRSV), causes a wide spectrum of respiratory disease, notably among infants and the elderly. Laboratory animal studies permit detailed experimental modeling of hRSV disease and are therefore indispensable in the search for novel therapies and preventative strategies. Present animal models include several target species for hRSV, including chimpanzees, cattle, sheep, cotton rats, and mice, as well as alternative animal pneumovirus models, such as bovine RSV and pneumonia virus of mice. These diverse animal models reproduce different features of hRSV disease, and their utilization should therefore be based on the scientific hypothesis under investigation. The purpose of this review is to summarize the strengths and limitations of each of these animal models. Our intent is to provide a resource for investigators and an impetus for future research.

  12. Comparative Computational Modeling of Airflows and Vapor Dosimetry in the Respiratory Tracts of Rat, Monkey, and Human

    PubMed Central

    Corley, Richard A.

    2012-01-01

    Computational fluid dynamics (CFD) models are useful for predicting site-specific dosimetry of airborne materials in the respiratory tract and elucidating the importance of species differences in anatomy, physiology, and breathing patterns. We improved the imaging and model development methods to the point where CFD models for the rat, monkey, and human now encompass airways from the nose or mouth to the lung. A total of 1272, 2172, and 135 pulmonary airways representing 17±7, 19±9, or 9±2 airway generations were included in the rat, monkey and human models, respectively. A CFD/physiologically based pharmacokinetic model previously developed for acrolein was adapted for these anatomically correct extended airway models. Model parameters were obtained from the literature or measured directly. Airflow and acrolein uptake patterns were determined under steady-state inhalation conditions to provide direct comparisons with prior data and nasal-only simulations. Results confirmed that regional uptake was sensitive to airway geometry, airflow rates, acrolein concentrations, air:tissue partition coefficients, tissue thickness, and the maximum rate of metabolism. Nasal extraction efficiencies were predicted to be greatest in the rat, followed by the monkey, and then the human. For both nasal and oral breathing modes in humans, higher uptake rates were predicted for lower tracheobronchial tissues than either the rat or monkey. These extended airway models provide a unique foundation for comparing material transport and site-specific tissue uptake across a significantly greater range of conducting airways in the rat, monkey, and human than prior CFD models. PMID:22584687

  13. Ethological concepts enhance the translational value of animal models.

    PubMed

    Peters, Suzanne M; Pothuizen, Helen H J; Spruijt, Berry M

    2015-07-15

    The translational value of animal models is an issue of ongoing discussion. We argue that 'Refinement' of animal experiments is needed and this can be achieved by exploiting an ethological approach when setting up and conducting experiments. Ethology aims to assess the functional meaning of behavioral changes, due to experimental manipulation or treatment, in animal models. Although the use of ethological concepts is particularly important for studies involving the measurement of animal behavior (as is the case for most studies on neuro-psychiatric conditions), it will also substantially benefit other disciplines, such as those investigating the immune system or inflammatory response. Using an ethological approach also involves using more optimal testing conditions are employed that have a biological relevance to the animal. Moreover, using a more biological relevant analysis of the data will help to clarify the functional meaning of the modeled readout (e.g. whether it is psychopathological or adaptive in nature). We advocate for instance that more behavioral studies should use animals in group-housed conditions, including the recording of their ultrasonic vocalizations, because (1) social behavior is an essential feature of animal models for human 'social' psychopathologies, such as autism and schizophrenia, and (2) social conditions are indispensable conditions for appropriate behavioral studies in social species, such as the rat. Only when taking these elements into account, the validity of animal experiments and, thus, the translation value of animal models can be enhanced.

  14. Modeling the dosimetry of organ-at-risk in head and neck IMRT planning: An intertechnique and interinstitutional study

    SciTech Connect

    Lian, Jun Chera, Bhishamjit S.; Chang, Sha; Yuan, Lulin Yoo, David P.; Yin, FangFang; Wu, Q. Jackie; Ge, Yaorong

    2013-12-15

    Purpose: To build a statistical model to quantitatively correlate the anatomic features of structures and the corresponding dose-volume histogram (DVH) of head and neck (HN) Tomotherapy (Tomo) plans. To study if the model built upon one intensity modulated radiation therapy (IMRT) technique (such as conventional Linac) can be used to predict anticipated organs-at-risk (OAR) DVH of patients treated with a different IMRT technique (such as Tomo). To study if the model built upon the clinical experience of one institution can be used to aid IMRT planning for another institution. Methods: Forty-four Tomotherapy intensity modulate radiotherapy plans of HN cases (Tomo-IMRT) from Institution A were included in the study. A different patient group of 53 HN fixed gantry IMRT (FG-IMRT) plans was selected from Institution B. The analyzed OARs included the parotid, larynx, spinal cord, brainstem, and submandibular gland. Two major groups of anatomical features were considered: the volumetric information and the spatial information. The volume information includes the volume of target, OAR, and overlapped volume between target and OAR. The spatial information of OARs relative to PTVs was represented by the distance-to-target histogram (DTH). Important anatomical and dosimetric features were extracted from DTH and DVH by principal component analysis. Two regression models, one for Tomotherapy plan and one for IMRT plan, were built independently. The accuracy of intratreatment-modality model prediction was validated by a leave one out cross-validation method. The intertechnique and interinstitution validations were performed by using the FG-IMRT model to predict the OAR dosimetry of Tomo-IMRT plans. The dosimetry of OARs, under the same and different institutional preferences, was analyzed to examine the correlation between the model prediction and planning protocol. Results: Significant patient anatomical factors contributing to OAR dose sparing in HN Tomotherapy plans have been

  15. A new surrogate modeling technique combining Kriging and polynomial chaos expansions – Application to uncertainty analysis in computational dosimetry

    SciTech Connect

    Kersaudy, Pierric; Sudret, Bruno; Varsier, Nadège; Picon, Odile; Wiart, Joe

    2015-04-01

    In numerical dosimetry, the recent advances in high performance computing led to a strong reduction of the required computational time to assess the specific absorption rate (SAR) characterizing the human exposure to electromagnetic waves. However, this procedure remains time-consuming and a single simulation can request several hours. As a consequence, the influence of uncertain input parameters on the SAR cannot be analyzed using crude Monte Carlo simulation. The solution presented here to perform such an analysis is surrogate modeling. This paper proposes a novel approach to build such a surrogate model from a design of experiments. Considering a sparse representation of the polynomial chaos expansions using least-angle regression as a selection algorithm to retain the most influential polynomials, this paper proposes to use the selected polynomials as regression functions for the universal Kriging model. The leave-one-out cross validation is used to select the optimal number of polynomials in the deterministic part of the Kriging model. The proposed approach, called LARS-Kriging-PC modeling, is applied to three benchmark examples and then to a full-scale metamodeling problem involving the exposure of a numerical fetus model to a femtocell device. The performances of the LARS-Kriging-PC are compared to an ordinary Kriging model and to a classical sparse polynomial chaos expansion. The LARS-Kriging-PC appears to have better performances than the two other approaches. A significant accuracy improvement is observed compared to the ordinary Kriging or to the sparse polynomial chaos depending on the studied case. This approach seems to be an optimal solution between the two other classical approaches. A global sensitivity analysis is finally performed on the LARS-Kriging-PC model of the fetus exposure problem.

  16. A new surrogate modeling technique combining Kriging and polynomial chaos expansions - Application to uncertainty analysis in computational dosimetry

    NASA Astrophysics Data System (ADS)

    Kersaudy, Pierric; Sudret, Bruno; Varsier, Nadège; Picon, Odile; Wiart, Joe

    2015-04-01

    In numerical dosimetry, the recent advances in high performance computing led to a strong reduction of the required computational time to assess the specific absorption rate (SAR) characterizing the human exposure to electromagnetic waves. However, this procedure remains time-consuming and a single simulation can request several hours. As a consequence, the influence of uncertain input parameters on the SAR cannot be analyzed using crude Monte Carlo simulation. The solution presented here to perform such an analysis is surrogate modeling. This paper proposes a novel approach to build such a surrogate model from a design of experiments. Considering a sparse representation of the polynomial chaos expansions using least-angle regression as a selection algorithm to retain the most influential polynomials, this paper proposes to use the selected polynomials as regression functions for the universal Kriging model. The leave-one-out cross validation is used to select the optimal number of polynomials in the deterministic part of the Kriging model. The proposed approach, called LARS-Kriging-PC modeling, is applied to three benchmark examples and then to a full-scale metamodeling problem involving the exposure of a numerical fetus model to a femtocell device. The performances of the LARS-Kriging-PC are compared to an ordinary Kriging model and to a classical sparse polynomial chaos expansion. The LARS-Kriging-PC appears to have better performances than the two other approaches. A significant accuracy improvement is observed compared to the ordinary Kriging or to the sparse polynomial chaos depending on the studied case. This approach seems to be an optimal solution between the two other classical approaches. A global sensitivity analysis is finally performed on the LARS-Kriging-PC model of the fetus exposure problem.

  17. Animal Models of Tourette Syndrome—From Proliferation to Standardization

    PubMed Central

    Yael, Dorin; Israelashvili, Michal; Bar-Gad, Izhar

    2016-01-01

    Tourette syndrome (TS) is a childhood onset disorder characterized by motor and vocal tics and associated with multiple comorbid symptoms. Over the last decade, the accumulation of findings from TS patients and the emergence of new technologies have led to the development of novel animal models with high construct validity. In addition, animal models which were previously associated with other disorders were recently attributed to TS. The proliferation of TS animal models has accelerated TS research and provided a better understanding of the mechanism underlying the disorder. This newfound success generates novel challenges, since the conclusions that can be drawn from TS animal model studies are constrained by the considerable variation across models. Typically, each animal model examines a specific subset of deficits and centers on one field of research (physiology/genetics/pharmacology/etc.). Moreover, different studies do not use a standard lexicon to characterize different properties of the model. These factors hinder the evaluation of individual model validity as well as the comparison across models, leading to a formation of a fuzzy, segregated landscape of TS pathophysiology. Here, we call for a standardization process in the study of TS animal models as the next logical step. We believe that a generation of standard examination criteria will improve the utility of these models and enable their consolidation into a general framework. This should lead to a better understanding of these models and their relationship to TS, thereby improving the research of the mechanism underlying this disorder and aiding the development of new treatments. PMID:27065791

  18. Animal Models for Salmonellosis: Applications in Vaccine Research.

    PubMed

    Higginson, Ellen E; Simon, Raphael; Tennant, Sharon M

    2016-09-01

    Salmonellosis remains an important cause of human disease worldwide. While there are several licensed vaccines for Salmonella enterica serovar Typhi, these vaccines are generally ineffective against other Salmonella serovars. Vaccines that target paratyphoid and nontyphoidal Salmonella serovars are very much in need. Preclinical evaluation of candidate vaccines is highly dependent on the availability of appropriate scientific tools, particularly animal models. Many different animal models exist for various Salmonella serovars, from whole-animal models to smaller models, such as those recently established in insects. Here, we discuss various mouse, rat, rabbit, calf, primate, and insect models for Salmonella infection, all of which have their place in research. However, choosing the right model is imperative in selecting the best vaccine candidates for further clinical testing. In this minireview, we summarize the various animal models that are used to assess salmonellosis, highlight some of the advantages and disadvantages of each, and discuss their value in vaccine development.

  19. Animal Models for Salmonellosis: Applications in Vaccine Research

    PubMed Central

    Higginson, Ellen E.; Simon, Raphael

    2016-01-01

    Salmonellosis remains an important cause of human disease worldwide. While there are several licensed vaccines for Salmonella enterica serovar Typhi, these vaccines are generally ineffective against other Salmonella serovars. Vaccines that target paratyphoid and nontyphoidal Salmonella serovars are very much in need. Preclinical evaluation of candidate vaccines is highly dependent on the availability of appropriate scientific tools, particularly animal models. Many different animal models exist for various Salmonella serovars, from whole-animal models to smaller models, such as those recently established in insects. Here, we discuss various mouse, rat, rabbit, calf, primate, and insect models for Salmonella infection, all of which have their place in research. However, choosing the right model is imperative in selecting the best vaccine candidates for further clinical testing. In this minireview, we summarize the various animal models that are used to assess salmonellosis, highlight some of the advantages and disadvantages of each, and discuss their value in vaccine development. PMID:27413068

  20. Systematic Reviews of Animal Models: Methodology versus Epistemology

    PubMed Central

    Greek, Ray; Menache, Andre

    2013-01-01

    Systematic reviews are currently favored methods of evaluating research in order to reach conclusions regarding medical practice. The need for such reviews is necessitated by the fact that no research is perfect and experts are prone to bias. By combining many studies that fulfill specific criteria, one hopes that the strengths can be multiplied and thus reliable conclusions attained. Potential flaws in this process include the assumptions that underlie the research under examination. If the assumptions, or axioms, upon which the research studies are based, are untenable either scientifically or logically, then the results must be highly suspect regardless of the otherwise high quality of the studies or the systematic reviews. We outline recent criticisms of animal-based research, namely that animal models are failing to predict human responses. It is this failure that is purportedly being corrected via systematic reviews. We then examine the assumption that animal models can predict human outcomes to perturbations such as disease or drugs, even under the best of circumstances. We examine the use of animal models in light of empirical evidence comparing human outcomes to those from animal models, complexity theory, and evolutionary biology. We conclude that even if legitimate criticisms of animal models were addressed, through standardization of protocols and systematic reviews, the animal model would still fail as a predictive modality for human response to drugs and disease. Therefore, systematic reviews and meta-analyses of animal-based research are poor tools for attempting to reach conclusions regarding human interventions. PMID:23372426

  1. Systematic reviews of animal models: methodology versus epistemology.

    PubMed

    Greek, Ray; Menache, Andre

    2013-01-01

    Systematic reviews are currently favored methods of evaluating research in order to reach conclusions regarding medical practice. The need for such reviews is necessitated by the fact that no research is perfect and experts are prone to bias. By combining many studies that fulfill specific criteria, one hopes that the strengths can be multiplied and thus reliable conclusions attained. Potential flaws in this process include the assumptions that underlie the research under examination. If the assumptions, or axioms, upon which the research studies are based, are untenable either scientifically or logically, then the results must be highly suspect regardless of the otherwise high quality of the studies or the systematic reviews. We outline recent criticisms of animal-based research, namely that animal models are failing to predict human responses. It is this failure that is purportedly being corrected via systematic reviews. We then examine the assumption that animal models can predict human outcomes to perturbations such as disease or drugs, even under the best of circumstances. We examine the use of animal models in light of empirical evidence comparing human outcomes to those from animal models, complexity theory, and evolutionary biology. We conclude that even if legitimate criticisms of animal models were addressed, through standardization of protocols and systematic reviews, the animal model would still fail as a predictive modality for human response to drugs and disease. Therefore, systematic reviews and meta-analyses of animal-based research are poor tools for attempting to reach conclusions regarding human interventions.

  2. A Statistical Quality Model for Data-Driven Speech Animation.

    PubMed

    Ma, Xiaohan; Deng, Zhigang

    2012-11-01

    In recent years, data-driven speech animation approaches have achieved significant successes in terms of animation quality. However, how to automatically evaluate the realism of novel synthesized speech animations has been an important yet unsolved research problem. In this paper, we propose a novel statistical model (called SAQP) to automatically predict the quality of on-the-fly synthesized speech animations by various data-driven techniques. Its essential idea is to construct a phoneme-based, Speech Animation Trajectory Fitting (SATF) metric to describe speech animation synthesis errors and then build a statistical regression model to learn the association between the obtained SATF metric and the objective speech animation synthesis quality. Through delicately designed user studies, we evaluate the effectiveness and robustness of the proposed SAQP model. To the best of our knowledge, this work is the first-of-its-kind, quantitative quality model for data-driven speech animation. We believe it is the important first step to remove a critical technical barrier for applying data-driven speech animation techniques to numerous online or interactive talking avatar applications.

  3. The use of animal models in diabetes research

    PubMed Central

    King, Aileen JF

    2012-01-01

    Diabetes is a disease characterized by a relative or absolute lack of insulin, leading to hyperglycaemia. There are two main types of diabetes: type 1 diabetes and type 2 diabetes. Type 1 diabetes is due to an autoimmune destruction of the insulin-producing pancreatic beta cells, and type 2 diabetes is caused by insulin resistance coupled by a failure of the beta cell to compensate. Animal models for type 1 diabetes range from animals with spontaneously developing autoimmune diabetes to chemical ablation of the pancreatic beta cells. Type 2 diabetes is modelled in both obese and non-obese animal models with varying degrees of insulin resistance and beta cell failure. This review outlines some of the models currently used in diabetes research. In addition, the use of transgenic and knock-out mouse models is discussed. Ideally, more than one animal model should be used to represent the diversity seen in human diabetic patients. LINKED ARTICLES Animal Models This paper is the latest in a series of publications on the use of animal models in pharmacology research. Readers might be interested in the previous papers. Robinson V (2009). Less is more: reducing the reliance on animal models for nausea and vomiting research. Holmes AM, Rudd JA, Tattersall FD, Aziz Q, Andrews PLR (2009). Opportunities for the replacement of animals in the study of nausea and vomiting. Giacomotto J and Ségalat L (2010). High-throughput screening and small animal models, where are we? McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL (2010). Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG (2010). The ARRIVE guidelines. Emerson M (2010). Refinement, reduction and replacement approaches to in vivo cardiovascular research. Berge O-G (2011). Predictive validity of behavioural animal models for chronic pain. Vickers SP, Jackson HC and Cheetham SC (2011). The utility of animal models to evaluate

  4. Nephrectomized and hepatectomized animal models as tools in preclinical pharmacokinetics.

    PubMed

    Vestergaard, Bill; Agersø, Henrik; Lykkesfeldt, Jens

    2013-08-01

    Early understanding of the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in to the drug development process. In vitro methodologies can be used to investigate metabolic patterns, but in general, they lack several aspects of the whole-body physiology. In contrast, the complexity of intact animals does not necessarily allow individual processes to be identified. Animal models lacking a major excretion organ can be used to investigate these individual metabolic processes. Animal models of nephrectomy and hepatectomy have considerable potential as tools in preclinical pharmacokinetics to assess organs of importance for drug clearance and thereby knowledge of potential metabolic processes to manipulate to improve pharmacokinetic properties of the molecules. Detailed knowledge of anatomy and surgical techniques is crucial to successfully establish the models, and a well-balanced anaesthesia and adequate monitoring of the animals are also of major importance. An obvious drawback of animal models lacking an organ is the disruption of normal homoeostasis and the induction of dramatic and ultimately mortal systemic changes in the animals. Refining of the surgical techniques and the post-operative supportive care of the animals can increase the value of these models by minimizing the systemic changes induced, and thorough validation of nephrectomy and hepatectomy models is needed before use of such models as a tool in preclinical pharmacokinetics. The present MiniReview discusses pros and cons of the available techniques associated with establishing nephrectomy and hepatectomy models.

  5. Reviewing model application to support animal health decision making.

    PubMed

    Singer, Alexander; Salman, Mo; Thulke, Hans-Hermann

    2011-04-01

    Animal health is of societal importance as it affects human welfare, and anthropogenic interests shape decision making to assure animal health. Scientific advice to support decision making is manifold. Modelling, as one piece of the scientific toolbox, is appreciated for its ability to describe and structure data, to give insight in complex processes and to predict future outcome. In this paper we study the application of scientific modelling to support practical animal health decisions. We reviewed the 35 animal health related scientific opinions adopted by the Animal Health and Animal Welfare Panel of the European Food Safety Authority (EFSA). Thirteen of these documents were based on the application of models. The review took two viewpoints, the decision maker's need and the modeller's approach. In the reviewed material three types of modelling questions were addressed by four specific model types. The correspondence between tasks and models underpinned the importance of the modelling question in triggering the modelling approach. End point quantifications were the dominating request from decision makers, implying that prediction of risk is a major need. However, due to knowledge gaps corresponding modelling studies often shed away from providing exact numbers. Instead, comparative scenario analyses were performed, furthering the understanding of the decision problem and effects of alternative management options. In conclusion, the most adequate scientific support for decision making - including available modelling capacity - might be expected if the required advice is clearly stated.

  6. Animator

    ERIC Educational Resources Information Center

    Tech Directions, 2008

    2008-01-01

    Art and animation work is the most significant part of electronic game development, but is also found in television commercials, computer programs, the Internet, comic books, and in just about every visual media imaginable. It is the part of the project that makes an abstract design idea concrete and visible. Animators create the motion of life in…

  7. Animal models of henipavirus infection: a review.

    PubMed

    Weingartl, Hana M; Berhane, Yohannes; Czub, Markus

    2009-09-01

    Hendra virus (HeV) and Nipah virus (NiV) form a separate genus Henipavirus within the family Paramyxoviridae, and are classified as biosafety level four pathogens due to their high case fatality rate following human infection and because of the lack of effective vaccines or therapy. Both viruses emerged from their natural reservoir during the last decade of the 20th century, causing severe disease in humans, horses and swine, and infecting a number of other mammalian species. The current review summarises current published data relating to experimental infection of small and large animals, including the natural reservoir species, the Pteropus bat, with HeV or NiV. Susceptibility to infection and virus distribution in the individual species is discussed, along with the pathogenesis, pathological changes, and potential routes of transmission.

  8. Large animal models for vaccine development and testing.

    PubMed

    Gerdts, Volker; Wilson, Heather L; Meurens, Francois; van Drunen Littel-van den Hurk, Sylvia; Wilson, Don; Walker, Stewart; Wheler, Colette; Townsend, Hugh; Potter, Andrew A

    2015-01-01

    The development of human vaccines continues to rely on the use of animals for research. Regulatory authorities require novel vaccine candidates to undergo preclinical assessment in animal models before being permitted to enter the clinical phase in human subjects. Substantial progress has been made in recent years in reducing and replacing the number of animals used for preclinical vaccine research through the use of bioinformatics and computational biology to design new vaccine candidates. However, the ultimate goal of a new vaccine is to instruct the immune system to elicit an effective immune response against the pathogen of interest, and no alternatives to live animal use currently exist for evaluation of this response. Studies identifying the mechanisms of immune protection; determining the optimal route and formulation of vaccines; establishing the duration and onset of immunity, as well as the safety and efficacy of new vaccines, must be performed in a living system. Importantly, no single animal model provides all the information required for advancing a new vaccine through the preclinical stage, and research over the last two decades has highlighted that large animals more accurately predict vaccine outcome in humans than do other models. Here we review the advantages and disadvantages of large animal models for human vaccine development and demonstrate that much of the success in bringing a new vaccine to market depends on choosing the most appropriate animal model for preclinical testing.

  9. Current animal models of obsessive compulsive disorder: an update.

    PubMed

    Albelda, N; Joel, D

    2012-06-01

    During the last 30 years there have been many attempts to develop animal models of obsessive compulsive disorder (OCD), in the hope that they may provide a route for furthering our understanding and treatment of this disorder. The present review provides the reader with an overview of the currently active animal models of OCD, their strengths and limitations, so that the reader can use the review as a guide for establishing new animal models of OCD, evaluating existing animal models and choosing among them according to one's needs. We review current genetic, pharmacological, neurodevelopmental and behavioral animal models of OCD, and evaluate their face validity (derived from phenomenological similarity between the behavior in the animal model and the specific symptoms of the human condition), predictive validity (derived from similarity in response to treatment) and construct validity (derived from similarity in the underlying mechanisms [physiological or psychological]). On the basis of this evaluation we discuss the usefulness of the different models for screening drugs for anti-compulsive activity, detecting new targets for high frequency stimulation, studying the neural mechanisms of OCD and unraveling the role of gonadal hormones. We then describe potential new treatment strategies that emerge from the convergence of data obtained in different models on the one hand, and how different models can be used to model different subtypes or dimensions of OCD, on the other hand.

  10. Preclinical animal models of multiple myeloma

    PubMed Central

    Lwin, Seint T; Edwards, Claire M; Silbermann, Rebecca

    2016-01-01

    Multiple myeloma is an incurable plasma-cell malignancy characterized by osteolytic bone disease and immunosuppression. Murine models of multiple myeloma and myeloma bone disease are critical tools for an improved understanding of the pathogenesis of the disease and the development of novel therapeutic strategies. This review will cover commonly used immunocompetent and xenograft models of myeloma, describing the advantages and disadvantages of each model system. In addition, this review provides detailed protocols for establishing systemic and local models of myeloma using both murine and human myeloma cell lines. PMID:26909147

  11. Social defeat as an animal model for depression.

    PubMed

    Hollis, Fiona; Kabbaj, Mohamed

    2014-01-01

    Depression is one of the most disabling medical conditions in the world today, yet its etiologies remain unclear and current treatments are not wholly effective. Animal models are a powerful tool to investigate possible causes and treatments for human diseases. We describe an animal model of social defeat as a possible model for human depression. We discuss the paradigm, behavioral correlates to depression, and potential underlying neurobiological mechanisms with an eye toward possible future therapies.

  12. Reproducibility Issues: Avoiding Pitfalls in Animal Inflammation Models.

    PubMed

    Laman, Jon D; Kooistra, Susanne M; Clausen, Björn E

    2017-01-01

    In light of an enhanced awareness of ethical questions and ever increasing costs when working with animals in biomedical research, there is a dedicated and sometimes fierce debate concerning the (lack of) reproducibility of animal models and their relevance for human inflammatory diseases. Despite evident advancements in searching for alternatives, that is, replacing, reducing, and refining animal experiments-the three R's of Russel and Burch (1959)-understanding the complex interactions of the cells of the immune system, the nervous system and the affected tissue/organ during inflammation critically relies on in vivo models. Consequently, scientific advancement and ultimately novel therapeutic interventions depend on improving the reproducibility of animal inflammation models. As a prelude to the remaining hands-on protocols described in this volume, here, we summarize potential pitfalls of preclinical animal research and provide resources and background reading on how to avoid them.

  13. Implementation and validation of a fluence pencil kernels model for GaN-based dosimetry in photon beam radiotherapy

    NASA Astrophysics Data System (ADS)

    Wang, Ruoxi; Pittet, Patrick; Ribouton, Julien; Lu, Guo-Neng; Chaikh, Abdulhamid; Ahnesjö, Anders

    2013-10-01

    Gallium nitride (GaN), a direct-gap semiconductor that is radioluminescent, can be used as a transducer yielding a high signal from a small detecting volume and thus potentially suitable for use in small fields and for high dose gradients. A common drawback of semiconductor dosimeters with effective atomic numbers higher than soft tissues is that their responses depend on the presence of low energy photons for which the photoelectric cross section varies strongly with atomic number, which may affect the accuracy of dosimetric measurements. To tackle this ‘over-response’ issue, we propose a model for GaN-based dosimetry with readout correction. The local photon spectrum is calculated by convolving fluence pencil kernel spectra with the beam aperture fluence distribution. The response of a GaN detector is modelled by combining large cavity theory and small cavity theory for the low and high energy components of the local spectrum. Monte Carlo simulations are employed for determination of specific correction factors for different GaN transducer sizes and irradiation conditions. Some model parameters such as the cut-off energy and partitioning energy are discussed. The accuracy of the GaN dosimetric response model has been evaluated for tissue phantom ratio experiments along the central axis. These experiments have shown that calculated and measured GaN responses stay within ±3% at all depths beyond the build-up depth. The calculated GaN response factor is also in good agreement with measured data (±2.5%). The validated model with response compensation improves significantly the accuracy of dosimetric measurements: below 2.5% deviation as compared to 13% without compensation, for a 10 × 10 cm2 field, at depth from 1.5 to 22 cm.

  14. Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology.

    PubMed

    Olivier, Alicia K; Gibson-Corley, Katherine N; Meyerholz, David K

    2015-03-15

    Multiple organ systems, including the gastrointestinal tract, pancreas, and hepatobiliary systems, are affected by cystic fibrosis (CF). Many of these changes begin early in life and are difficult to study in young CF patients. Recent development of novel CF animal models has expanded opportunities in the field to better understand CF pathogenesis and evaluate traditional and innovative therapeutics. In this review, we discuss manifestations of CF disease in gastrointestinal, pancreatic, and hepatobiliary systems of humans and animal models. We also compare the similarities and limitations of animal models and discuss future directions for modeling CF.

  15. Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology

    PubMed Central

    Olivier, Alicia K.; Gibson-Corley, Katherine N.

    2015-01-01

    Multiple organ systems, including the gastrointestinal tract, pancreas, and hepatobiliary systems, are affected by cystic fibrosis (CF). Many of these changes begin early in life and are difficult to study in young CF patients. Recent development of novel CF animal models has expanded opportunities in the field to better understand CF pathogenesis and evaluate traditional and innovative therapeutics. In this review, we discuss manifestations of CF disease in gastrointestinal, pancreatic, and hepatobiliary systems of humans and animal models. We also compare the similarities and limitations of animal models and discuss future directions for modeling CF. PMID:25591863

  16. LET dependence of the response of EBT2 films in proton dosimetry modeled as a bimolecular chemical reaction

    NASA Astrophysics Data System (ADS)

    Perles, L. A.; Mirkovic, D.; Anand, A.; Titt, U.; Mohan, R.

    2013-12-01

    The dose response for films exposed to clinical x-ray beams is not linear and a calibration curve based on absorbed dose can be used to account for this effect. However for proton dosimetry the dose response of films exhibits an additional dependence because of the variation of the linear energy transfer (LET) as the protons penetrate matter. In the present study, we hypothesized that the dose response for EBT2 films can be mathematically described as a bimolecular chemical reaction. Furthermore, we have shown that the LET effect can be incorporated in the dose-response curve. A set of EBT2 films was exposed to pristine 161.6 MeV proton beams. The films were exposed to doses ranging from 0.93 to 14.82 Gy at a depth of 2 cm in water. The procedure was repeated with one film exposed to a lower energy beam (85.6 MeV). We also computed the LET and dose to water in the sensitive layer of the films with a validated Monte Carlo system, taking into account the film construction (polyester, adhesive and sensitive layers). The bimolecular model was able to accurately fit the experimental data with a correlation factor of 0.9998, and the LET correction factor was determined and incorporated into the dose-response function. We also concluded that the film orientation is important when determining the LET correction factor because of the asymmetric construction of the film.

  17. Alpha-synuclein propagation: New insights from animal models.

    PubMed

    Dehay, Benjamin; Vila, Miquel; Bezard, Erwan; Brundin, Patrik; Kordower, Jeffrey H

    2016-02-01

    Aggregation of alpha-synuclein is implicated in several neurodegenerative diseases collectively termed synucleinopathies. Emerging evidence strongly implicates cell-to-cell transmission of misfolded alpha-synuclein as a common pathogenetic mechanism in synucleinopathies. The impact of alpha-synuclein pathology on neuronal dysfunction and behavioral impairments is being explored in animal models. This review provides an update on how research in animal models supports the concept that misfolded alpha-synuclein spreads from cell to cell and describes how findings in animal models might relate to the disease process in humans. Finally, we discuss the current underlying molecular and cellular mechanisms and future therapeutic strategies targeting alpha-synuclein propagation.

  18. A systematic review of animal models for Staphylococcus aureus osteomyelitis

    PubMed Central

    Reizner, W.; Hunter, J.G.; O’Malley, N.T.; Southgate, R.D.; Schwarz, E.M.; Kates, S.L.

    2015-01-01

    Staphylococcus aureus (S. aureus) osteomyelitis is a significant complication for orthopaedic patients undergoing surgery, particularly with fracture fixation and arthroplasty. Given the difficulty in studying S. aureus infections in human subjects, animal models serve an integral role in exploring the pathogenesis of osteomyelitis, and aid in determining the efficacy of prophylactic and therapeutic treatments. Animal models should mimic the clinical scenarios seen in patients as closely as possible to permit the experimental results to be translated to the corresponding clinical care. To help understand existing animal models of S. aureus, we conducted a systematic search of PubMed & Ovid MEDLINE to identify in vivo animal experiments that have investigated the management of S. aureus osteomyelitis in the context of fractures and metallic implants. In this review, experimental studies are categorized by animal species and are further classified by the setting of the infection. Study methods are summarized and the relevant advantages and disadvantages of each species and model are discussed. While no ideal animal model exists, the understanding of a model’s strengths and limitations should assist clinicians and researchers to appropriately select an animal model to translate the conclusions to the clinical setting. PMID:24668594

  19. Animal Models of Psychosis: Current State and Future Directions

    PubMed Central

    Forrest, Alexandra D.; Coto, Carlos A.; Siegel, Steven J.

    2014-01-01

    Psychosis is an abnormal mental state characterized by disorganization, delusions and hallucinations. Animal models have become an increasingly important research tool in the effort to understand both the underlying pathophysiology and treatment of psychosis. There are multiple animal models for psychosis, with each formed by the coupling of a manipulation and a measurement. In this manuscript we do not address the diseases of which psychosis is a prominent comorbidity. Instead, we summarize the current state of affairs and future directions for animal models of psychosis. To accomplish this, our manuscript will first discuss relevant behavioral and electrophysiological measurements. We then provide an overview of the different manipulations that are combined with these measurements to produce animal models. The strengths and limitations of each model will be addressed in order to evaluate its cross-species comparability. PMID:25215267

  20. [Genetically modified animals as model systems of psoriasis].

    PubMed

    Soboleva, A G; Mezentsev, A V; Bruskin, S A

    2014-01-01

    Psoriasis is a chronic autoimmune skin disorder. Experimental models of psoriasis can be used to study the disease in controlled conditions. Moreover, the experimental models allow to study a certain aspect of the pathological process. Although none of the multiple mouse models reproduces the human disease precisely, lab animals as model systems can be very helpful because of two reasons. First, introduction of new mutations into animal genome allows to reveal the new genes that may play a certain role in pathogenesis of the disease. Second, the experiments that are carried on the lab animals can be used for testing the new drugs and selection of the most efficient chemical agents from a variety of the proposed experimental preparations. The aim of this paper was to summarize the data on the lab animals that serve as experimental models of psoriasis.

  1. Animal models in epigenetic research: institutional animal care and use committee considerations across the lifespan.

    PubMed

    Harris, Craig

    2012-01-01

    The rapid expansion and evolution of epigenetics as a core scientific discipline have raised new questions about how endogenous and environmental factors can inform the mechanisms through which biological form and function are regulated. Existing and proposed animal models used for epigenetic research have targeted a myriad of health and disease endpoints that may be acute, chronic, and transgenerational in nature. Initiating events and outcomes may extend across the entire lifespan to elicit unanticipated phenotypes that are of particular concern to institutional animal care and use committees (IACUCs). The dynamics and plasticity of epigenetic mechanisms produce effects and consequences that are manifest differentially within discreet spatial and temporal contexts, including prenatal development, stem cells, assisted reproductive technologies, production of sexual dimorphisms, senescence, and others. Many dietary and nutritional interventions have also been shown to have a significant impact on biological functions and disease susceptibilities through altered epigenetic programming. The environmental, chemical, toxic, therapeutic, and psychosocial stressors used in animal studies to elicit epigenetic changes can become extreme and should raise IACUC concerns for the well-being and proper care of all research animals involved. Epigenetics research is rapidly becoming an integral part of the search for mechanisms in every major area of biomedical and behavioral research and will foster the continued development of new animal models. From the IACUC perspective, care must be taken to acknowledge the particular needs and concerns created by superimposition of epigenetic mechanisms over diverse fields of investigation to ensure the proper care and use of animals without impeding scientific progress.

  2. Emerging preclinical animal models for FSHD

    PubMed Central

    Lek, Angela; Rahimov, Fedik; Jones, Peter L.; Kunkel, Louis M.

    2015-01-01

    Facioscapulohumeral dystrophy (FSHD) is a unique and complex genetic disease that is not entirely solved. Recent advances in the field have led to a consensus genetic premise for the disorder, enabling researchers to now pursue the design of preclinical models. In this review, we explore all available FSHD models (DUX4-dependent and -independent) for their utility in therapeutic discovery and potential to yield novel disease insights. Due to the complex nature of FSHD, there is currently no single model that accurately recapitulates the genetic and pathophysiological spectrum of the disorder. Existing models are limited to emphasize only specific aspects of the disease, thus highlighting the need for more collaborative research and novel paradigms to advance the translational research space of FSHD. PMID:25801126

  3. Animal models for testing anti-prion drugs.

    PubMed

    Fernández-Borges, Natalia; Elezgarai, Saioa R; Eraña, Hasier; Castilla, Joaquín

    2013-01-01

    Prion diseases belong to a group of fatal infectious diseases with no effective therapies available. Throughout the last 35 years, less than 50 different drugs have been tested in different experimental animal models without hopeful results. An important limitation when searching for new drugs is the existence of appropriate models of the disease. The three different possible origins of prion diseases require the existence of different animal models for testing anti-prion compounds. Wild type, over-expressing transgenic mice and other more sophisticated animal models have been used to evaluate a diversity of compounds which some of them were previously tested in different in vitro experimental models. The complexity of prion diseases will require more pre-screening studies, reliable sporadic (or spontaneous) animal models and accurate chemical modifications of the selected compounds before having an effective therapy against human prion diseases. This review is intended to put on display the more relevant animal models that have been used in the search of new antiprion therapies and describe some possible procedures when handling chemical compounds presumed to have anti-prion activity prior to testing them in animal models.

  4. Exploring the Validity of Valproic Acid Animal Model of Autism

    PubMed Central

    Mabunga, Darine Froy N.; Gonzales, Edson Luck T.; Kim, Ji-woon; Kim, Ki Chan

    2015-01-01

    The valproic acid (VPA) animal model of autism spectrum disorder (ASD) is one of the most widely used animal model in the field. Like any other disease models, it can't model the totality of the features seen in autism. Then, is it valid to model autism? This model demonstrates many of the structural and behavioral features that can be observed in individuals with autism. These similarities enable the model to define relevant pathways of developmental dysregulation resulting from environmental manipulation. The uncovering of these complex pathways resulted to the growing pool of potential therapeutic candidates addressing the core symptoms of ASD. Here, we summarize the validity points of VPA that may or may not qualify it as a valid animal model of ASD. PMID:26713077

  5. Why test animals to treat humans? On the validity of animal models.

    PubMed

    Shelley, Cameron

    2010-09-01

    Critics of animal modeling have advanced a variety of arguments against the validity of the practice. The point of one such form of argument is to establish that animal modeling is pointless and therefore immoral. In this article, critical arguments of this form are divided into three types, the pseudoscience argument, the disanalogy argument, and the predictive validity argument. I contend that none of these criticisms currently succeed, nor are they likely to. However, the connection between validity and morality is important, suggesting that critical efforts would be instructive if they addressed it in a more nuanced way.

  6. Animal models of substance abuse and addiction: implications for science, animal welfare, and society.

    PubMed

    Lynch, Wendy J; Nicholson, Katherine L; Dance, Mario E; Morgan, Richard W; Foley, Patricia L

    2010-06-01

    Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial areas of biology, pathophysiology, clinical treatments, and drug screening for abuse liability; and discusses some of the unique veterinary, husbandry, and IACUC challenges associated with these models.

  7. Thin film tritium dosimetry

    DOEpatents

    Moran, Paul R.

    1976-01-01

    The present invention provides a method for tritium dosimetry. A dosimeter comprising a thin film of a material having relatively sensitive RITAC-RITAP dosimetry properties is exposed to radiation from tritium, and after the dosimeter has been removed from the source of the radiation, the low energy electron dose deposited in the thin film is determined by radiation-induced, thermally-activated polarization dosimetry techniques.

  8. Animal model: dysmorphogenesis and death in a chicken embryo model.

    PubMed

    Fineman, R M; Schoenwolf, G C

    1987-07-01

    The chicken embryo is a useful animal model for investigating problems in developmental biology and teratology. Here we report data that further define the causes of 2 different patterns of malformation (one associated with amnion abnormalities, the other with isolated neural tube defects) and death induced by making a window in the shell and subshell membranes during the first day of incubation. The interpretation of these data suggests to us the following hypotheses. An early amnion deficit spectrum or syndrome (EADS) in chicken embryos is caused by a brief (less than 10 sec) perturbation that occurs during the windowing procedure. This perturbation results in an acute increase in mechanical tension to the developing embryo and support structures, dehydration localized to the area of the blastoderm, and/or increased friction between the blastoderm and overlying vitelline and shell membranes. Isolated neural tube defects (NTDs) are caused by a longer perturbation (greater than 3 hr) consisting of increased mechanical stress across the blastoderm. The mechanical stress is associated with the introduction of a new air space over the animal pole of the yolk during windowing. The new air space causes the shape of the yolk to change (ie, to be deformed), resulting in an increase in mechanical tension across the vitelline membrane and blastoderm. NTDs involving the head are associated with significant early embryonic mortality, whereas those involving the trunk are not. Death may also be caused by cardiovascular anomalies observed in EADS. It is concluded that disturbances in morphogenesis and death in this model are, therefore, the result of extrinsic forces (eg, mechanical stress, localized dehydration, or friction) acting on different tissue types at various critical times in development. Intensity and duration of these forces on the developing blastoderm are important variables.

  9. ASSESSMENT OF VENOUS THROMBOSIS IN ANIMAL MODELS

    PubMed Central

    SP, Grover; CE, Evans; AS, Patel; B, Modarai; P, Saha; A, Smith

    2016-01-01

    Deep vein thrombosis and common complications, including pulmonary embolism and post thrombotic syndrome, represent a major source of morbidity and mortality worldwide. Experimental models of venous thrombosis have provided considerable insight into the cellular and molecular mechanisms that regulate thrombus formation and subsequent resolution. Here we critically appraise the ex vivo and in vivo techniques used to assess venous thrombosis in these models. Particular attention is paid to imaging modalities, including magnetic resonance imaging, micro computed tomography and high frequency ultrasound that facilitate longitudinal assessment of thrombus size and composition. PMID:26681755

  10. Animal models for screening anxiolytic-like drugs: a perspective

    PubMed Central

    Bourin, Michel

    2015-01-01

    Contemporary biological psychiatry uses experimental animal models to increase our understanding of affective disorder pathogenesis. Modern anxiolytic drug discovery mainly targets specific pathways and molecular determinants within a single phenotypic domain. However, greater understanding of the mechanisms of action is possible through animal models. Primarily developed with rats, animal models in anxiety have been adapted with mixed success for mice, easy-to-use mammals with better genetic possibilities than rats. In this review, we focus on the three most common animal models of anxiety in mice used in the screening of anxiolytics. Both conditioned and unconditioned models are described, in order to represent all types of animal models of anxiety. Behavioral studies require careful attention to variable parameters linked to environment, handling, or paradigms; this is also discussed. Finally, we focus on the consequences of re-exposure to the apparatus. Test-retest procedures can provide new answers, but should be intensively studied in order to revalidate the entire paradigm as an animal model of anxiety. PMID:26487810

  11. Animal models for screening anxiolytic-like drugs: a perspective.

    PubMed

    Bourin, Michel

    2015-09-01

    Contemporary biological psychiatry uses experimental animal models to increase our understanding of affective disorder pathogenesis. Modern anxiolytic drug discovery mainly targets specific pathways and molecular determinants within a single phenotypic domain. However, greater understanding of the mechanisms of action is possible through animal models. Primarily developed with rats, animal models in anxiety have been adapted with mixed success for mice, easy-to-use mammals with better genetic possibilities than rats. In this review, we focus on the three most common animal models of anxiety in mice used in the screening of anxiolytics. Both conditioned and unconditioned models are described, in order to represent all types of animal models of anxiety. Behavioral studies require careful attention to variable parameters linked to environment, handling, or paradigms; this is also discussed. Finally, we focus on the consequences of re-exposure to the apparatus. Test-retest procedures can provide new answers, but should be intensively studied in order to revalidate the entire paradigm as an animal model of anxiety.

  12. Animal Models in Cardiovascular Research: Hypertension and Atherosclerosis

    PubMed Central

    Ng, Chun-Yi; Jaarin, Kamsiah

    2015-01-01

    Hypertension and atherosclerosis are among the most common causes of mortality in both developed and developing countries. Experimental animal models of hypertension and atherosclerosis have become a valuable tool for providing information on etiology, pathophysiology, and complications of the disease and on the efficacy and mechanism of action of various drugs and compounds used in treatment. An animal model has been developed to study hypertension and atherosclerosis for several reasons. Compared to human models, an animal model is easily manageable, as compounding effects of dietary and environmental factors can be controlled. Blood vessels and cardiac tissue samples can be taken for detailed experimental and biomolecular examination. Choice of animal model is often determined by the research aim, as well as financial and technical factors. A thorough understanding of the animal models used and complete analysis must be validated so that the data can be extrapolated to humans. In conclusion, animal models for hypertension and atherosclerosis are invaluable in improving our understanding of cardiovascular disease and developing new pharmacological therapies. PMID:26064920

  13. Animal models for arthritis: innovative tools for prevention and treatment.

    PubMed

    Kollias, George; Papadaki, Piyi; Apparailly, Florence; Vervoordeldonk, Margriet J; Holmdahl, Rikard; Baumans, Vera; Desaintes, Christian; Di Santo, James; Distler, Jörg; Garside, Paul; Hegen, Martin; Huizinga, Tom W J; Jüngel, Astrid; Klareskog, Lars; McInnes, Iain; Ragoussis, Ioannis; Schett, Georg; Hart, Bert 't; Tak, Paul P; Toes, Rene; van den Berg, Wim; Wurst, Wolfgang; Gay, Steffen

    2011-08-01

    The development of novel treatments for rheumatoid arthritis (RA) requires the interplay between clinical observations and studies in animal models. Given the complex molecular pathogenesis and highly heterogeneous clinical picture of RA, there is an urgent need to dissect its multifactorial nature and to propose new strategies for preventive, early and curative treatments. Research on animal models has generated new knowledge on RA pathophysiology and aetiology and has provided highly successful paradigms for innovative drug development. Recent focus has shifted towards the discovery of novel biomarkers, with emphasis on presymptomatic and emerging stages of human RA, and towards addressing the pathophysiological mechanisms and subsequent efficacy of interventions that underlie different disease variants. Shifts in the current paradigms underlying RA pathogenesis have also led to increased demand for new (including humanised) animal models. There is therefore an urgent need to integrate the knowledge on human and animal models with the ultimate goal of creating a comprehensive 'pathogenesis map' that will guide alignment of existing and new animal models to the subset of disease they mimic. This requires full and standardised characterisation of all models at the genotypic, phenotypic and biomarker level, exploiting recent technological developments in 'omics' profiling and computational biology as well as state of the art bioimaging. Efficient integration and dissemination of information and resources as well as outreach to the public will be necessary to manage the plethora of data accumulated and to increase community awareness and support for innovative animal model research in rheumatology.

  14. Laboratory animal models for human Taenia solium.

    PubMed

    Avila, Guillermina; Teran, Nancy; Aguilar-Vega, Laura; Maravilla, Pablo; Mata-Miranda, Pilar; Flisser, Ana

    2006-01-01

    Human beings are the only hosts of adult Taenia solium; thus, many aspects of the host-parasite relationship are unknown. The development of successful experimental models of taeniasis allows in-depth investigations of the host-parasite relationship. We established experimental models in hamsters, gerbils and chinchillas. Here we review our findings regarding the characteristics of the tapeworms, their anchoring site and development, as well as the humoral and cellular immune response they elicit. We also used statistics to analyze the data obtained in different infections performed along several years. Furthermore, we compared the size of T. solium rostellum and strobila recovered from hamsters and gerbils to those obtained from humans. Our data indicate that these rodents are adequate experimental models for studying T. solium in its adult stage; that parasites induce immune responses and that hamsters seem to be more permissive hosts than gerbils, since parasites survive for longer times, grow longer and develop more, and the inflammatory response in the intestinal mucosa against T. solium is moderate. Finally, chinchillas are the most successful experimental definitive model for adult T. solium, since tapeworms with gravid proglottids are obtained, and the life cycle can be continued to the intermediate host.

  15. Mathematical modelling of animate and intentional motion.

    PubMed Central

    Rittscher, Jens; Blake, Andrew; Hoogs, Anthony; Stein, Gees

    2003-01-01

    Our aim is to enable a machine to observe and interpret the behaviour of others. Mathematical models are employed to describe certain biological motions. The main challenge is to design models that are both tractable and meaningful. In the first part we will describe how computer vision techniques, in particular visual tracking, can be applied to recognize a small vocabulary of human actions in a constrained scenario. Mainly the problems of viewpoint and scale invariance need to be overcome to formalize a general framework. Hence the second part of the article is devoted to the question whether a particular human action should be captured in a single complex model or whether it is more promising to make extensive use of semantic knowledge and a collection of low-level models that encode certain motion primitives. Scene context plays a crucial role if we intend to give a higher-level interpretation rather than a low-level physical description of the observed motion. A semantic knowledge base is used to establish the scene context. This approach consists of three main components: visual analysis, the mapping from vision to language and the search of the semantic database. A small number of robust visual detectors is used to generate a higher-level description of the scene. The approach together with a number of results is presented in the third part of this article. PMID:12689374

  16. Animal models of frailty: current applications in clinical research.

    PubMed

    Kane, Alice E; Hilmer, Sarah N; Mach, John; Mitchell, Sarah J; de Cabo, Rafael; Howlett, Susan E

    2016-01-01

    The ethical, logistical, and biological complications of working with an older population of people inherently limits clinical studies of frailty. The recent development of animal models of frailty, and tools for assessing frailty in animal models provides an invaluable opportunity for frailty research. This review summarizes currently published animal models of frailty including the interleukin-10 knock-out mouse, the mouse frailty phenotype assessment tool, and the mouse clinical frailty index. It discusses both current and potential roles of these models in research into mechanisms of frailty, interventions to prevent/delay frailty, and the effect of frailty on outcomes. Finally, this review discusses some of the challenges and opportunities of translating research findings from animals to humans.

  17. Animal challenge models of henipavirus infection and pathogenesis.

    PubMed

    Geisbert, Thomas W; Feldmann, Heinz; Broder, Christopher C

    2012-01-01

    The henipaviruses, Hendra virus (HeV), and Nipah virus (NiV), are enigmatic emerging pathogens that causes severe and often fatal neurologic and/or respiratory disease in both animals and humans. Amongst people, case fatality rates range between 40 and 75% and there are no vaccines or treatments approved for human use. A number of species of animals including guinea pigs, hamsters, cats, ferrets, pigs, and African green monkeys have been employed as animal models of human henipavirus infection. Here, we review the development of animal models for henipavirus infection, discuss the pathology and pathogenesis of these models, and assess the utility of each model to recapitulate important aspects of henipavirus-mediated disease seen in humans.

  18. Animal models of frailty: current applications in clinical research

    PubMed Central

    Kane, Alice E; Hilmer, Sarah N; Mach, John; Mitchell, Sarah J; de Cabo, Rafael; Howlett, Susan E

    2016-01-01

    The ethical, logistical, and biological complications of working with an older population of people inherently limits clinical studies of frailty. The recent development of animal models of frailty, and tools for assessing frailty in animal models provides an invaluable opportunity for frailty research. This review summarizes currently published animal models of frailty including the interleukin-10 knock-out mouse, the mouse frailty phenotype assessment tool, and the mouse clinical frailty index. It discusses both current and potential roles of these models in research into mechanisms of frailty, interventions to prevent/delay frailty, and the effect of frailty on outcomes. Finally, this review discusses some of the challenges and opportunities of translating research findings from animals to humans. PMID:27822024

  19. Retinal degeneration in animal models with a defective visual cycle

    PubMed Central

    Maeda, Akiko; Palczewski, Krzysztof

    2014-01-01

    Continuous generation of visual chromophore through the visual (retinoid) cycle is essential to maintain eyesight and retinal heath. Impairments in this cycle and related pathways adversely affect vision. In this review, we summarize the chemical reactions of vitamin A metabolites involved in the retinoid cycle and describe animal models of associated human diseases. Development of potential therapies for retinal disorders in these animal models is also introduced. PMID:25210527

  20. Large animal models of neurological disorders for gene therapy.

    PubMed

    Gagliardi, Christine; Bunnell, Bruce A

    2009-01-01

    he development of therapeutic interventions for genetic disorders and diseases that affect the central nervous system (CNS) has proven challenging. There has been significant progress in the development of gene therapy strategies in murine models of human disease, but gene therapy outcomes in these models do not always translate to the human setting. Therefore, large animal models are crucial to the development of diagnostics, treatments, and eventual cures for debilitating neurological disorders. This review focuses on the description of large animal models of neurological diseases such as lysosomal storage diseases, Parkinsons disease, Huntingtons disease, and neuroAIDS. The review also describes the contributions of these models to progress in gene therapy research.

  1. Modeling Behavior and Variation for Crowd Animation

    DTIC Science & Technology

    2009-08-01

    navigation strategies in complex environments. In Proceedings of the 2003 Intl. Confer- ence on Humanoid Robots , October 2003. 4.7.3 [15] Wallace Ching and...generate spatial and temporal variants from a small amount of data. We think of our work as one step towards the problem of motion variation; we...Treuille and his colleagues [102] generate crowd motions by thinking of crowds of agents as particles in a fluid. They model a potential field in

  2. Animal models for chronic lymphocytic leukemia.

    PubMed

    Pekarsky, Yuri; Zanesi, Nicola; Aqeilan, Rami I; Croce, Carlo M

    2007-04-01

    B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, results from an expansion of a rare population of CD5+ mature B-lymphocytes. Although clinical features and genomic abnormalities in B-CLL have been studied in considerable detail, the molecular mechanisms underlying disease development has remained unclear until recently. In the last 4 years, several transgenic mouse models for B-CLL were generated. Investigations of these mouse models revealed that deregulation of three pathways, Tcl1-Akt pathway, TNF-NF-kB pathway, and Bcl2-mediated anti-apoptotic pathway, result in the development of B-CLL. While deregulation of TCL1 alone caused a B-CLL phenotype in mice, overexpression of Bcl2 required aberrantly activated TNF-NF-kB pathway signaling to yield the disease phenotype. In this article, we present what has been learned from mice with B-CLL phenotype and how these mouse models of B-CLL were used to test therapeutic treatments for this common leukemia.

  3. Elements of episodic-like memory in animal models.

    PubMed

    Crystal, Jonathon D

    2009-03-01

    Representations of unique events from one's past constitute the content of episodic memories. A number of studies with non-human animals have revealed that animals remember specific episodes from their past (referred to as episodic-like memory). The development of animal models of memory holds enormous potential for gaining insight into the biological bases of human memory. Specifically, given the extensive knowledge of the rodent brain, the development of rodent models of episodic memory would open new opportunities to explore the neuroanatomical, neurochemical, neurophysiological, and molecular mechanisms of memory. Development of such animal models holds enormous potential for studying functional changes in episodic memory in animal models of Alzheimer's disease, amnesia, and other human memory pathologies. This article reviews several approaches that have been used to assess episodic-like memory in animals. The approaches reviewed include the discrimination of what, where, and when in a radial arm maze, dissociation of recollection and familiarity, object recognition, binding, unexpected questions, and anticipation of a reproductive state. The diversity of approaches may promote the development of converging lines of evidence on the difficult problem of assessing episodic-like memory in animals.

  4. Proteomics in farm animals models of human diseases.

    PubMed

    Ceciliani, Fabrizio; Restelli, Laura; Lecchi, Cristina

    2014-10-01

    The need to provide in vivo complex environments to understand human diseases strongly relies on the use of animal models, which traditionally include small rodents and rabbits. It is becoming increasingly evident that the few species utilised to date cannot be regarded as universal. There is a great need for new animal species that are naturally endowed with specific features relevant to human diseases. Farm animals, including pigs, cows, sheep and horses, represent a valid alternative to commonly utilised rodent models. There is an ample scope for the application of proteomic techniques in farm animals, and the establishment of several proteomic maps of plasma and tissue has clearly demonstrated that farm animals provide a disease environment that closely resembles that of human diseases. The present review offers a snapshot of how proteomic techniques have been applied to farm animals to improve their use as biomedical models. Focus will be on specific topics of biomedical research in which farm animal models have been characterised through the application of proteomic techniques.

  5. Using animal models to develop therapeutics for Tourette Syndrome.

    PubMed

    Swerdlow, Neal R; Sutherland, Ashley N

    2005-12-01

    The science of Tourette Syndrome (TS) is advancing at multiple levels of analysis and will be enhanced through the use of animal models. Particular challenges in the development of TS animal models reflect complex features of this disorder, including its waxing and waning course and its "invisible" sensory and psychic symptoms. Animal models can achieve face, predictive, or construct validity based on their particular features. Predictive validity, of most direct relevance to drug development for TS, is achieved to some degree by a several animal models, although the reliance of most of these models on measures of motor suppression may ultimately limit their utility. Other models achieve construct validity with proposed pathophysiological mechanisms related to the immune and neural circuit etiologies of TS. One model-deficient sensorimotor gating of the startle reflex-is discussed in terms of its present and future applications towards advancing our understanding of the pathophysiology and treatment of TS. In addition to models that will advance the pharmacotherapy of TS, other animal models may enhance the utility of nonpharmacologic TS treatments, ranging from behavior therapy to deep brain stimulation (DBS).

  6. Animal models of osteoarthritis: classification, update, and measurement of outcomes.

    PubMed

    Kuyinu, Emmanuel L; Narayanan, Ganesh; Nair, Lakshmi S; Laurencin, Cato T

    2016-02-02

    Osteoarthritis (OA) is one of the most commonly occurring forms of arthritis in the world today. It is a debilitating chronic illness causing pain and immense discomfort to the affected individual. Significant research is currently ongoing to understand its pathophysiology and develop successful treatment regimens based on this knowledge. Animal models have played a key role in achieving this goal. Animal models currently used to study osteoarthritis can be classified based on the etiology under investigation, primary osteoarthritis, and post-traumatic osteoarthritis, to better clarify the relationship between these models and the pathogenesis of the disease. Non-invasive animal models have shown significant promise in understanding early osteoarthritic changes. Imaging modalities play a pivotal role in understanding the pathogenesis of OA and the correlation with pain. These imaging studies would also allow in vivo surveillance of the disease as a function of time in the animal model. This review summarizes the current understanding of the disease pathogenesis, invasive and non-invasive animal models, imaging modalities, and pain assessment techniques in the animals.

  7. Animal model of sensitization by inhalation.

    PubMed Central

    Barboriak, J J; Knoblock, H W; Hensley, G T; Gombas, O F; Fink, J N

    1976-01-01

    Groups of rats exposed to daily inhalation challenge with aerosolized pigeon serum developed precipitating antibody within 2 weeks and definitive granulomatous inflammatory changes in the lung after 7 weeks of exposure. The dissociation of the two responses to an inhalation challenge indicate that the rat model may serve for screening of the various inhalant antigens for their sensitizing potential, and for investigation of the contributory role of some of the factors involved in the pathogenesis of hypersensitivity pneumonitis. Images FIG. 1 FIG. 2 PMID:939055

  8. The Use of Animal Models for Stroke Research: A Review

    PubMed Central

    Casals, Juliana B; Pieri, Naira CG; Feitosa, Matheus LT; Ercolin, Anna CM; Roballo, Kelly CS; Barreto, Rodrigo SN; Bressan, Fabiana F; Martins, Daniele S; Miglino, Maria A; Ambrósio, Carlos E

    2011-01-01

    Stroke has been identified as the second leading cause of death worldwide. Stroke is a focal neurologic deficit caused by a change in cerebral circulation. The use of animal models in recent years has improved our understanding of the physiopathology of this disease. Rats and mice are the most commonly used stroke models, but the demand for larger models, such as rabbits and even nonhuman primates, is increasing so as to better understand the disease and its treatment. Although the basic mechanisms of stroke are nearly identical among mammals, we here discuss the differences between the human encephalon and various animals. In addition, we compare common surgical techniques used to induce animal models of stroke. A more complete anatomic knowledge of the cerebral vessels of various model species is needed to develop more reliable models for objective results that improve knowledge of the pathology of stroke in both human and veterinary medicine. PMID:22330245

  9. [Comments on an animal model of depression].

    PubMed

    Vaugeois, J-M; El Yacoubi, M; Costentin, J

    2004-09-01

    Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its pathophysiology relies on the availability of experimental models potentially mimicking the disease. Here is presented a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, "helpless" mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increase pressure of rapid eye movement sleep. Compared with "nonhelpless" mice, they display higher basal serum corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin1A autoreceptor stimulation induced greatest hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.

  10. Animal models for prenatal gene therapy: the nonhuman primate model.

    PubMed

    Mattar, Citra N; Biswas, Arijit; Choolani, Mahesh; Chan, Jerry K Y

    2012-01-01

    Intrauterine gene therapy (IUGT) potentially enables the treatment and possible cure of monogenic -diseases that cause severe fetal damage. The main benefits of this approach will be the ability to correct the disorder before the onset of irreversible pathology and inducing central immune tolerance to the vector and transgene if treatment is instituted in early gestation. Cure has been demonstrated in small animal models, but because of the significant differences in immune ontogeny and the much shorter gestation compared to humans, it is unlikely that questions of long-term efficacy and safety will be adequately addressed in rodents. The nonhuman primate (NHP) allows investigation of key issues, in particular, the different outcomes in early and late-gestation IUGT associated with different stages of immune maturity, longevity of transgene expression, and delayed-onset adverse events in treated offspring and mothers including insertional mutagenesis. Here, we describe a model based on the Macaca fascicularis using ultrasound and fetoscopic approaches to systemic vector delivery and the processes involved in vector administration and longitudinal analyses.

  11. Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

    PubMed Central

    McElvaney, Noel G.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF. PMID:27340661

  12. Are animal models relevant to key aspects of human parturition?

    PubMed

    Mitchell, Bryan F; Taggart, Michael J

    2009-09-01

    Preterm birth remains the most serious complication of pregnancy and is associated with increased rates of infant death or permanent neurodevelopmental disability. Our understanding of the regulation of parturition remains inadequate. The scientific literature, largely derived from rodent animal models, suggests two major mechanisms regulating the timing of parturition: the withdrawal of the steroid hormone progesterone and a proinflammatory response by the immune system. However, available evidence strongly suggests that parturition in the human has significantly different regulators and mediators from those in most of the animal models. Our objectives are to critically review the data and concepts that have arisen from use of animal models for parturition and to rationalize the use of a new model. Many animal models have contributed to advances in our understanding of the regulation of parturition. However, we suggest that those animals dependent on progesterone withdrawal to initiate parturition clearly have a limitation to their translation to the human. In such models, a linear sequence of events (e.g., luteolysis, progesterone withdrawal, uterine activation, parturition) gives rise to the concept of a "trigger" mechanism. Conversely, we propose that human parturition may arise from the concomitant maturation of several systems in parallel. We have termed this novel concept "modular accumulation of physiological systems" (MAPS). We also emphasize the urgency to determine the precise role of the immune system in the process of parturition in situations other than intrauterine infection. Finally, we accentuate the need to develop a nonprimate animal model whose physiology is more relevant to human parturition. We suggest that the guinea pig displays several key physiological characteristics of gestation that more closely resemble human pregnancy than do currently favored animal models. We conclude that the application of novel concepts and new models are

  13. The utility of animal models in developing immunosuppressive agents.

    PubMed

    McDaid, James; Scott, Christopher J; Kissenpfennig, Adrien; Chen, Huifang; Martins, Paulo N

    2015-07-15

    The immune system comprises an integrated network of cellular interactions. Some responses are predictable, while others are more stochastic. While in vitro the outcome of stimulating a single type of cell may be stereotyped and reproducible, in vivo this is often not the case. This phenomenon often merits the use of animal models in predicting the impact of immunosuppressant drugs. A heavy burden of responsibility lies on the shoulders of the investigator when using animal models to study immunosuppressive agents. The principles of the three R׳s: refine (less suffering,), reduce (lower animal numbers) and replace (alternative in vitro assays) must be applied, as described elsewhere in this issue. Well designed animal model experiments have allowed us to develop all the immunosuppressive agents currently available for treating autoimmune disease and transplant recipients. In this review, we examine the common animal models used in developing immunosuppressive agents, focusing on drugs used in transplant surgery. Autoimmune diseases, such as multiple sclerosis, are covered elsewhere in this issue. We look at the utility and limitations of small and large animal models in measuring potency and toxicity of immunosuppressive therapies.

  14. Animal models to study thyroid hormone action in cerebellum.

    PubMed

    Koibuchi, Noriyuki

    2009-06-01

    Thyroid hormone plays a crucial role in the development and functional maintenance of the central nervous system including the cerebellum. To study the molecular mechanisms of thyroid hormone action, various animal models have been used. These are classified: (1) congenital hypothyroid animals due to thyroid gland dysgenesis or thyroid dyshormonogenesis, (2) thyroid hormone receptor (TR) gene-mutated animals, and (3) thyroid hormone transport or metabolism-modified animals. TR is a ligand-activated transcription factor. In the presence of ligand, it activates transcription of target gene, whereas it represses the transcription without ligand. Thus, phenotype of TR-knockout mouse is different from that of hypothyroid animal (low thyroid hormone level), in which unliganded TR actively represses the transcription. On the other hand, human patient harboring mutant TR expresses different phenotypes depending on the function of mutated TR. To mimic this phenotype, other animal models are generated. In addition, recent human studies have shown that thyroid hormone transporters such as monocarboxylate transporter (MCT) 8 may play an important role in thyroid hormone-mediated brain development. However, MCT8 knockout mouse show different phenotypes from a human patient. This article introduces representative animal models currently used to study various aspects of thyroid hormone, particularly to study the involvement of the thyroid hormone system on the development and functional maintenance of the cerebellum.

  15. Sex differences in animal models of psychiatric disorders

    PubMed Central

    Kokras, N; Dalla, C

    2014-01-01

    Psychiatric disorders are characterized by sex differences in their prevalence, symptomatology and treatment response. Animal models have been widely employed for the investigation of the neurobiology of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclinical pharmacological studies. In this review, we highlight the need for the inclusion of both male and female animals in experimental studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioural findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance-related disorders, obsessive–compulsive disorder, schizophrenia, bipolar disorder and autism. Moreover, when available, we include studies conducted across different stages of the oestrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting, and no clear conclusion regarding the direction of sex differences and the effect of the oestrous cycle is drawn. Moreover, there is a lack of considerable amount of studies using psychiatric drugs in both male and female animals, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioural indices are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use standard procedures across different laboratories. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20 PMID:24697577

  16. Impairments of Synaptic Plasticity in Aged Animals and in Animal Models of Alzheimer's Disease

    PubMed Central

    Balietti, Marta; Tamagnini, Francesco; Fattoretti, Patrizia; Burattini, Costanza; Casoli, Tiziana; Platano, Daniela; Lattanzio, Fabrizia

    2012-01-01

    Abstract Aging is associated with a gradual decline in cognitive functions, and more dramatic cognitive impairments occur in patients affected by Alzheimer's disease (AD). Electrophysiological and molecular studies performed in aged animals and in animal models of AD have shown that cognitive decline is associated with significant modifications in synaptic plasticity (i.e., activity-dependent changes in synaptic strength) and have elucidated some of the cellular mechanisms underlying this process. Morphological studies have revealed a correlation between the quality of memory performance and the extent of structural changes of synaptic contacts occurring during memory consolidation. We briefly review recent experimental evidence here. PMID:22533439

  17. SU-E-T-284: Revisiting Reference Dosimetry for the Model S700 Axxent 50 KV{sub p} Electronic Brachytherapy Source

    SciTech Connect

    Hiatt, JR; Rivard, MJ

    2014-06-01

    Purpose: The model S700 Axxent electronic brachytherapy source by Xoft was characterized in 2006 by Rivard et al. The source design was modified in 2006 to include a plastic centering insert at the source tip to more accurately position the anode. The objectives of the current study were to establish an accurate Monte Carlo source model for simulation purposes, to dosimetrically characterize the new source and obtain its TG-43 brachytherapy dosimetry parameters, and to determine dose differences between the source with and without the centering insert. Methods: Design information from dissected sources and vendor-supplied CAD drawings were used to devise the source model for radiation transport simulations of dose distributions in a water phantom. Collision kerma was estimated as a function of radial distance, r, and polar angle, θ, for determination of reference TG-43 dosimetry parameters. Simulations were run for 10{sup 10} histories, resulting in statistical uncertainties on the transverse plane of 0.03% at r=1 cm and 0.08% at r=10 cm. Results: The dose rate distribution the transverse plane did not change beyond 2% between the 2006 model and the current study. While differences exceeding 15% were observed near the source distal tip, these diminished to within 2% for r>1.5 cm. Differences exceeding a factor of two were observed near θ=150° and in contact with the source, but diminished to within 20% at r=10 cm. Conclusions: Changes in source design influenced the overall dose rate and distribution by more than 2% over a third of the available solid angle external from the source. For clinical applications using balloons or applicators with tissue located within 5 cm from the source, dose differences exceeding 2% were observed only for θ>110°. This study carefully examined the current source geometry and presents a modern reference TG-43 dosimetry dataset for the model S700 source.

  18. Animal models of obsessive–compulsive disorder: utility and limitations

    PubMed Central

    Alonso, Pino; López-Solà, Clara; Real, Eva; Segalàs, Cinto; Menchón, José Manuel

    2015-01-01

    Obsessive–compulsive disorder (OCD) is a disabling and common neuropsychiatric condition of poorly known etiology. Many attempts have been made in the last few years to develop animal models of OCD with the aim of clarifying the genetic, neurochemical, and neuroanatomical basis of the disorder, as well as of developing novel pharmacological and neurosurgical treatments that may help to improve the prognosis of the illness. The latter goal is particularly important given that around 40% of patients with OCD do not respond to currently available therapies. This article summarizes strengths and limitations of the leading animal models of OCD including genetic, pharmacologically induced, behavioral manipulation-based, and neurodevelopmental models according to their face, construct, and predictive validity. On the basis of this evaluation, we discuss that currently labeled “animal models of OCD” should be regarded not as models of OCD but, rather, as animal models of different psychopathological processes, such as compulsivity, stereotypy, or perseverance, that are present not only in OCD but also in other psychiatric or neurological disorders. Animal models might constitute a challenging approach to study the neural and genetic mechanism of these phenomena from a trans-diagnostic perspective. Animal models are also of particular interest as tools for developing new therapeutic options for OCD, with the greatest convergence focusing on the glutamatergic system, the role of ovarian and related hormones, and the exploration of new potential targets for deep brain stimulation. Finally, future research on neurocognitive deficits associated with OCD through the use of analogous animal tasks could also provide a genuine opportunity to disentangle the complex etiology of the disorder. PMID:26346234

  19. Animal models of Parkinson's disease: a gateway to therapeutics?

    PubMed

    Le, Weidong; Sayana, Pavani; Jankovic, Joseph

    2014-01-01

    Parkinson's disease (PD) is a progressive, neurodegenerative disorder of unknown etiology, although a complex interaction between environmental and genetic factors has been implicated as a pathogenic mechanism of selected neuronal loss. A better understanding of the etiology, pathogenesis, and molecular mechanisms underlying the disease process may be gained from research on animal models. While cell and tissue models are helpful in unraveling involved molecular pathways, animal models are much better suited to study the pathogenesis and potential treatment strategies. The animal models most relevant to PD include those generated by neurotoxic chemicals that selectively disrupt the catecholaminergic system such as 6-hydroxydopamine; 1-methyl-1,2,3,6-tetrahydropiridine; agricultural pesticide toxins, such as rotenone and paraquat; the ubiquitin proteasome system inhibitors; inflammatory modulators; and several genetically manipulated models, such as α-synuclein, DJ-1, PINK1, Parkin, and leucine-rich repeat kinase 2 transgenic or knock-out animals. Genetic and nongenetic animal models have their own unique advantages and limitations, which must be considered when they are employed in the study of pathogenesis or treatment approaches. This review provides a summary and a critical review of our current knowledge about various in vivo models of PD used to test novel therapeutic strategies.

  20. Animal models of suicide-trait-related behaviors.

    PubMed

    Malkesman, Oz; Pine, Daniel S; Tragon, Tyson; Austin, Daniel R; Henter, Ioline D; Chen, Guang; Manji, Husseini K

    2009-04-01

    Although antidepressants are moderately effective in treating major depressive disorder (MDD), concerns have arisen that selective serotonin-reuptake inhibitors (SSRIs) are associated with suicidal thinking and behavior, especially in children, adolescents and young adults. Almost no experimental research in model systems has considered the mechanisms by which SSRIs might be associated with this potential side effect in some susceptible individuals. Suicide is a complex behavior and impossible to fully reproduce in an animal model. However, by investigating traits that show strong cross-species parallels in addition to associations with suicide in humans, animal models might elucidate the mechanisms by which SSRIs are associated with suicidal thinking and behavior. Traits linked with suicide in humans that can be successfully modeled in rodents include aggression, impulsivity, irritability and hopelessness/helplessness. Modeling these relevant traits in animals can help to clarify the impact of SSRIs on these traits, suggesting avenues for reducing suicide risk in this vulnerable population.

  1. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

    PubMed Central

    Takahashi, Yoshihisa; Soejima, Yurie; Fukusato, Toshio

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages. PMID:22654421

  2. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Takahashi, Yoshihisa; Soejima, Yurie; Fukusato, Toshio

    2012-05-21

    Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

  3. REVIEW OF DOSIMETRY FIELD

    DTIC Science & Technology

    three, oxalic acid , polyisobutylene, and Mylar film, seem sufficiently promising to warrant further development. Their current states of development...ceric sulfate dosimeters be included in the dosimetry handbook, but that additional work should be done on oxalic acid , polyisobutylene, and Mylar as dosimetry materials. (Author)

  4. Development and validation of a measurement-based source model for kilovoltage cone-beam CT Monte Carlo dosimetry simulations

    PubMed Central

    McMillan, Kyle; McNitt-Gray, Michael; Ruan, Dan

    2013-01-01

    underestimated measurements by 1.35%–5.31% (mean difference = −3.42%, SD = 1.09%). Conclusions: This work demonstrates the feasibility of using a measurement-based kV CBCT source model to facilitate dose calculations with Monte Carlo methods for both the radiographic and CBCT mode of operation. While this initial work validates simulations against measurements for simple geometries, future work will involve utilizing the source model to investigate kV CBCT dosimetry with more complex anthropomorphic phantoms and patient specific models. PMID:24320440

  5. Large animal models of hematopoietic stem cell gene therapy.

    PubMed

    Trobridge, G D; Kiem, H-P

    2010-08-01

    Large animal models have been instrumental in advancing hematopoietic stem cell (HSC) gene therapy. Here we review the advantages of large animal models, their contributions to the field of HSC gene therapy and recent progress in this field. Several properties of human HSCs including their purification, their cell-cycle characteristics, their response to cytokines and the proliferative demands placed on them after transplantation are more similar in large animal models than in mice. Progress in the development and use of retroviral vectors and ex vivo transduction protocols over the last decade has led to efficient gene transfer in both dogs and nonhuman primates. Importantly, the approaches developed in these models have translated well to the clinic. Large animals continue to be useful to evaluate the efficacy and safety of gene therapy, and dogs with hematopoietic diseases have now been cured by HSC gene therapy. Nonhuman primates allow evaluation of aspects of transplantation as well as disease-specific approaches such as AIDS (acquired immunodeficiency syndrome) gene therapy that can not be modeled well in the dog. Finally, large animal models have been used to evaluate the genotoxicity of viral vectors by comparing integration sites in hematopoietic repopulating cells and monitoring clonality after transplantation.

  6. Animal models of COPD: What do they tell us?

    PubMed

    Jones, Bernadette; Donovan, Chantal; Liu, Gang; Gomez, Henry M; Chimankar, Vrushali; Harrison, Celeste L; Wiegman, Cornelis H; Adcock, Ian M; Knight, Darryl A; Hirota, Jeremy A; Hansbro, Philip M

    2017-01-01

    COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.

  7. [Laboratory animal anaesthesia: influence of anaesthetic protocols on experimental models].

    PubMed

    Bazin, J-E; Constantin, J-M; Gindre, G

    2004-08-01

    different animal species and human and animals about the effects of anaesthetic agents are very hazardous. Great differences exist between the effects observed in vitro and in whole animals. The effects of the anaesthetics could be totally different if they are used alone or in association. The same anaesthetic could have opposite effects from an organ to another. For results validation, the anaesthesia side effects (hypoventilation, hypotension, cooling em leader ) have to be minimized. All new experimental models should require discussing the possible interferences between anaesthesia and results and to compare results obtained with different anaesthetic protocols.

  8. Life sciences research in space: The requirement for animal models

    NASA Technical Reports Server (NTRS)

    Fuller, C. A.; Philips, R. W.; Ballard, R. W.

    1987-01-01

    Use of animals in NASA space programs is reviewed. Animals are needed because life science experimentation frequently requires long-term controlled exposure to environments, statistical validation, invasive instrumentation or biological tissue sampling, tissue destruction, exposure to dangerous or unknown agents, or sacrifice of the subject. The availability and use of human subjects inflight is complicated by the multiple needs and demands upon crew time. Because only living organisms can sense, integrate and respond to the environment around them, the sole use of tissue culture and computer models is insufficient for understanding the influence of the space environment on intact organisms. Equipment for spaceborne experiments with animals is described.

  9. Monte Carlo modelling of diode detectors for small field MV photon dosimetry: detector model simplification and the sensitivity of correction factors to source parameterization.

    PubMed

    Cranmer-Sargison, G; Weston, S; Evans, J A; Sidhu, N P; Thwaites, D I

    2012-08-21

    The goal of this work was to examine the use of simplified diode detector models within a recently proposed Monte Carlo (MC) based small field dosimetry formalism and to investigate the influence of electron source parameterization has on MC calculated correction factors. BEAMnrc was used to model Varian 6 MV jaw-collimated square field sizes down to 0.5 cm. The IBA stereotactic field diode (SFD), PTW T60016 (shielded) and PTW T60017 (un-shielded) diodes were modelled in DOSRZnrc and isocentric output ratios (OR(fclin)(detMC)) calculated at depths of d = 1.5, 5.0 and 10.0 cm. Simplified detector models were then tested by evaluating the percent difference in (OR(fclin)(detMC)) between the simplified and complete detector models. The influence of active volume dimension on simulated output ratio and response factor was also investigated. The sensitivity of each MC calculated replacement correction factor (k(fclin,fmsr)(Qclin,Qmsr)), as a function of electron FWHM between 0.100 and 0.150 cm and energy between 5.5 and 6.5 MeV, was investigated for the same set of small field sizes using the simplified detector models. The SFD diode can be approximated simply as a silicon chip in water, the T60016 shielded diode can be modelled as a chip in water plus the entire shielding geometry and the T60017 unshielded diode as a chip in water plus the filter plate located upstream. The detector-specific (k(fclin,fmsr)(Qclin,Qmsr)), required to correct measured output ratios using the SFD, T60016 and T60017 diode detectors are insensitive to incident electron energy between 5.5 and 6.5 MeV and spot size variation between FWHM = 0.100 and 0.150 cm. Three general conclusions come out of this work: (1) detector models can be simplified to produce OR(fclin)(detMC) to within 1.0% of those calculated using the complete geometry, where typically not only the silicon chip, but also any high density components close to the chip, such as scattering plates or shielding material is necessary

  10. Use of animal models to develop antiaddiction medications.

    PubMed

    Gardner, Eliot L

    2008-10-01

    Although addiction is a uniquely human phenomenon, some of its pathognomonic features can be modeled at the animal level. Such features include the euphoric "high" produced by acute administration of addictive drugs; the dysphoric "crash" produced by acute withdrawal; drug-seeking and drug-taking behaviors; and relapse to drug-seeking behavior after achieving successful abstinence. Animal models exist for each of these features. In this review, I focus on various animal models of addiction and how they can be used to search for clinically effective antiaddiction medications. I conclude by noting some of the new and novel medications that have been developed preclinically using such models and the hope for further developments along such lines.

  11. Use of Animal Models to Develop Antiaddiction Medications

    PubMed Central

    Gardner, Eliot L.

    2008-01-01

    Although addiction is a uniquely human phenomenon, some of its pathognomonic features can be modeled at the animal level. Such features include the euphoric “high” produced by acute administration of addictive drugs; the dysphoric “crash” produced by acute withdrawal, drug-seeking, and drug-taking behaviors; and relapse to drug-seeking behavior after achieving successful abstinence. Animal models exist for each of these features. In this review, I focus on various animal models of addiction and how they can be used to search for clinically effective antiaddiction medications. I conclude by noting some of the new and novel medications that have been developed preclinically using such models and the hope for further developments along such lines. PMID:18803910

  12. Canine tumors: a spontaneous animal model of human carcinogenesis.

    PubMed

    Pinho, Salomé S; Carvalho, Sandra; Cabral, Joana; Reis, Celso A; Gärtner, Fátima

    2012-03-01

    The enormous biologic complexity of human cancer has stimulated the development of more appropriate experimental models that could resemble in a natural and spontaneous manner the physiopathologic aspects of cancer biology. Companion animals have many desired characteristics that fill the gap between in vitro and in vivo studies, and these characteristics have proven to be important in understanding many complex molecular aspects of human cancer. Spontaneous tumors in dogs share a wide variety of epidemiologic, biologic, and clinical features with human cancer, which makes this animal model both attractive and underused in oncology research. In this review, we summarize the importance of naturally occurring canine tumors as valuable tools for studying numerous aspects of human cancer as well as the potential use of this animal model for the development of new cancer treatments. We address specifically the use of canine mammary tumors as an increasingly powerful model to study human breast cancer.

  13. Animal models of female pelvic organ prolapse: lessons learned

    PubMed Central

    Couri, Bruna M; Lenis, Andrew T; Borazjani, Ali; Paraiso, Marie Fidela R; Damaser, Margot S

    2012-01-01

    Pelvic organ prolapse is a vaginal protrusion of female pelvic organs. It has high prevalence worldwide and represents a great burden to the economy. The pathophysiology of pelvic organ prolapse is multifactorial and includes genetic predisposition, aberrant connective tissue, obesity, advancing age, vaginal delivery and other risk factors. Owing to the long course prior to patients becoming symptomatic and ethical questions surrounding human studies, animal models are necessary and useful. These models can mimic different human characteristics – histological, anatomical or hormonal, but none present all of the characteristics at the same time. Major animal models include knockout mice, rats, sheep, rabbits and nonhuman primates. In this article we discuss different animal models and their utility for investigating the natural progression of pelvic organ prolapse pathophysiology and novel treatment approaches. PMID:22707980

  14. Behavioral Models of Tinnitus and Hyperacusis in Animals

    PubMed Central

    Hayes, Sarah H.; Radziwon, Kelly E.; Stolzberg, Daniel J.; Salvi, Richard J.

    2014-01-01

    The phantom perception of tinnitus and reduced sound-level tolerance associated with hyperacusis have a high comorbidity and can be debilitating conditions for which there are no widely accepted treatments. One factor limiting the development of treatments for tinnitus and hyperacusis is the lack of reliable animal behavioral models of these disorders. Therefore, the purpose of this review is to highlight the current animal models of tinnitus and hyperacusis, and to detail the advantages and disadvantages of each paradigm. To date, this is the first review to include models of both tinnitus and hyperacusis. PMID:25278931

  15. Recent developments in experimental animal models of Henipavirus infection.

    PubMed

    Rockx, Barry

    2014-07-01

    Hendra (HeV) and Nipah (NiV) viruses (genus Henipavirus (HNV; family Paramyxoviridae) are emerging zoonotic agents that can cause severe respiratory distress and acute encephalitis in humans. Given the lack of effective therapeutics and vaccines for human use, these viruses are considered as public health concerns. Several experimental animal models of HNV infection have been developed in recent years. Here, we review the current status of four of the most promising experimental animal models (mice, hamsters, ferrets, and African green monkeys) and their suitability for modeling the clinical disease, transmission, pathogenesis, prevention, and treatment for HNV infection in humans.

  16. Animal models of self-injurious behaviour: an overview.

    PubMed

    Devine, Darragh P

    2012-01-01

    Self-injurious behaviour is highly prevalent in neurodevelopmental disorders. Interestingly, it is not restricted to any individual diagnostic group. Rather, it is exhibited in various forms across patient groups with distinct genetic defects and classifications of disorders. This suggests that there may be shared neuropathology that confers vulnerability. Convergent evidence from clinical pharmacotherapy, brain imaging studies, postmortem neurochemical analyses, and animal models indicates that dopaminergic insufficiency is a key culprit. This chapter provides an overview of studies in which animal models have been used to investigate the biochemical basis of self-injury, and highlights the convergence in findings between these models and expression of self-injury in humans.

  17. Animal models of post-traumatic stress disorder: face validity

    PubMed Central

    Goswami, Sonal; Rodríguez-Sierra, Olga; Cascardi, Michele; Paré, Denis

    2013-01-01

    Post-traumatic stress disorder (PTSD) is a debilitating condition that develops in a proportion of individuals following a traumatic event. Despite recent advances, ethical limitations associated with human research impede progress in understanding PTSD. Fortunately, much effort has focused on developing animal models to help study the pathophysiology of PTSD. Here, we provide an overview of animal PTSD models where a variety of stressors (physical, psychosocial, or psychogenic) are used to examine the long-term effects of severe trauma. We emphasize models involving predator threat because they reproduce human individual differences in susceptibility to, and in the long-term consequences of, psychological trauma. PMID:23754973

  18. [The importance of animal models for progress in science].

    PubMed

    Weiser, H

    1989-06-01

    Experimental animals may serve as models for human beings, if analogies between animal and human functions exist. Therefore, the selection of species and strain plays an important role in the development of such models. Knowledge of the nutritional and physiological characteristics of a species is a prerequisite for the composition of complete diets. Often, preliminary work has to begin at the breeding farm in order to make use of such curative models possible. Only when the high requirements of standardization of experimental animals are met can clinical and subclinical symptoms be determined distinctly. By means of sensitive biochemical reactions, imbalances and interactions of nutritive and active ingredients, as well as successful substitutions, can be recorded. The study of absorption and metabolism of preparations is made possible by observing these reactions. However, negative influence on the results of analysis must be eliminated by correct selection of narcotics, and the proper excision and storage of organs. Because of its importance for the planning and evaluation of experiments, biometry is an integral part of every research project. The scientific information which must be gained from the whole experimental animal cannot be substituted by either isolated organs and cell cultures, or by means of computer simulation. A demanding effort, which includes biotechnological methods, is necessary to further reduce the number of experimental animals and, simultaneously, to enhance experimental evidence. In any case, all scientific aims must be in accordance with the ethical principles of the Society for the Prevention of Cruelty to Animals.

  19. Animal models of GM2 gangliosidosis: utility and limitations

    PubMed Central

    Lawson, Cheryl A; Martin, Douglas R

    2016-01-01

    GM2 gangliosidosis, a subset of lysosomal storage disorders, is caused by a deficiency of the glycohydrolase, β-N-acetylhexosaminidase, and includes the closely related Tay–Sachs and Sandhoff diseases. The enzyme deficiency prevents the normal, stepwise degradation of ganglioside, which accumulates unchecked within the cellular lysosome, particularly in neurons. As a result, individuals with GM2 gangliosidosis experience progressive neurological diseases including motor deficits, progressive weakness and hypotonia, decreased responsiveness, vision deterioration, and seizures. Mice and cats are well-established animal models for Sandhoff disease, whereas Jacob sheep are the only known laboratory animal model of Tay–Sachs disease to exhibit clinical symptoms. Since the human diseases are relatively rare, animal models are indispensable tools for further study of pathogenesis and for development of potential treatments. Though no effective treatments for gangliosidoses currently exist, animal models have been used to test promising experimental therapies. Herein, the utility and limitations of gangliosidosis animal models and how they have contributed to the development of potential new treatments are described. PMID:27499644

  20. A novel animal model for skin flap prelamination with biomaterials

    NASA Astrophysics Data System (ADS)

    Zhou, Xianyu; Luo, Xusong; Liu, Fei; Gu, Chuan; Wang, Xi; Yang, Qun; Qian, Yunliang; Yang, Jun

    2016-09-01

    Several animal models of skin flap construction were reported using biomaterials in a way similar to prefabrication. However, there are few animal model using biomaterials similar to prelamination, another main way of clinical skin flap construction that has been proved to be reliable. Can biomaterials be added in skin flap prelamination to reduce the use of autogenous tissues? Beside individual clinical attempts, animal model is needed for randomized controlled trial to objectively evaluate the feasibility and further investigation. Combining human Acellular Dermal Matrix (hADM) and autologous skin graft, we prelaminated flaps based on inguinal fascia. One, two, three and four weeks later, hADM exhibited a sound revascularization and host cell infiltration. Prelaminated skin flaps were then raised and microsurgically transplanted back to groin region. Except for flaps after one week of prelamination, flaps from other subgroups successfully reconstructed defects. After six to sixteen weeks of transplantation, hADM was proved to being able to maintain its original structure, having a wealth of host tissue cells and achieving full revascularization.To our knowledge, this is the first animal model of prelaminating skin flap with biomaterials. Success of this animal model indicates that novel flap prelamination with biomaterials is feasible.

  1. Alzheimer’s disease and epilepsy: insight from animal models

    PubMed Central

    Scharfman, Helen E

    2012-01-01

    Alzheimer’s disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy. PMID:22723738

  2. A novel animal model for skin flap prelamination with biomaterials

    PubMed Central

    Zhou, Xianyu; Luo, Xusong; Liu, Fei; Gu, Chuan; Wang, Xi; Yang, Qun; Qian, Yunliang; Yang, Jun

    2016-01-01

    Several animal models of skin flap construction were reported using biomaterials in a way similar to prefabrication. However, there are few animal model using biomaterials similar to prelamination, another main way of clinical skin flap construction that has been proved to be reliable. Can biomaterials be added in skin flap prelamination to reduce the use of autogenous tissues? Beside individual clinical attempts, animal model is needed for randomized controlled trial to objectively evaluate the feasibility and further investigation. Combining human Acellular Dermal Matrix (hADM) and autologous skin graft, we prelaminated flaps based on inguinal fascia. One, two, three and four weeks later, hADM exhibited a sound revascularization and host cell infiltration. Prelaminated skin flaps were then raised and microsurgically transplanted back to groin region. Except for flaps after one week of prelamination, flaps from other subgroups successfully reconstructed defects. After six to sixteen weeks of transplantation, hADM was proved to being able to maintain its original structure, having a wealth of host tissue cells and achieving full revascularization.To our knowledge, this is the first animal model of prelaminating skin flap with biomaterials. Success of this animal model indicates that novel flap prelamination with biomaterials is feasible. PMID:27659066

  3. Animal models of GM2 gangliosidosis: utility and limitations.

    PubMed

    Lawson, Cheryl A; Martin, Douglas R

    2016-01-01

    GM2 gangliosidosis, a subset of lysosomal storage disorders, is caused by a deficiency of the glycohydrolase, β-N-acetylhexosaminidase, and includes the closely related Tay-Sachs and Sandhoff diseases. The enzyme deficiency prevents the normal, stepwise degradation of ganglioside, which accumulates unchecked within the cellular lysosome, particularly in neurons. As a result, individuals with GM2 gangliosidosis experience progressive neurological diseases including motor deficits, progressive weakness and hypotonia, decreased responsiveness, vision deterioration, and seizures. Mice and cats are well-established animal models for Sandhoff disease, whereas Jacob sheep are the only known laboratory animal model of Tay-Sachs disease to exhibit clinical symptoms. Since the human diseases are relatively rare, animal models are indispensable tools for further study of pathogenesis and for development of potential treatments. Though no effective treatments for gangliosidoses currently exist, animal models have been used to test promising experimental therapies. Herein, the utility and limitations of gangliosidosis animal models and how they have contributed to the development of potential new treatments are described.

  4. Animal models to study the pathogenesis of human and animal Clostridium perfringens infections

    PubMed Central

    Uzal, Francisco A.; McClane, Bruce A.; Cheung, Jackie K.; Theoret, James; Garcia, Jorge P.; Moore, Robert J.; Rood, Julian I.

    2016-01-01

    The most common animal models used to study Clostridium perfringens infections in humans and animals are reviewed here. The classical C. perfringens-mediated histotoxic disease of humans is clostridial myonecrosis or gas gangrene and the use of a mouse myonecrosis model coupled with genetic studies has contributed greatly to our understanding of disease pathogenesis. Similarly, the use of a chicken model has enhanced our understanding of type A-mediated necrotic enteritis in poultry and has led to the identification of NetB as the primary toxin involved in disease. C. perfringens type A food poisoning is a highly prevalent bacterial illness in the USA and elsewhere. Rabbits and mice are the species most commonly used to study the action of enterotoxin, the causative toxin. Other animal models used to study the effect of this toxin are rats, non-human primates, sheep and cattle. In rabbits and mice, CPE produces severe necrosis of the small intestinal epithelium along with fluid accumulation. C. perfringens type D infection has been studied by inoculating epsilon toxin (ETX) intravenously into mice, rats, sheep, goats and cattle, and by intraduodenal inoculation of whole cultures of this microorganism in mice, sheep, goats and cattle. Molecular Koch's postulates have been fulfilled for enterotoxigenic C. perfringens type A in rabbits and mice, for C. perfringens type A necrotic enteritis and gas gangrene in chickens and mice, respectively, for C. perfringens type C in mice, rabbits and goats, and for C. perfringens type D in mice, sheep and goats. PMID:25770894

  5. Animal models to study the pathogenesis of human and animal Clostridium perfringens infections.

    PubMed

    Uzal, Francisco A; McClane, Bruce A; Cheung, Jackie K; Theoret, James; Garcia, Jorge P; Moore, Robert J; Rood, Julian I

    2015-08-31

    The most common animal models used to study Clostridium perfringens infections in humans and animals are reviewed here. The classical C. perfringens-mediated histotoxic disease of humans is clostridial myonecrosis or gas gangrene and the use of a mouse myonecrosis model coupled with genetic studies has contributed greatly to our understanding of disease pathogenesis. Similarly, the use of a chicken model has enhanced our understanding of type A-mediated necrotic enteritis in poultry and has led to the identification of NetB as the primary toxin involved in disease. C. perfringens type A food poisoning is a highly prevalent bacterial illness in the USA and elsewhere. Rabbits and mice are the species most commonly used to study the action of enterotoxin, the causative toxin. Other animal models used to study the effect of this toxin are rats, non-human primates, sheep and cattle. In rabbits and mice, CPE produces severe necrosis of the small intestinal epithelium along with fluid accumulation. C. perfringens type D infection has been studied by inoculating epsilon toxin (ETX) intravenously into mice, rats, sheep, goats and cattle, and by intraduodenal inoculation of whole cultures of this microorganism in mice, sheep, goats and cattle. Molecular Koch's postulates have been fulfilled for enterotoxigenic C. perfringens type A in rabbits and mice, for C. perfringens type A necrotic enteritis and gas gangrene in chickens and mice, respectively, for C. perfringens type C in mice, rabbits and goats, and for C. perfringens type D in mice, sheep and goats.

  6. A model of CT dose profiles in Banach space; with applications to CT dosimetry

    NASA Astrophysics Data System (ADS)

    Weir, Victor J.

    2016-07-01

    In this paper the scatter component of computed tomography dose profiles is modeled using the solution to a nonlinear ordinary differential equation. This scatter function is summed with a modeled primary function of approximate trapezoidal shape. The primary dose profile is modeled to include the analytic continuation of the Heaviside step function. A mathematical theory is developed in a Banach space. The modeled function is used to accurately fit data from a 256-slice GE Revolution scanner. A 60 cm long body phantom is assembled and used for data collection with both a pencil chamber and a Farmer-type chamber.

  7. The use of animal models in behavioural neuroscience research.

    PubMed

    Bovenkerk, Bernice; Kaldewaij, Frederike

    2015-01-01

    Animal models are used in experiments in the behavioural neurosciences that aim to contribute to the prevention and treatment of cognitive and affective disorders in human beings, such as anxiety and depression. Ironically, those animals that are likely to be the best models for psychopathology are also likely to be considered the ones that are most morally problematic to use, if it seems probable that (and if indeed they are initially selected as models because) they have experiences that are similar to human experiences that we have strong reasons to avoid causing, and indeed aim to alleviate (such as pain, anxiety or sadness). In this paper, against the background of contemporary discussions in animal ethics and the philosophy of animal minds, we discuss the views that it is morally permissible to use animals in these kinds of experiments, and that it is better to use less cognitively complex animals (such as zebrafish) than more complex animals (such as dogs). First, we criticise some justifications for the claim that human beings and more complex animals have higher moral status. We argue that contemporary approaches that attribute equal moral status to all beings that are capable of conscious strivings strivings (e.g. avoiding pain and anxiety; aiming to eat and play) are based on more plausible assumptions. Second, we argue that it is problematic to assume that less cognitively complex animals have a lesser sensory and emotional experience than more complex beings across the board. In specific cases, there might be good reasons to assume that more complex beings would be harmed more by a specific physical or environmental intervention, but it might also be that they sometimes are harmed less because of a better ability to cope. Determining whether a specific experiment is justified is therefore a complex issue. Our aim in this chapter is to stimulate further reflection on these common assumptions behind the use of animal models for psychopathologies. In

  8. Dosimetry and Risk Assessment: Fundamental Concepts

    SciTech Connect

    Fisher, Darrell R.

    2005-12-29

    Radiation dosimetry is important for characterizing radiation exposures and for risk assessment. In a medical setting, dosimetry is important for evaluating the safety of administered radiopharmaceuticals and for planning the safe administration of therapeutic radionuclides. Environmental dosimetry helps establish the safety of radionuclide releases from electric power production and other human activities. Internal and external dosimetry help us understand the consequences of radiation exposure. The absorbed dose is the fundamental quantity in radiation dosimetry from which all other operational values in radiation protection are obtained. Equivalent dose to tissue and effective dose to the whole body are derivatives of absorbed dose and constructs of risk. Mathematical systems supported by computer software facilitate dose calculations and make it possible to estimate internal dose based on bioassay or other biokinetic data. Risk coefficients for radiation-induced cancer rely primarily on data from animal studies and long-term observations of the Hiroshima and Nagasaki bomb survivors. Low-dose research shows that mechanisms of radiation interactions with tissue are dose-dependent, but the resulting biological effects are not necessarily linear with absorbed dose. Thus, the analysis of radiation effects and associated risks must account for the influences of microscopic energy distributions at the cellular level, dose-rate, cellular repair of sub-lethal radiation damage, and modifying factors such as bystander effects, adaptive response, and genomic instability.

  9. Vapor Dosimetry in the Nose and Upper Airways of Humans

    SciTech Connect

    Thrall, Karla D.

    2010-04-01

    A number of methodologies have been reported for measuring vapor uptake efficiencies in the upper respiratory tract of experimental animals (1). Hybrid computational fluid dynamic (CFD) and physiologically based pharmacokinetic (PBPK) models, as described by Frederick et al. (2) that incorporate information on the anatomy of both rats and humans have been used to improve interspecies dosimetric corrections for human health risk assessments. However, validation of these models requires sufficient experimental data, and robust data defining the role of the upper respiratory tract in modulating the absorption of gases and vapors in human volunteers, are lacking. A survey of the available literature shows a limited number of experimental studies to evaluate the dosimetry of vapors in the nose and upper airways of humans. The scarcity of literature data undoubtedly reflects the complication of conducting controlled studies in human volunteers, and with the exception of a few limited studies, little experimental data is available. This chapter will highlight studies specific for nasal dosimetry data from humans and briefly review modeling approaches for predictive extrapolations from animal data.

  10. The pain of pain: challenges of animal behavior models.

    PubMed

    Barrett, James E

    2015-04-15

    Berend Olivier has had a long-standing interest in the utility of animal models for a wide variety of therapeutic indications. His work has spanned multiple types of models, blending ethological, or species typical and naturalistic behaviors, along with methodologies based on learned behavior. He has consistently done so, from an analytical as well as predictive perspective, and has made multiple contributions while working in both the pharmaceutical industry and within an academic institution. Although focused primarily on psychiatric disorders, Berend has conducted research in the area of pain in humans and in animals, demonstrating an expansive appreciation for the breadth, scope and significance of the science and applications of the discipline of pharmacology to these diverse areas. This review focuses on the use of animal models in pain research from the perspective of the long-standing deficiencies in the development of therapeutics in this area and from a preclinical perspective where the translational weaknesses have been quite problematic. The challenges confronting animal models of pain, however, are not unique to this area of research, as they cut across several therapeutic areas. Despite the deficiencies, failures and concerns, existing animal models of pain continue to be of widespread use and are essential to progress in pain research as well as in other areas. Although not focusing on specific animal models of pain, this paper seeks to examine general issues facing the use of these models. It does so by exploring alternative approaches which capture recent developments, which build upon principles and concepts we have learned from Berend's contributions, and which provide the prospect of helping to address the absence of novel therapeutics in this area.

  11. Dosimetry Modeling for Predicting Radiolytic Production at the Spent Fuel - Water Interface

    SciTech Connect

    Miller, William H.; Kline, Amanda J.; Hanson, Brady D.

    2006-04-30

    Modeling of the alpha, beta, and gamma dose from spent fuel as a function of particle size and fuel to water ratio was examined. These doses will be combined with modeling of G values and interactions to determine the concentration of various species formed at the fuel water interface and their affect on dissolution rates.

  12. Computer simulation models are implementable as replacements for animal experiments.

    PubMed

    Badyal, Dinesh K; Modgill, Vikas; Kaur, Jasleen

    2009-04-01

    It has become increasingly difficult to perform animal experiments, because of issues related to the procurement of animals, and strict regulations and ethical issues related to their use. As a result, it is felt that the teaching of pharmacology should be more clinically oriented and that unnecessary animal experimentation should be avoided. Although a number of computer simulation models (CSMs) are available, they are not being widely used. Interactive demonstrations were conducted to encourage the departmental faculty to use CSMs. Four different animal experiments were selected, that dealt with actions of autonomic drugs. The students observed demonstrations of animal experiments involving conventional methods and the use of CSMs. This was followed by hands-on experience of the same experiment, but using CSMs in small groups, instead of hands-on experience with the animal procedures. Test scores and feedback showed that there was better understanding of the mechanisms of action of the drugs, gained in a shorter time. The majority of the students found the teaching programme used to be good to excellent. CSMs can be used repeatedly and independently by students, and this avoids unnecessary experimentation and also causing pain and trauma to animals. The CSM programme can be implemented in existing teaching schedules for pharmacology undergraduate teaching with basic infrastructure support, and is readily adaptable for use by other institutes.

  13. Lessons Learned from Animal Models of Inherited Bleeding Disorders

    PubMed Central

    Nichols, Timothy C.

    2014-01-01

    Advances in treatment of hemophilia and von Willebrand disease (VWD) depend heavily on the availability of well-characterized animal models. These animals faithfully recapitulate the severe bleeding phenotype that occurs in humans with these inherited bleeding disorders. Research in these animal models represents important early and intermediate steps of translational research aimed at addressing current limitations in treatment such as the development of inhibitory antibodies to coagulation factors VIII and IX (FVIII, FIX) or von Willebrand factor (VWF), the life-long need for frequent venous access, the expense of therapy, and the ongoing need for improved ex vivo coagulation assays and in vivo methods for assessing hemostasis. The primary strengths of research that utilizes these highly relevant animal models include the development of better and safer treatments for hemophilia and VWD. Careful consideration of the strengths and limitations of the specific models is essential for optimizing chances for successful translation of advances to clinical medicine that benefits humans and animals. PMID:26052366

  14. Pain assessment in animal models: do we need further studies?

    PubMed

    Gigliuto, Carmelo; De Gregori, Manuela; Malafoglia, Valentina; Raffaeli, William; Compagnone, Christian; Visai, Livia; Petrini, Paola; Avanzini, Maria Antonietta; Muscoli, Carolina; Viganò, Jacopo; Calabrese, Francesco; Dominioni, Tommaso; Allegri, Massimo; Cobianchi, Lorenzo

    2014-01-01

    In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal-dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals.

  15. Amphibians as animal models for laboratory research in physiology.

    PubMed

    Burggren, Warren W; Warburton, Stephen

    2007-01-01

    The concept of animal models is well honored, and amphibians have played a prominent part in the success of using key species to discover new information about all animals. As animal models, amphibians offer several advantages that include a well-understood basic physiology, a taxonomic diversity well suited to comparative studies, tolerance to temperature and oxygen variation, and a greater similarity to humans than many other currently popular animal models. Amphibians now account for approximately 1/4 to 1/3 of lower vertebrate and invertebrate research, and this proportion is especially true in physiological research, as evident from the high profile of amphibians as animal models in Nobel Prize research. Currently, amphibians play prominent roles in research in the physiology of musculoskeletal, cardiovascular, renal, respiratory, reproductive, and sensory systems. Amphibians are also used extensively in physiological studies aimed at generating new insights in evolutionary biology, especially in the investigation of the evolution of air breathing and terrestriality. Environmental physiology also utilizes amphibians, ranging from studies of cryoprotectants for tissue preservation to physiological reactions to hypergravity and space exploration. Amphibians are also playing a key role in studies of environmental endocrine disruptors that are having disproportionately large effects on amphibian populations and where specific species can serve as sentinel species for environmental pollution. Finally, amphibian genera such as Xenopus, a genus relatively well understood metabolically and physiologically, will continue to contribute increasingly in this new era of systems biology and "X-omics."

  16. Pain assessment in animal models: do we need further studies?

    PubMed Central

    Gigliuto, Carmelo; De Gregori, Manuela; Malafoglia, Valentina; Raffaeli, William; Compagnone, Christian; Visai, Livia; Petrini, Paola; Avanzini, Maria Antonietta; Muscoli, Carolina; Viganò, Jacopo; Calabrese, Francesco; Dominioni, Tommaso; Allegri, Massimo; Cobianchi, Lorenzo

    2014-01-01

    In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals. PMID:24855386

  17. Diabetic cardiac autonomic neuropathy: insights from animal models.

    PubMed

    Stables, Catherine L; Glasser, Rebecca L; Feldman, Eva L

    2013-10-01

    Cardiac autonomic neuropathy (CAN) is a relatively common and often devastating complication of diabetes. The major clinical signs are tachycardia, exercise intolerance, and orthostatic hypotension, but the most severe aspects of this complication are high rates of cardiac events and mortality. One of the earliest manifestations of CAN is reduced heart rate variability, and detection of this, along with abnormal results in postural blood pressure testing and/or the Valsalva maneuver, are central to diagnosis of the disease. The treatment options for CAN, beyond glycemic control, are extremely limited and lack evidence of efficacy. The underlying molecular mechanisms are also poorly understood. Thus, CAN is associated with a poor prognosis and there is a compelling need for research to understand, prevent, and reverse CAN. In this review of the literature we examine the use and usefulness of animal models of CAN in diabetes. Compared to other diabetic complications, the number of animal studies of CAN is very low. The published studies range across a variety of species, methods of inducing diabetes, and timescales examined, leading to high variability in study outcomes. The lack of well-characterized animal models makes it difficult to judge the relevance of these models to the human disease. One major advantage of animal studies is the ability to probe underlying molecular mechanisms, and the limited numbers of mechanistic studies conducted to date are outlined. Thus, while animal models of CAN in diabetes are crucial to better understanding and development of therapies, they are currently under-used.

  18. Animal Models in Behçet's Disease.

    PubMed

    Yildirim, Ozlem

    2012-01-01

    Behçet's disease is a chronic, recurrent, multisystemic, inflammatory disorder affecting mainly the oral and urogenital mucosa and the uveal tract. Although the etiology and pathogenesis of Behçet's disease are unknown, numerous etiologies have been proposed, including environmental, infectious, and immunological factors; an autoimmune basis, characterized by circulating immune complexes and complement activation, has gained increasing acceptance. To test and understand immunopathogenesis of Behçet's disease, animal models were developed based on enviromental pollutants, bacterial and human heat shock protein derived peptides, and virus injections. Using these animal models separately and/or concurrently allows for a more effective investigation into Behçet's disease. Animal models developed in the last 10 years aim at the development of efficient and safe treatment options.

  19. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    SciTech Connect

    Yang, Xiaoxia Doerge, Daniel R.; Fisher, Jeffrey W.

    2013-07-01

    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys.

  20. Minireview: Epigenetic programming of diabetes and obesity: animal models.

    PubMed

    Seki, Yoshinori; Williams, Lyda; Vuguin, Patricia M; Charron, Maureen J

    2012-03-01

    A growing body of evidence suggests that the intrauterine (IU) environment has a significant and lasting effect on the long-term health of the growing fetus and the development of metabolic disease in later life as put forth in the fetal origins of disease hypothesis. Metabolic diseases have been associated with alterations in the epigenome that occur without changes in the DNA sequence, such as cytosine methylation of DNA, histone posttranslational modifications, and micro-RNA. Animal models of epigenetic modifications secondary to an altered IU milieu are an invaluable tool to study the mechanisms that determine the development of metabolic diseases, such as diabetes and obesity. Rodent and nonlitter bearing animals are good models for the study of disease, because they have similar embryology, anatomy, and physiology to humans. Thus, it is feasible to monitor and modify the IU environment of animal models in order to gain insight into the molecular basis of human metabolic disease pathogenesis. In this review, the database of PubMed was searched for articles published between 1999 and 2011. Key words included epigenetic modifications, IU growth retardation, small for gestational age, animal models, metabolic disease, and obesity. The inclusion criteria used to select studies included animal models of epigenetic modifications during fetal and neonatal development associated with adult metabolic syndrome. Experimental manipulations included: changes in the nutritional status of the pregnant female (calorie-restricted, high-fat, or low-protein diets during pregnancy), as well as the father; interference with placenta function, or uterine blood flow, environmental toxin exposure during pregnancy, as well as dietary modifications during the neonatal (lactation) as well as pubertal period. This review article is focused solely on studies in animal models that demonstrate epigenetic changes that are correlated with manifestation of metabolic disease, including diabetes

  1. ELECTRON ABSORBED FRACTIONS IN AN IMAGE-BASED MICROSCOPIC SKELETAL DOSIMETRY MODEL OF CHINESE ADULT MALE.

    PubMed

    Gao, Shenshen; Ren, Li; Qiu, Rui; Wu, Zhen; Li, Chunyan; Li, Junli

    2017-01-10

    Based on the Chinese reference adult male voxel model, a set of microscopic skeletal models of Chinese adult male is constructed through the processes of computed tomography (CT) imaging, bone coring, micro-CT imaging, image segmentation, merging into macroscopic bone model and implementation in Geant4. At the step of image segmentation, a new bone endosteum (BE) segmentation method is realized by sampling. The set of model contains 32 spongiosa samples with voxel size of 19 μm cubes. The microscopic spongiosa bone data for Chinese adult male are provided. Electron absorbed fractions in red bone marrow (RBM) and BE are calculated. Source tissues include the bone marrow (red and yellow), trabecular bone (surfaces and volumes) and cortical bone (surfaces and volumes). Target tissues include RBM and BE. Electron energies range from 10 keV to 10 MeV. Additionally, comparison of the result with other investigations is provided.

  2. Nicotine neuroprotection against nigrostriatal damage: importance of the animal model.

    PubMed

    Quik, Maryka; O'Neill, Michael; Perez, Xiomara A

    2007-05-01

    Parkinson's disease is a neurodegenerative movement disorder that is characterized by a loss of nigrostriatal dopamine-containing neurons. Unexpectedly, there is a reduced incidence of Parkinson's disease in tobacco users. This finding is important because the identification of the component(s) responsible for this effect could lead to therapeutic strategies to slow down or halt the progression of Parkinson's disease. Results from cell culture models consistently show that nicotine protects against neurotoxicity. However, data from animal models of nigrostriatal damage are conflicting, thus raising questions about a neuroprotective role of nicotine. Accumulating evidence indicates that discrepancies are observed primarily in mouse models of the disease. By contrast, reproducible protection occurs in rat models and in a nonhuman primate parkinsonian model that closely resembles the human disease. These findings highlight the need to use the appropriate animal model and treatment conditions when testing putative neuroprotective agents.

  3. Continuous-time discrete-space models for animal movement

    USGS Publications Warehouse

    Hanks, Ephraim M.; Hooten, Mevin B.; Alldredge, Mat W.

    2015-01-01

    The processes influencing animal movement and resource selection are complex and varied. Past efforts to model behavioral changes over time used Bayesian statistical models with variable parameter space, such as reversible-jump Markov chain Monte Carlo approaches, which are computationally demanding and inaccessible to many practitioners. We present a continuous-time discrete-space (CTDS) model of animal movement that can be fit using standard generalized linear modeling (GLM) methods. This CTDS approach allows for the joint modeling of location-based as well as directional drivers of movement. Changing behavior over time is modeled using a varying-coefficient framework which maintains the computational simplicity of a GLM approach, and variable selection is accomplished using a group lasso penalty. We apply our approach to a study of two mountain lions (Puma concolor) in Colorado, USA.

  4. Animal models of efficacy to accelerate drug discovery in malaria.

    PubMed

    Jiménez-Díaz, María Belén; Viera, Sara; Fernández-Alvaro, Elena; Angulo-Barturen, Iñigo

    2014-01-01

    The emergence of resistance to artemisinins and the renewed efforts to eradicate malaria demand the urgent development of new drugs. In this endeavour, the evaluation of efficacy in animal models is often a go/no go decision assay in drug discovery. This important role relies on the capability of animal models to assess the disposition, toxicology and efficacy of drugs in a single test. Although the relative merits of each efficacy model of malaria as human surrogate have been extensively discussed, there are no critical analyses on the use of such models in current drug discovery. In this article, we intend to analyse how efficacy models are used to discover new antimalarial drugs. Our analysis indicates that testing drug efficacy is often the last assay in each discovery stage and the experimental designs utilized are not optimized to expedite decision-making and inform clinical development. In light of this analysis, we propose new ways to accelerate drug discovery using efficacy models.

  5. An Eye Model for Computational Dosimetry Using A Multi-Scale Voxel Phantom

    NASA Astrophysics Data System (ADS)

    Caracappa, Peter F.; Rhodes, Ashley; Fiedler, Derek

    2014-06-01

    The lens of the eye is a radiosensitive tissue with cataract formation being the major concern. Recently reduced recommended dose limits to the lens of the eye have made understanding the dose to this tissue of increased importance. Due to memory limitations, the voxel resolution of computational phantoms used for radiation dose calculations is too large to accurately represent the dimensions of the eye. A revised eye model is constructed using physiological data for the dimensions of radiosensitive tissues, and is then transformed into a high-resolution voxel model. This eye model is combined with an existing set of whole body models to form a multi-scale voxel phantom, which is used with the MCNPX code to calculate radiation dose from various exposure types. This phantom provides an accurate representation of the radiation transport through the structures of the eye. Two alternate methods of including a high-resolution eye model within an existing whole body model are developed. The accuracy and performance of each method is compared against existing computational phantoms.

  6. Effect of Human Model Height and Sex on Induced Current Dosimetry in Household Induction Heater Users

    NASA Astrophysics Data System (ADS)

    Tarao, Hiroo; Hayashi, Noriyuki; Isaka, Katsuo

    Induced currents in the high-resolution, anatomical human models are numerically calculated by the impedance method. The human models are supposed to be exposed to highly inhomogeneous 20.9 kHz magnetic fields from a household induction heater (IH). In the case of the adult models, the currents ranging from 5 to 19 mA/m2 are induced for between the shoulder and lower abdomen. Meanwhile, in the case of the child models, the currents ranging from 5 to 21 mA/m2 are induced for between the head and abdomen. In particular, the induced currents near the brain tissue are almost the same as those near the abdomen. When the induced currents in the central nervous system tissues are considered, the induced currents in the child model are 2.1 to 6.9 times as large as those in the adult model under the same B-field exposure environment. These results suggest the importance of further investigation intended for a pregnant female who uses the IH as well as for a child (or the IH users of small standing height).

  7. Animal models of skin disease for drug discovery

    PubMed Central

    Avci, Pinar; Sadasivam, Magesh; Gupta, Asheesh; De Melo, Wanessa CMA; Huang, Ying-Ying; Yin, Rui; Rakkiyappan, Chandran; Kumar, Raj; Otufowora, Ayodeji; Nyame, Theodore; Hamblin, Michael R

    2013-01-01

    Introduction Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field. Areas covered In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined. Expert opinion Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia. PMID:23293893

  8. Animal Models of Diabetic Retinopathy: Summary and Comparison

    PubMed Central

    Lo, Amy C. Y.

    2013-01-01

    Diabetic retinopathy (DR) is a microvascular complication associated with chronic exposure to hyperglycemia and is a major cause of blindness worldwide. Although clinical assessment and retinal autopsy of diabetic patients provide information on the features and progression of DR, its underlying pathophysiological mechanism cannot be deduced. In order to have a better understanding of the development of DR at the molecular and cellular levels, a variety of animal models have been developed. They include pharmacological induction of hyperglycemia and spontaneous diabetic rodents as well as models of angiogenesis without diabetes (to compensate for the absence of proliferative DR symptoms). In this review, we summarize the existing protocols to induce diabetes using STZ. We also describe and compare the pathological presentations, in both morphological and functional aspects, of the currently available DR animal models. The advantages and disadvantages of using different animals, ranging from zebrafish, rodents to other higher-order mammals, are also discussed. Until now, there is no single model that displays all the clinical features of DR as seen in human. Yet, with the understanding of the pathological findings in these animal models, researchers can select the most suitable models for mechanistic studies or drug screening. PMID:24286086

  9. The role of animal models in tendon research

    PubMed Central

    Hast, M. W.; Zuskov, A.; Soslowsky, L. J.

    2014-01-01

    Tendinopathy is a debilitating musculoskeletal condition which can cause significant pain and lead to complete rupture of the tendon, which often requires surgical repair. Due in part to the large spectrum of tendon pathologies, these disorders continue to be a clinical challenge. Animal models are often used in this field of research as they offer an attractive framework to examine the cascade of processes that occur throughout both tendon pathology and repair. This review discusses the structural, mechanical, and biological changes that occur throughout tendon pathology in animal models, as well as strategies for the improvement of tendon healing. Cite this article: Bone Joint Res 2014;3:193–202. PMID:24958818

  10. Translational value of animal models of kidney failure.

    PubMed

    Ortiz, Alberto; Sanchez-Niño, Maria D; Izquierdo, Maria C; Martin-Cleary, Catalina; Garcia-Bermejo, Laura; Moreno, Juan A; Ruiz-Ortega, Marta; Draibe, Juliana; Cruzado, Josep M; Garcia-Gonzalez, Miguel A; Lopez-Novoa, Jose M; Soler, Maria J; Sanz, Ana B

    2015-07-15

    Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with decreased renal function and increased mortality risk, while the therapeutic armamentarium is unsatisfactory. The availability of adequate animal models may speed up the discovery of biomarkers for disease staging and therapy individualization as well as design and testing of novel therapeutic strategies. Some longstanding animal models have failed to result in therapeutic advances in the clinical setting, such as kidney ischemia-reperfusion injury and diabetic nephropathy models. In this regard, most models for diabetic nephropathy are unsatisfactory in that they do not evolve to renal failure. Satisfactory models for additional nephropathies are needed. These include anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, IgA nephropathy, anti-phospholipase-A2-receptor (PLA2R) membranous nephropathy and Fabry nephropathy. However, recent novel models hold promise for clinical translation. Thus, the AKI to CKD translation has been modeled, in some cases with toxins of interest for human CKD such as aristolochic acid. Genetically modified mice provide models for Alport syndrome evolving to renal failure that have resulted in clinical recommendations, polycystic kidney disease models that have provided clues for the development of tolvaptan, that was recently approved for the human disease in Japan; and animal models also contributed to target C5 with eculizumab in hemolytic uremic syndrome. Some ongoing trials explore novel concepts derived from models, such TWEAK targeting as tissue protection for lupus nephritis. We now review animal models reproducing diverse, genetic and acquired, causes of AKI and CKD evolving to kidney failure and discuss the contribution to clinical translation and prospects for the future.

  11. Validation of Human Physiologically Based Pharmacokinetic Model for Vinyl Acetate Against Human Nasal Dosimetry Data

    SciTech Connect

    Hinderliter, Paul M.; Thrall, Karla D.; Corley, Rick A.; Bloemen, Louis J.; Bogdanffy, M S.

    2005-05-01

    Vinyl acetate has been shown to induce nasal lesions in rodents in inhalation bioassays. A physiologically based pharmacokinetic (PBPK) model for vinyl acetate has been used in human risk assessment, but previous in vivo validation was conducted only in rats. Controlled human exposures to vinyl acetate were conducted to provide validation data for the application of the model in humans. Five volunteers were exposed to 1, 5, and 10 ppm 13 C1 , 13 C2 vinyl acetate via inhalation. A probe inserted into thenasopharyngeal region sampled both 13 C1 , 13 C2 vinyl acetate and the major metabolite 13 C1 , 13 C2 acetaldehyde during rest and light exercise. Nasopharyngeal air concentrations were analyzed in real time by ion trap mass spectrometry (MS/MS). Experimental concentrations of both vinyl acetate and acetaldehyde were then compared to predicted concentrations calculated from the previously published human model. Model predictions of vinyl acetate nasal extraction compared favorably with measured values of vinyl acetate, as did predictions of nasopharyngeal acetaldehyde when compared to measured acetaldehyde. The results showed that the current PBPK model structure and parameterization are appropriate for vinyl acetate. These analyses were conducted from 1 to 10 ppm vinyl acetate, a range relevant to workplace exposure standards but which would not be expected to saturate vinyl acetate metabolism. Risk assessment based on this model further concluded that 24 h per day exposures up to 1 ppm do not present concern regarding cancer or non-cancer toxicity. Validation of the vinyl acetate human PBPK model provides support for these conclusions.

  12. Validation of human physiologically based pharmacokinetic model for vinyl acetate against human nasal dosimetry data.

    PubMed

    Hinderliter, P M; Thrall, K D; Corley, R A; Bloemen, L J; Bogdanffy, M S

    2005-05-01

    Vinyl acetate has been shown to induce nasal lesions in rodents in inhalation bioassays. A physiologically based pharmacokinetic (PBPK) model for vinyl acetate has been used in human risk assessment, but previous in vivo validation was conducted only in rats. Controlled human exposures to vinyl acetate were conducted to provide validation data for the application of the model in humans. Five volunteers were exposed to 1, 5, and 10 ppm 13C1,13C2 vinyl acetate via inhalation. A probe inserted into the nasopharyngeal region sampled both 13C1,13C2 vinyl acetate and the major metabolite 13C1,13C2 acetaldehyde during rest and light exercise. Nasopharyngeal air concentrations were analyzed in real time by ion trap mass spectrometry (MS/MS). Experimental concentrations of both vinyl acetate and acetaldehyde were then compared to predicted concentrations calculated from the previously published human model. Model predictions of vinyl acetate nasal extraction compared favorably with measured values of vinyl acetate, as did predictions of nasopharyngeal acetaldehyde when compared to measured acetaldehyde. The results showed that the current PBPK model structure and parameterization are appropriate for vinyl acetate. These analyses were conducted from 1 to 10 ppm vinyl acetate, a range relevant to workplace exposure standards but which would not be expected to saturate vinyl acetate metabolism. Risk assessment based on this model further concluded that 24 h per day exposures up to 1 ppm do not present concern regarding cancer or non-cancer toxicity. Validation of the vinyl acetate human PBPK model provides support for these conclusions.

  13. Respiratory tract clearance model for dosimetry and bioassay of inhaled radionuclides

    SciTech Connect

    Bailey, M.R.; Birchall, A. ); Cuddihy, R.G. ); James, A.C. ); Roy, M. . Inst. de Protection et de Surete Nucleaire)

    1990-07-01

    The ICRP Task Group on Respiratory Tract Models is developing a model to describe the retention and clearance of deposited radionuclides for dose-intake calculations and interpretation of bioassay data. Clearance from each region is treated as competition between mechanical transport, which moves particles to the gastro-intestinal tract and lymph nodes, and the translocation of material to blood. It is assumed that mechanical transport rates are the same for all materials, and that rates of translocation to blood are the same in all regions. Time-dependent clearance is represented by combinations of compartments. Representative values of parameters to describe mechanical transport from the human respiratory tract have been estimated, and guidance is given on the determination of translocation rates. It is emphasized that the current version of the model described here is still provisional. 30 refs.

  14. Cardiovascular imaging: what have we learned from animal models?

    PubMed

    Santos, Arnoldo; Fernández-Friera, Leticia; Villalba, María; López-Melgar, Beatriz; España, Samuel; Mateo, Jesús; Mota, Ruben A; Jiménez-Borreguero, Jesús; Ruiz-Cabello, Jesús

    2015-01-01

    Cardiovascular imaging has become an indispensable tool for patient diagnosis and follow up. Probably the wide clinical applications of imaging are due to the possibility of a detailed and high quality description and quantification of cardiovascular system structure and function. Also phenomena that involve complex physiological mechanisms and biochemical pathways, such as inflammation and ischemia, can be visualized in a non-destructive way. The widespread use and evolution of imaging would not have been possible without animal studies. Animal models have allowed for instance, (i) the technical development of different imaging tools, (ii) to test hypothesis generated from human studies and finally, (iii) to evaluate the translational relevance assessment of in vitro and ex-vivo results. In this review, we will critically describe the contribution of animal models to the use of biomedical imaging in cardiovascular medicine. We will discuss the characteristics of the most frequent models used in/for imaging studies. We will cover the major findings of animal studies focused in the cardiovascular use of the repeatedly used imaging techniques in clinical practice and experimental studies. We will also describe the physiological findings and/or learning processes for imaging applications coming from models of the most common cardiovascular diseases. In these diseases, imaging research using animals has allowed the study of aspects such as: ventricular size, shape, global function, and wall thickening, local myocardial function, myocardial perfusion, metabolism and energetic assessment, infarct quantification, vascular lesion characterization, myocardial fiber structure, and myocardial calcium uptake. Finally we will discuss the limitations and future of imaging research with animal models.

  15. Animal Models of Maternal Immune Activation in Depression Research

    PubMed Central

    Ronovsky, Marianne; Berger, Stefanie; Molz, Barbara; Berger, Angelika; Pollak, Daniela D.

    2016-01-01

    Abstract: Background Depression and schizophrenia are debilitating mental illnesses with significant socio-economic impact. The high degree of comorbidity between the two disorders, and shared symptoms and risk factors, suggest partly common pathogenic mechanisms. Supported by human and animal studies, maternal immune activation (MIA) has been intimately associated with the development of schizophrenia. However, the link between MIA and depression has remained less clear, in part due to the lack of appropriate animal models. Objective Here we aim to summarize findings obtained from studies using MIA animal models and discuss their relevance for preclinical depression research. Methods Results on molecular, cellular and behavioral phenotypes in MIA animal models were collected by literature search (PubMed) and evaluated for their significance for depression. Results Several reports on offspring depression-related behavioral alterations indicate an involvement of MIA in the development of depression later in life. Depression-related behavioral phenotypes were frequently paralleled by neurogenic and neurotrophic deficits and modulated by several genetic and environmental factors. Conclusion Literature evidence analyzed in this review supports a relevance of MIA as animal model for a specific early life adversity, which may prime an individual for the development of distinct psychopathologies later life. MIA animal models may present a unique tool for the identification of additional exogenous and endogenous factors, which are required for the manifestation of a specific neuropsychiatric disorder, such as depression, later in life. Hereby, novel insights into the molecular mechanisms involved in the pathophysiology of depression may be obtained, supporting the identification of alternative therapeutic strategies. PMID:26666733

  16. Contemporary Animal Models For Human Gene Therapy Applications.

    PubMed

    Gopinath, Chitra; Nathar, Trupti Job; Ghosh, Arkasubhra; Hickstein, Dennis Durand; Remington Nelson, Everette Jacob

    2015-01-01

    Over the past three decades, gene therapy has been making considerable progress as an alternative strategy in the treatment of many diseases. Since 2009, several studies have been reported in humans on the successful treatment of various diseases. Animal models mimicking human disease conditions are very essential at the preclinical stage before embarking on a clinical trial. In gene therapy, for instance, they are useful in the assessment of variables related to the use of viral vectors such as safety, efficacy, dosage and localization of transgene expression. However, choosing a suitable disease-specific model is of paramount importance for successful clinical translation. This review focuses on the animal models that are most commonly used in gene therapy studies, such as murine, canine, non-human primates, rabbits, porcine, and a more recently developed humanized mice. Though small and large animals both have their own pros and cons as disease-specific models, the choice is made largely based on the type and length of study performed. While small animals with a shorter life span could be well-suited for degenerative/aging studies, large animals with longer life span could suit longitudinal studies and also help with dosage adjustments to maximize therapeutic benefit. Recently, humanized mice or mouse-human chimaeras have gained interest in the study of human tissues or cells, thereby providing a more reliable understanding of therapeutic interventions. Thus, animal models are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to a gene therapy clinical trial.

  17. Cardiovascular imaging: what have we learned from animal models?

    PubMed Central

    Santos, Arnoldo; Fernández-Friera, Leticia; Villalba, María; López-Melgar, Beatriz; España, Samuel; Mateo, Jesús; Mota, Ruben A.; Jiménez-Borreguero, Jesús; Ruiz-Cabello, Jesús

    2015-01-01

    Cardiovascular imaging has become an indispensable tool for patient diagnosis and follow up. Probably the wide clinical applications of imaging are due to the possibility of a detailed and high quality description and quantification of cardiovascular system structure and function. Also phenomena that involve complex physiological mechanisms and biochemical pathways, such as inflammation and ischemia, can be visualized in a non-destructive way. The widespread use and evolution of imaging would not have been possible without animal studies. Animal models have allowed for instance, (i) the technical development of different imaging tools, (ii) to test hypothesis generated from human studies and finally, (iii) to evaluate the translational relevance assessment of in vitro and ex-vivo results. In this review, we will critically describe the contribution of animal models to the use of biomedical imaging in cardiovascular medicine. We will discuss the characteristics of the most frequent models used in/for imaging studies. We will cover the major findings of animal studies focused in the cardiovascular use of the repeatedly used imaging techniques in clinical practice and experimental studies. We will also describe the physiological findings and/or learning processes for imaging applications coming from models of the most common cardiovascular diseases. In these diseases, imaging research using animals has allowed the study of aspects such as: ventricular size, shape, global function, and wall thickening, local myocardial function, myocardial perfusion, metabolism and energetic assessment, infarct quantification, vascular lesion characterization, myocardial fiber structure, and myocardial calcium uptake. Finally we will discuss the limitations and future of imaging research with animal models. PMID:26539113

  18. Animal models in the drug discovery pipeline for Alzheimer's disease

    PubMed Central

    Van Dam, Debby; De Deyn, Peter Paul

    2011-01-01

    With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes – which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371009

  19. Light dosimetry for focused and defocused beam irradiation in multi-layered tissue models

    NASA Astrophysics Data System (ADS)

    Petrova, Kremena S.; Stoykova, Elena V.

    2006-09-01

    Treatment of acupuncture points, trigger points, joint inflammations in low level laser therapy as well as various applications of lasers for treatment of soft tissues in dental medicine, require irradiation by a narrow converging laser beam. The aim of this study is to compare light delivery produced by focused or defocused narrow beam irradiation in a multi-layered skin tissue model at increasing depth of the target. The task is solved by 3-D Monte-Carlo simulation for matched and mismatched refractive indices at the tissue/ambient medium interface. The modeled light beams have a circular cross-section at the tissue entrance with uniform or Gaussian intensity distribution. Three are the tissue models used in simulation : i) a bloodless skin layer; ii) a bloodless skin layer with embedded scattering object; iii) a skin layer with small blood vessels of varying size, which are modeled as infinite cylinders parallel to the tissue surface located at different depths. Optical properties (absorption coefficient, scattering coefficient, anisotropy factor, g, and index of refraction) of different tissue constituents are chosen from the literature.

  20. COMPUTATIONAL TOXICOLOGY: AN IN SILLICO DOSIMETRY MODEL FOR THE ASSESSMENT OF AIR POLLUTANTS

    EPA Science Inventory

    To accurately assess the threat to human health presented by airborne contaminants, it is necessary to know the deposition patterns of particulate matter (PM) within the respiratory system. To provide a foundation for computational toxicology, we have developed an in silico model...

  1. [Animal models for the study of Helicobacter pylori infection].

    PubMed

    Miszczyk, Eliza; Walencka, Maria; Mikołajczyk-Chmiela, Magdalena

    2014-05-15

    The Gram-negative bacillus Helicobacter pylori is widely recognized as a major etiologic agent responsible for chronic active gastritis, peptic ulcers, the development of gastric cancer and mucosa-associated lymphoid tissue (MALT lymphoma). Still, little is known about the natural history of H. pylori infection, since patients usually after many years of not suffering from symptoms of the infection are simply asymptomatic. Since the research investigators carried out on human models has many limitations, there is an urgent need for the development of an animal model optimal and suitable for the monitoring of H. pylori infections. This review summarizes the recent findings on the suitability of animal models used in H. pylori research. Several animal models are useful for the assessment of pathological, microbiological and immunological consequences of infection, which makes it possible to monitor the natural history of H. pylori infection. Preclinical investigations on animal models are an essential stage of research which enrich the knowledge on treatment and prevention strategies.

  2. Animal models for prenatal gene therapy: the sheep model.

    PubMed

    Abi-Nader, Khalil N; Boyd, Michael; Flake, Alan W; Mehta, Vedanta; Peebles, Donald; David, Anna L

    2012-01-01

    Large animal experiments are vital in the field of prenatal gene therapy, to allow translation from small animals into man. Sheep provide many advantages for such experiments. They have been widely used in research into fetal physiology and pregnancy and the sheep fetus is a similar size to that in the human. Sheep are tolerant to in utero manipulations such as fetoscopy or even hysterotomy, and they are cheaper and easier to maintain than non-human primates. In this chapter, we describe the animal husbandry involved in generating time-mated sheep pregnancies, the large number of injection routes in the fetus that can be achieved using ultrasound or fetoscopic-guided injection, and laparotomy when these more minimally invasive routes of injection are not feasible.

  3. SU-E-T-196: Heat Diffusion Modeling for Digital Holographic Interferometry Dosimetry

    SciTech Connect

    Cavan, A; Meyer, J

    2014-06-01

    Purpose: We have previously demonstrated that with Digital Holographic Interferometry (DHI) 2D spatial calorimetric measurements of high dose rate radiation sources can be obtained. The impact of heat transfer must be considered when undertaking any form of calorimetric measurement, as the radiation induced temperature distributions are subject to degradation due to heat diffusion. Unaccounted for, this limits the accuracy of the approach especially for long delivery times. Methods: 3D modelling of the heat diffusion in water was undertaken, and two different approaches developed to account for this effect. The mathematical framework to describe heat diffusion in 3D was applied, with the differential equations solved numerically using an implicit method. The first approach involved the comparison of the DHI measurements to an independent dose model of the source. The model was forward modeled to account for the heat diffusion during irradiation, allowing a direct comparison to validate the measured results. The second approach involved the correction of the measured data directly, by comparing the temperature distribution of two instances and subtracting the effects of heat diffusion of the first distribution from the second instance. This required the use of the Abel transform to approximate the 3D dose distribution from the 2D DHI results, thus limiting the approach to radiation applications possessing cylindrical symmetry. Results: The first approach resulted in higher accuracy and was more straightforward, but has a major limitation in that the measured results are only able to be utilized in comparison with an independent dose model. The applicability of the second approach is affected by noise in the measurement data and introduces higher uncertainties, but results in higher usability of the final data. Conclusion: Both approaches were implemented, and if used in conjunction would provide the most utility for the interpretation and use of DHI measurements.

  4. Large Animal Models of Neurological Disorders for Gene Therapy

    PubMed Central

    Gagliardi, Christine; Bunnell, Bruce A.

    2009-01-01

    The development of therapeutic interventions for genetic disorders and diseases that affect the central nervous system (CNS) has proven challenging. There has been significant progress in the development of gene therapy strategies in murine models of human disease, but gene therapy outcomes in these models do not always translate to the human setting. Therefore, large animal models are crucial to the development of diagnostics, treatments, and eventual cures for debilitating neurological disorders. This review focuses on the description of large animal models of neurological diseases such as lysosomal storage diseases, Parkinson’s disease, Huntington’s disease, and neuroAIDS. The review also describes the contributions of these models to progress in gene therapy research. PMID:19293458

  5. What Animal Models Can Tell Us About Glaucoma.

    PubMed

    Struebing, Felix L; Geisert, Eldon E

    2015-01-01

    Well defined animal models facilitate the study of ocular diseases. Each model brings a unique perspective to the understanding of the disease process, and in some cases, the models are critical to the development of therapeutic approaches for treatments. This is especially the case for glaucoma. Glaucoma is a family of diseases that can be caused by very different biological processes. The one thing in common is the end result, the loss of retinal ganglion cells and blindness. In this review, we will attempt to relate the findings from a number of animal models to specific types of glaucoma, emphasizing the contributions that each of the models makes to our overall understanding of the complex collection of diseases we call glaucoma.

  6. [Animal models of injury and repair in developing brain].

    PubMed

    Cuestas, Eduardo; Caceres, Alfredo; Palacio, Santiago

    2007-01-01

    Animal models of injury and repair in developing brain. Brain injury is a major contributor to neonatal morbidity and mortality, a considerable group of these children will develop long term neurological sequels. Despite the great clinical and social significance and the advances in neonatal medicine, no therapy yet does exist that prevent or decrease detrimental effects in cases of neonatal brain injury. Our objective was to review recent research in relation to the hypothesis for repair mechanism in the developing brain, based in animal models that show developmental compensatory mechanisms that promote neural and functional plasticity. A better understanding of these adaptive mechanisms will help clinicians to apply knowledge derived from animals to human clinical situations.

  7. Social conflict exacerbates an animal model of multiple sclerosis.

    PubMed

    Meagher, Mary W; Johnson, Robin R; Vichaya, Elisabeth Good; Young, Erin E; Lunt, Shannon; Welsh, C Jane

    2007-07-01

    A growing body of evidence suggests that social conflict is associated with inflammatory disease onset and exacerbations in multiple sclerosis (MS) patients and in animal models of MS. This review illustrates how animal research can be used to elucidate the biobehavioral mechanisms underlying the adverse health effects of social conflict. The authors review studies indicating that social conflict exacerbates a virally initiated animal model of MS. This research suggests that the deleterious effects of social conflict may be partially mediated by stress-induced increases in pro-inflammatory cytokine levels in the central nervous system. In addition, they provide evidence that the adverse health effects of social conflict can be prevented by blocking the stress-induced increases in cytokine activity. This suggests that interventions designed to prevent or reverse the stress-induced increases in cytokine activity may be able to prevent or reverse some of the negative health effects of social conflict in humans.

  8. Animal models of major depression and their clinical implications.

    PubMed

    Czéh, Boldizsár; Fuchs, Eberhard; Wiborg, Ove; Simon, Mária

    2016-01-04

    Major depressive disorder is a common, complex, and potentially life-threatening mental disorder that imposes a severe social and economic burden worldwide. Over the years, numerous animal models have been established to elucidate pathophysiology that underlies depression and to test novel antidepressant treatment strategies. Despite these substantial efforts, the animal models available currently are of limited utility for these purposes, probably because none of the models mimics this complex disorder fully. It is presumable that psychiatric illnesses, such as affective disorders, are related to the complexity of the human brain. Here, we summarize the animal models that are used most commonly for depression, and discuss their advantages and limitations. We discuss genetic models, including the recently developed optogenetic tools and the stress models, such as the social stress, chronic mild stress, learned helplessness, and early-life stress paradigms. Moreover, we summarize briefly the olfactory bulbectomy model, as well as models that are based on pharmacological manipulations and disruption of the circadian rhythm. Finally, we highlight common misinterpretations and often-neglected important issues in this field.

  9. Alcohol-related neurodegeneration and recovery: mechanisms from animal models.

    PubMed

    Crews, Fulton T

    2008-01-01

    Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use. Animal experiments, which can control many factors, have established that alcohol can cause damage to brain cells (i.e., neurons), which results in their loss of structure or function (i.e., neurodegeneration) in multiple brain regions, similar to the damage found in human alcoholics. In addition, animal studies indicate that inhibition of the creation of neurons (i.e., neurogenesis) and other brain-cell genesis contributes to alcoholic neurodegeneration. Animal studies also suggest that neurodegeneration changes cognition, contributing to alcohol use disorders. Risk factors such as adolescent age and genetic predisposition toward alcohol consumption worsen neurodegeneration. Mild impairment of executive functions similar to that found in humans occurs in animals following binge alcohol treatment. Thus, animal studies suggest that heavy alcohol use contributes to neurodegeneration and the progressive loss of control over drinking. Despite the negative consequences of heavy drinking, there is hope of recovery with abstinence, which in animal models can result in neural stem-cell proliferation and the formation of new neurons and other brain cells, indicative of brain growth.

  10. TU-G-BRD-03: IMRT Dosimetry Differences in An Institution with Community and Academic Model

    SciTech Connect

    Srivastava, S; Andersen, A; Das, I; Cheng, C

    2015-06-15

    Purpose: Radiation outcome among institutions can be interpreted meaningfully if the dose delivery and prescription to the target volume is documented accurately and consistently. ICRU-83 recommended specific guidelines in IMRT for target volume definitions and dose reporting. This retrospective study evaluates the pattern of IMRT dose prescription and recording in an academic institution (AI) and a community hospital (CH) models in a single institution with reference to ICRU-83 recommendation. Materials & Methods: Dosimetric information of 625 (500 from academic and 125 from community) patients treated with IMRT was collected retrospectively from the AI and a CH. The dose-volume histogram (DVH) for the target volume of each patient was extracted. Standard dose parameters such as D2, D50, D95, D98, D100, as well as the homogeneity index (HI) defined as (D2-D98)/D50 and monitor units (MUs) were collected. Results: Significant dosimetric variations were observed in disease sites and between AI and CH. The variation in the mean value of D95 for AI is 98.48±4.12 and for CH is 96.41±4.13. A similar pattern was noticed for D50 (104.18±6.04 for AI and 101.05±3.49 for CH). Thus, nearly 95% of patients received dosage higher than 100% to the site viewed by D50 and varied between AI and CH models. The average variation of HI is found to be 0.12±0.08 and 0.11±0.08 for AI and CH model, showing better IMRT treatment plans for academic model compared to community. Conclusion: Even with the implementation of ICRU-83 guidelines, there is a large variation in dose prescription and delivery in IMRT. The variation is institution and site specific. For any meaningful comparison of the IMRT outcome, strict guidelines for dose reporting should be maintained in every institution.

  11. Miniature pigs: a large animal model of cochlear implantation

    PubMed Central

    Yi, Haijin; Guo, Weiwei; Chen, Wei; Chen, Lei; Ye, Jingying; Yang, Shiming

    2016-01-01

    The objective of this paper was to investigate the suitability of the miniature pig as a large animal model of cochlear implantation (CI). Micro-CT scanning and three-dimensional reconstructions of the inner ear were completed in six animals. Photographs of the procedures and measurements of the inner ear were made. The CI procedure was simulated in 10 animals. Electrically evoked auditory brain stem responses (EABRs) and radiographic images were evaluated during or after the CI procedure. Morphological examination and measurements of inner ears of the miniature pigs were completed by micro-CT scanning. The height of the scala tympani was 873.12 µm in the 1st turn, 641.46 µm in the 2nd turn, 445.13 µm in the third turn and 339.19 µm in the fourth turn. The length of the cochlea was 38.6 mm, larger than other animal models (7.2 mm in rats and 22 mm in macaque, for example) and similar to that in the human (36 mm). Commercial electrodes used in humans (870 µm at the end and 630 µm at the tip in diameter) were implanted in the pig’s cochlea, through which normal eABRs were obtained. Radiographic images after the CI procedure revealed electrodes located in the scala tympani of the first and second turns. Compared with traditional animal models, greater similarities of the inner ear between miniature pigs and humans make this animal a potentially useful model for CI studies. PMID:28078020

  12. Multi-scale hybrid models for radiopharmaceutical dosimetry with Geant4.

    PubMed

    Marcatili, S; Villoing, D; Garcia, M P; Bardiès, M

    2014-12-21

    The accuracy of radiopharmaceutical absorbed dose distributions computed through Monte Carlo (MC) simulations is mostly limited by the low spatial resolution of 3D imaging techniques used to define the simulation geometry. This issue also persists with the implementation of realistic hybrid models built using polygonal mesh and/or NURBS as they require to be simulated in their voxel form in order to reduce computation times. The existing trade-off between voxel size and simulation speed leads on one side, in an overestimation of the size of small radiosensitive structures such as the skin or hollow organs walls and, on the other, to unnecessarily detailed voxelization of large, homogeneous structures.We developed a set of computational tools based on VTK and Geant4 in order to build multi-resolution organ models. Our aim is to use different voxel sizes to represent anatomical regions of different clinical relevance: the MC implementation of these models is expected to improve spatial resolution in specific anatomical structures without significantly affecting simulation speed. Here we present the tools developed through a proof of principle example. Our approach is validated against the standard Geant4 technique for the simulation of voxel geometries.

  13. Evaluation of Toxicity Ranking for Metal Oxide Nanoparticles via an in Vitro Dosimetry Model.

    PubMed

    Liu, Rong; Liu, Haoyang Haven; Ji, Zhaoxia; Chang, Chong Hyun; Xia, Tian; Nel, Andre E; Cohen, Yoram

    2015-09-22

    It has been argued that in vitro toxicity testing of engineered nanoparticles (NPs) should consider delivered dose (i.e., NP mass settled per suspension volume) rather than relying exclusively on administered dose (initial NP mass concentration). Delivered dose calculations require quantification of NP sedimentation in tissue cell culture media, taking into consideration fundamental suspension properties. In this article, we calculate delivered dose using a first-principles "particles in a box" sedimentation model, which accounts for the particle size distribution, fractal dimension, and permeability of agglomerated NPs. The sedimentation model was evaluated against external and our own experimental sedimentation data for metal oxide NPs. We then utilized the model to construct delivered dose-response analysis for a library of metal oxide NPs (previously used for hazard ranking and prediction making) in different cell culture media. Hierarchical hazard ranking of the seven (out of 24) toxic metal oxide NPs in our library, using EC50 calculated on the basis of delivered dose, did not measurably differ from our ranking based on administered dose. In contrast, simplified sedimentation calculations based on the assumption of impermeable NP agglomerates of a single average size significantly underestimated the settled NPs' mass, resulting in misinterpretation of toxicity ranking. It is acknowledged that in vitro dose-response outcomes are likely to be shaped by complex toxicodynamics, which include NP/cellular association, triggering of dynamic cell response pathways involved in NP uptake, and multiple physicochemical parameters that influence NP sedimentation and internalization.

  14. The MCART radiation physics core: the quest for radiation dosimetry standardization.

    PubMed

    Kazi, Abdul M; MacVittie, Thomas J; Lasio, Giovanni; Lu, Wei; Prado, Karl L

    2014-01-01

    Dose-related radiobiological research results can only be compared meaningfully when radiation dosimetry is standardized. To this purpose, the National Institute of Allergy and Infectious Diseases (NIAID)-sponsored Medical Countermeasures Against Radiological Threats (MCART) consortium recently created a Radiation Physics Core (RPC) as an entity to assume responsibility of standardizing radiation dosimetry practices among its member laboratories. The animal research activities in these laboratories use a variety of ionizing photon beams from several irradiators such as 250-320 kVp x-ray generators, Cs irradiators, Co teletherapy machines, and medical linear accelerators (LINACs). In addition to this variety of sources, these centers use a range of irradiation techniques and make use of different dose calculation schemes to conduct their experiments. An extremely important objective in these research activities is to obtain a Dose Response Relationship (DRR) appropriate to their respective organ-specific models of acute and delayed radiation effects. A clear and unambiguous definition of the DRR is essential for the development of medical countermeasures. It is imperative that these DRRs are transparent between centers. The MCART RPC has initiated the establishment of standard dosimetry practices among member centers and is introducing a Remote Dosimetry Monitoring Service (RDMS) to ascertain ongoing quality assurance. This paper will describe the initial activities of the MCART RPC toward implementing these standardization goals. It is appropriate to report a summary of initial activities with the intent of reporting the full implementation at a later date.

  15. Basic principles in the radiation dosimetry of nuclear medicine.

    PubMed

    Stabin, Michael; Xu, Xie George

    2014-05-01

    The basic principles of the use of radiation dosimetry in nuclear medicine are reviewed. The basic structure of the main mathematical equations are given and formal dosimetry systems are discussed. An extensive overview of the history and current status of anthropomorphic models (phantoms) is given. The sources and magnitudes of uncertainties in calculated internal dose estimates are reviewed.

  16. Hyperbolic value addition and general models of animal choice.

    PubMed

    Mazur, J E

    2001-01-01

    Three mathematical models of choice--the contextual-choice model (R. Grace, 1994), delay-reduction theory (N. Squires & E. Fantino, 1971), and a new model called the hyperbolic value-added model--were compared in their ability to predict the results from a wide variety of experiments with animal subjects. When supplied with 2 or 3 free parameters, all 3 models made fairly accurate predictions for a large set of experiments that used concurrent-chain procedures. One advantage of the hyperbolic value-added model is that it is derived from a simpler model that makes accurate predictions for many experiments using discrete-trial adjusting-delay procedures. Some results favor the hyperbolic value-added model and delay-reduction theory over the contextual-choice model, but more data are needed from choice situations for which the models make distinctly different predictions.

  17. Concise Review: Stem Cell Trials Using Companion Animal Disease Models.

    PubMed

    Hoffman, Andrew M; Dow, Steven W

    2016-07-01

    Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic animal models. In veterinary medicine, companion animals naturally develop many diseases that resemble human conditions, therefore, representing a novel source of preclinical models. To understand how companion animal disease models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models. Stem Cells 2016;34:1709-1729.

  18. An Animal Oral Exposure Model – Sensitization vs. Tolerance

    EPA Science Inventory

    Animal models are needed to assess novel proteins produced through biotechnology for potential dietary allergenicity. The exact characteristics that give certain foods allergenic potential are unclear, but must include both the potential to sensitize (induce IgE) as well as the c...

  19. Neonatal chest drain insertion--an animal model.

    PubMed Central

    Hourihane, J. O.; Crawshaw, P. A.; Hall, M. A.

    1995-01-01

    Trainees rarely see a neonatal pneumothorax because of the combination of decreased doctors' hours, the use of surfactant, and modern ventilator techniques. An animal model, using a dead rabbit, is described that could be used to train doctors and others in the management of this serious complication of neonatal care. PMID:7712271

  20. Animal models and high field imaging and spectroscopy.

    PubMed

    Öz, Gülin; Tkáč, Ivan; Uğurbil, Kamil

    2013-09-01

    A plethora of magnetic resonance (MR) techniques developed in the last two decades provide unique and noninvasive measurement capabilities for studies of basic brain function and brain diseases in humans. Animal model experiments have been an indispensible part of this development. MR imaging and spectroscopy measurements have been employed in animal models, either by themselves or in combination with complementary and often invasive techniques, to enlighten us about the information content of such MR methods and/or verify observations made in the human brain. They have also been employed, with or independently of human efforts, to examine mechanisms underlying pathological developments in the brain, exploiting the wealth of animal models available for such studies. In this endeavor, the desire to push for ever-higher spatial and/or spectral resolution, better signal-to-noise ratio, and unique image contrast has inevitably led to the introduction of increasingly higher magnetic fields. As a result, today, animal model studies are starting to be conducted at magnetic fields ranging from ~ 11 to 17 Tesla, significantly enhancing the armamentarium of tools available for the probing brain function and brain pathologies.

  1. Uniportal video-assisted thoracoscopic lobectomy in the animal model

    PubMed Central

    Gonzalez-Rivas, Diego; Fernández-Prado, Ricardo; Delgado, María; Fieira, Eva M.; Centeno, Alberto

    2014-01-01

    We introduce the training on uniportal video-assisted thoracoscopic (VATS) lobectomy in sheep. This animal model is helpful to learn the different view, the importance of lung exposure and the key points of the instrumentation. In this article we present three videos with the left upper lobectomy, the left lower lobectomy and the right upper lobectomy in the sheep. PMID:25379206

  2. Aquatic Animal Models – Not Just for Ecotox Anymore

    EPA Science Inventory

    A wide range of internationally harmonized toxicity test guidelines employing aquatic animal models have been established for regulatory use. For fish alone, there are over a dozen internationally harmonized toxicity test guidelines that have been, or are being, validated. To dat...

  3. An Aerosolized Brucella spp. Challenge Model for Laboratory Animals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To characterize the optimal aerosol dosage of Brucella abortus strain 2308 (S2308) and B. melitensis (S16M) in a laboratory animal model of brucellosis, dosages of 10**3 to 10**10 CFU were nebulized to mice. Although tissue weights were minimally influenced, total colony-forming units (CFU) per tis...

  4. Intestinal Microbiota in Animal Models of Inflammatory Diseases.

    PubMed

    Hörmannsperger, G; Schaubeck, M; Haller, D

    2015-01-01

    The intestinal microbiota has long been known to play an important role in the maintenance of health. In addition, alterations of the intestinal microbiota have recently been associated with a range of immune-mediated and metabolic disorders. Characterizing the composition and functionality of the intestinal microbiota, unravelling relevant microbe-host interactions, and identifying disease-relevant microbes are therefore currently of major interest in scientific and medical communities. Experimental animal models for the respective diseases of interest are pivotal in order to address functional questions on microbe-host interaction and to clarify the clinical relevance of microbiome alterations associated with disease initiation and development. This review presents an overview of the outcomes of highly sophisticated experimental studies on microbe-host interaction in animal models of inflammatory diseases, with a focus on inflammatory bowel disease (IBD). We will address the advantages and drawbacks of analyzing microbe-host interaction in complex colonized animal models compared with gnotobiotic animal models using monoassociation, simplified microbial consortia (SMC), or microbial humanization.

  5. Animation Model to Conceptualize ATP Generation: A Mitochondrial Oxidative Phosphorylation

    ERIC Educational Resources Information Center

    Jena, Ananta Kumar

    2015-01-01

    Adenosine triphosphate (ATP) is the molecular unit of intracellular energy and it is the product of oxidative phosphorylation of cellular respiration uses in cellular processes. The study explores the growth of the misconception levels amongst the learners and evaluates the effectiveness of animation model over traditional methods. The data…

  6. A probabilistic respiratory tract dosimetry model with application to beta-particle and photon emitters

    NASA Astrophysics Data System (ADS)

    Farfan, Eduardo Balderrama

    2002-01-01

    Predicting equivalent dose in the human respiratory tract is significant in the assessment of health risks associated with the inhalation of radioactive aerosols. A complete respiratory tract methodology based on the International Commission on Radiological Protection Publication 66 model was used in this research project for beta-particle and photon emitters. The conventional methodology has been to use standard values (from Reference Man) for parameters to obtain a single dose value. However, the methods used in the current study allow lung dose values to be determined as probability distributions to reflect the spread or variability in doses. To implement the methodology, a computer code, LUDUC, has been modified to include inhalation scenarios of beta-particle and photon emitters. For beta particles, a new methodology was implemented into Monte Carlo simulations to determine absorbed fractions in target tissues within the thoracic region of the respiratory tract. For photons, a new mathematical phantom of extrathoracic and thoracic regions was created based on previous studies to determine specific absorbed fractions in several tissues and organs of the human body due to inhalation of radioactive materials. The application of the methodology and developed data will be helpful in dose reconstruction and prediction efforts concerning the inhalation of short-lived radionuclides or radionuclides of Inhalation Class S. The resulting dose distributions follow a lognormal distribution shape for all scenarios examined. Applying the probabilistic computer code LUDUC to inhalation of strontium and yttrium aerosols has shown several trends, which could also be valid for many S radionuclide compounds that are beta-particle emitters. The equivalent doses are, in general, found to follow lognormal distributions. Therefore, these distributions can be described by geometric means and geometric standard deviations. Furthermore, a mathematical phantom of the extrathoracic and

  7. Fourth international radiopharmaceutical dosimetry symposium

    SciTech Connect

    Schlafke-Stelson, A.T.; Watson, E.E.

    1986-04-01

    The focus of the Fourth International Radiopharmaceutical Dosimetry Symposium was to explore the impact of current developments in nuclear medicine on absorbed dose calculations. This book contains the proceedings of the meeting including the edited discussion that followed the presentations. Topics that were addressed included the dosimetry associated with radiolabeled monoclonal antibodies and blood elements, ultrashort-lived radionuclides, and positron emitters. Some specific areas of discussion were variations in absorbed dose as a result of alterations in the kinetics, the influence of radioactive contaminants on dose, dose in children and in the fetus, available instrumentation and techniques for collecting the kinetic data needed for dose calculation, dosimetry requirements for the review and approval of new radiopharmaceuticals, and a comparison of the effect on the thyroid of internal versus external irradiation. New models for the urinary blader, skeleton including the active marrow, and the blood were presented. Several papers dealt with the validity of traditional ''average-organ'' dose estimates to express the dose from particulate radiation that has a short range in tissue. These problems are particularly important in the use of monoclonal antibodies and agents used to measure intracellular functions. These proceedings have been published to provide a resource volume for anyone interested in the calculation of absorbed radiation dose.

  8. A measurement-based X-ray source model characterization for CT dosimetry computations.

    PubMed

    Sommerville, Mitchell; Poirier, Yannick; Tambasco, Mauro

    2015-11-01

    The purpose of this study was to show that the nominal peak tube voltage potential (kVp) and measured half-value layer (HVL) can be used to generate energy spectra and fluence profiles for characterizing a computed tomography (CT) X-ray source, and to validate the source model and an in-house kV X-ray dose computation algorithm (kVDoseCalc) for computing machine- and patient-specific CT dose. Spatial variation of the X-ray source spectra of a Philips Brilliance and a GE Optima Big Bore CT scanner were found by measuring the HVL along the direction of the internal bow-tie filter axes. Third-party software, Spektr, and the nominal kVp settings were used to generate the energy spectra. Beam fluence was calculated by dividing the integral product of the spectra and the in-air NIST mass-energy attenuation coefficients by in-air dose measurements along the filter axis. The authors found the optimal number of photons to seed in kVDoseCalc to achieve dose convergence. The Philips Brilliance beams were modeled for 90, 120, and 140 kVp tube settings. The GE Optima beams were modeled for 80, 100, 120, and 140 kVp tube settings. Relative doses measured using a Capintec Farmer-type ionization chamber (0.65 cc) placed in a cylindrical polymethyl methacrylate (PMMA) phantom and irradiated by the Philips Brilliance, were compared to those computed with kVDoseCalc. Relative doses in an anthropomorphic thorax phantom (E2E SBRT Phantom) irradiated by the GE Optima were measured using a (0.015 cc) PTW Freiburg ionization chamber and compared to computations from kVDoseCalc. The number of photons required to reduce the average statistical uncertainty in dose to <0.3% was 2×105. The average percent difference between calculation and measurement over all 12 PMMA phantom positions was found to be 1.44%, 1.47%, and 1.41% for 90, 120, and 140 kVp, respectively. The maximum percent difference between calculation and measurement for all energies, measurement positions, and phantoms was less

  9. A measurement-based X-ray source model characterization for CT dosimetry computations.

    PubMed

    Sommerville, Mitchell; Poirier, Yannick; Tambasco, Mauro

    2015-11-08

    The purpose of this study was to show that the nominal peak tube voltage potential (kVp) and measured half-value layer (HVL) can be used to generate energy spectra and fluence profiles for characterizing a computed tomography (CT) X-ray source, and to validate the source model and an in-house kV X-ray dose computation algorithm (kVDoseCalc) for computing machine- and patient-specific CT dose. Spatial variation of the X-ray source spectra of a Philips Brilliance and a GE Optima Big Bore CT scanner were found by measuring the HVL along the direction of the internal bow-tie filter axes. Third-party software, Spektr, and the nominal kVp settings were used to generate the energy spectra. Beam fluence was calculated by dividing the integral product of the spectra and the in-air NIST mass-energy attenuation coefficients by in-air dose measurements along the filter axis. The authors found the optimal number of photons to seed in kVDoseCalc to achieve dose convergence. The Philips Brilliance beams were modeled for 90, 120, and 140 kVp tube settings. The GE Optima beams were modeled for 80, 100, 120, and 140 kVp tube settings. Relative doses measured using a Capintec Farmer-type ionization chamber (0.65 cc) placed in a cylindrical polymethyl methacrylate (PMMA) phantom and irradiated by the Philips Brilliance, were compared to those computed with kVDoseCalc. Relative doses in an anthropomorphic thorax phantom (E2E SBRT Phantom) irradiated by the GE Optima were measured using a (0.015 cc) PTW Freiburg ionization chamber and compared to computations from kVDoseCalc. The number of photons required to reduce the average statistical uncertainty in dose to < 0.3% was 2 × 105. The average percent difference between calculation and measurement over all 12 PMMA phantom positions was found to be 1.44%, 1.47%, and 1.41% for 90, 120, and 140 kVp, respectively. The maximum percent difference between calculation and measurement for all energies, measurement positions, and phantoms was

  10. Recent progresses in tritium radioecology and dosimetry

    SciTech Connect

    Galeriu, D.; Davis, P.; Raskob, W.; Melintescu, A.

    2008-07-15

    In this paper, some aspects of recent progress in tritium radioecology and dosimetry are presented, with emphasis on atmospheric releases to terrestrial ecosystems. The processes involved in tritium transfer through the environment are discussed, together with the current status of environmental tritium models. Topics include the deposition and reemission of HT and HTO, models for the assessment of routine and accidental HTO emissions, a new approach to modeling the dynamics of tritium in mammals, the dose consequences of tritium releases and aspects of human dosimetry. The need for additional experimental data is identified, together with the attributes that would be desirable in the next generation of tritium codes. (authors)

  11. How animal models of leukaemias have already benefited patients.

    PubMed

    Ablain, Julien; Nasr, Rihab; Zhu, Jun; Bazarbachi, Ali; Lallemand-Breittenbach, Valérie; de Thé, Hugues

    2013-04-01

    The relative genetic simplicity of leukaemias, the development of which likely relies on a limited number of initiating events has made them ideal for disease modelling, particularly in the mouse. Animal models provide incomparable insights into the mechanisms of leukaemia development and allow exploration of the molecular pillars of disease maintenance, an aspect often biased in cell lines or ex vivo systems. Several of these models, which faithfully recapitulate the characteristics of the human disease, have been used for pre-clinical purposes and have been instrumental in predicting therapy response in patients. We plea for a wider use of genetically defined animal models in the design of clinical trials, with a particular focus on reassessment of existing cancer or non-cancer drugs, alone or in combination.

  12. Animal models of head and neck squamous cell carcinoma.

    PubMed

    Supsavhad, Wachiraphan; Dirksen, Wessel P; Martin, Chelsea K; Rosol, Thomas J

    2016-04-01

    Head and neck squamous cell carcinoma (HNSCC) is the most common oral cancer worldwide. Local bone invasion into the maxilla or mandible and metastasis to regional lymph nodes often result in a poor prognosis, decreased quality of life and shortened survival time for HNSCC patients. Poor response to treatment and clinical outcomes are the major concerns in this aggressive cancer. Multiple animal models have been developed to replicate spontaneous HNSCC and investigate genetic alterations and novel therapeutic targets. This review provides an overview of HNSCC as well as the traditional animal models used in HNSCC preclinical research. The value and challenges of each in vivo model are discussed. Similarity between HNSCC in humans and cats and the possibility of using spontaneous feline oral squamous cell carcinoma (FOSCC) as a model for HNSCC in translational research are highlighted.

  13. Transgenic animal models of neurodegeneration based on human genetic studies

    PubMed Central

    Richie, Christopher T.; Hoffer, Barry J.; Airavaara, Mikko

    2011-01-01

    The identification of genes linked to neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Parkinson's disease (PD) has led to the development of animal models for studying mechanism and evaluating potential therapies. None of the transgenic models developed based on disease-associated genes have been able to fully recapitulate the behavioral and pathological features of the corresponding disease. However, there has been enormous progress made in identifying potential therapeutic targets and understanding some of the common mechanisms of neurodegeneration. In this review, we will discuss transgenic animal models for AD, ALS, HD and PD that are based on human genetic studies. All of the diseases discussed have active or complete clinical trials for experimental treatments that benefited from transgenic models of the disease. PMID:20931247

  14. Animal models and biomarkers of neuropathy in diabetic rodents

    PubMed Central

    Shaikh, A.S.; Somani, R.S.

    2010-01-01

    Diabetic neuropathy (DN) is a multifactor complication of diabetes. It is a late finding in type 1 diabetes, but can be an early finding in type 2 diabetes. The cause of DN is still unclear and, like other complications of diabetes, it may be the result of various pathological conditions. Animal models and biomarkers of DN have been extensively used in neuropathic research. The most useful model of DN should exhibit the key feature present in human pathology. Diabetic rodents show behavioral, functional, structural and molecular biomarkers and they are widely used as models to investigate the etiology of DN as well as to screen the efficacy of the potential therapeutic interventions. We have reviewed the different animal models and biomarkers of neuropathy in diabetic rodents of either type 1 or type 2 diabetes. PMID:20871761

  15. Effects of exercise on brain functions in diabetic animal models.

    PubMed

    Yi, Sun Shin

    2015-05-15

    Human life span has dramatically increased over several decades, and the quality of life has been considered to be equally important. However, diabetes mellitus (DM) characterized by problems related to insulin secretion and recognition has become a serious health problem in recent years that threatens human health by causing decline in brain functions and finally leading to neurodegenerative diseases. Exercise is recognized as an effective therapy for DM without medication administration. Exercise studies using experimental animals are a suitable option to overcome this drawback, and animal studies have improved continuously according to the needs of the experimenters. Since brain health is the most significant factor in human life, it is very important to assess brain functions according to the different exercise conditions using experimental animal models. Generally, there are two types of DM; insulin-dependent type 1 DM and an insulin-independent type 2 DM (T2DM); however, the author will mostly discuss brain functions in T2DM animal models in this review. Additionally, many physiopathologic alterations are caused in the brain by DM such as increased adiposity, inflammation, hormonal dysregulation, uncontrolled hyperphagia, insulin and leptin resistance, and dysregulation of neurotransmitters and declined neurogenesis in the hippocampus and we describe how exercise corrects these alterations in animal models. The results of changes in the brain environment differ according to voluntary, involuntary running exercises and resistance exercise, and gender in the animal studies. These factors have been mentioned in this review, and this review will be a good reference for studying how exercise can be used with therapy for treating DM.

  16. Freshwater Planarians as an Alternative Animal Model for Neurotoxicology.

    PubMed

    Hagstrom, Danielle; Cochet-Escartin, Olivier; Zhang, Siqi; Khuu, Cindy; Collins, Eva-Maria S

    2015-09-01

    Traditional toxicology testing has relied on low-throughput, expensive mammalian studies; however, timely testing of the large number of environmental toxicants requires new in vitro and in vivo platforms for inexpensive medium- to high-throughput screening. Herein, we describe the suitability of the asexual freshwater planarian Dugesia japonica as a new animal model for the study of developmental neurotoxicology. As these asexual animals reproduce by binary fission, followed by regeneration of missing body structures within approximately 1 week, development and regeneration occur through similar processes allowing us to induce neurodevelopment "at will" through amputation. This short time scale and the comparable sizes of full and regenerating animals enable parallel experiments in adults and developing worms to determine development-specific aspects of toxicity. Because the planarian brain, despite its simplicity, is structurally and molecularly similar to the mammalian brain, we are able to ascertain neurodevelopmental toxicity that is relevant to humans. As a proof of concept, we developed a 5-step semiautomatic screening platform to characterize the toxicity of 9 known neurotoxicants (consisting of common solvents, pesticides, and detergents) and a neutral agent, glucose, and quantified effects on viability, stimulated and unstimulated behavior, regeneration, and brain structure. Comparisons of our findings with other alternative toxicology animal models, such as zebrafish larvae and nematodes, demonstrated that planarians are comparably sensitive to the tested chemicals. In addition, we found that certain compounds induced adverse effects specifically in developing animals. We thus conclude that planarians offer new complementary opportunities for developmental neurotoxicology animal models.

  17. Freshwater Planarians as an Alternative Animal Model for Neurotoxicology

    PubMed Central

    Hagstrom, Danielle; Cochet-Escartin, Olivier; Zhang, Siqi; Khuu, Cindy; Collins, Eva-Maria S.

    2015-01-01

    Traditional toxicology testing has relied on low-throughput, expensive mammalian studies; however, timely testing of the large number of environmental toxicants requires new in vitro and in vivo platforms for inexpensive medium- to high-throughput screening. Herein, we describe the suitability of the asexual freshwater planarian Dugesia japonica as a new animal model for the study of developmental neurotoxicology. As these asexual animals reproduce by binary fission, followed by regeneration of missing body structures within approximately 1 week, development and regeneration occur through similar processes allowing us to induce neurodevelopment “at will” through amputation. This short time scale and the comparable sizes of full and regenerating animals enable parallel experiments in adults and developing worms to determine development-specific aspects of toxicity. Because the planarian brain, despite its simplicity, is structurally and molecularly similar to the mammalian brain, we are able to ascertain neurodevelopmental toxicity that is relevant to humans. As a proof of concept, we developed a 5-step semiautomatic screening platform to characterize the toxicity of 9 known neurotoxicants (consisting of common solvents, pesticides, and detergents) and a neutral agent, glucose, and quantified effects on viability, stimulated and unstimulated behavior, regeneration, and brain structure. Comparisons of our findings with other alternative toxicology animal models, such as zebrafish larvae and nematodes, demonstrated that planarians are comparably sensitive to the tested chemicals. In addition, we found that certain compounds induced adverse effects specifically in developing animals. We thus conclude that planarians offer new complementary opportunities for developmental neurotoxicology animal models. PMID:26116028

  18. Solar particle events observed at Mars: dosimetry measurements and model calculations.

    PubMed

    Cleghorn, Timothy F; Saganti, Premkumar B; Zeitlin, Cary J; Cucinotta, Francis A

    2004-01-01

    During the period from March 13, 2002 to mid-September, 2002, six solar particle events (SPE) were observed by the MARIE instrument onboard the Odyssey Spacecraft in Martian Orbit. These events were observed also by the GOES 8 satellite in Earth orbit, and thus represent the first time that the same SPE have been observed at these separate locations. The characteristics of these SPE are examined, given that the active regions of the solar disc from which the event originated can usually be identified. The dose rates at Martian orbit are calculated, both for the galactic and solar components of the ionizing particle radiation environment. The dose rates due to galactic cosmic rays (GCR) agree well with the HZETRN model calculations.

  19. Solar particle events observed at Mars: dosimetry measurements and model calculations

    NASA Technical Reports Server (NTRS)

    Cleghorn, Timothy F.; Saganti, Premkumar B.; Zeitlin, Cary J.; Cucinotta, Francis A.

    2004-01-01

    During the period from March 13, 2002 to mid-September, 2002, six solar particle events (SPE) were observed by the MARIE instrument onboard the Odyssey Spacecraft in Martian Orbit. These events were observed also by the GOES 8 satellite in Earth orbit, and thus represent the first time that the same SPE have been observed at these separate locations. The characteristics of these SPE are examined, given that the active regions of the solar disc from which the event originated can usually be identified. The dose rates at Martian orbit are calculated, both for the galactic and solar components of the ionizing particle radiation environment. The dose rates due to galactic cosmic rays (GCR) agree well with the HZETRN model calculations. Published by Elsevier Ltd on behalf of COSPAR.

  20. A model of the peritoneal cavity for use in internal dosimetry

    SciTech Connect

    Watson, E.E.; Stabin, M.G.; Davis, J.L.; Eckerman, K.F. )

    1989-12-01

    Several therapeutic and diagnostic techniques involve injection of radioactive material into the peritoneal cavity. Estimation of the radiation dose to the surface of the peritoneum or to surrounding organs is hampered by the lack of a suitable source region in the phantom commonly used for such calculations. We have modified the Fisher-Snyder phantom to include a region representing the peritoneal cavity which may be employed to estimate such radiation doses. A geometric model is described which is coordinated with the existing organ regions in the phantom. Specific absorbed fractions (derived by Monte Carlo techniques) for photon emissions originating within the cavity are listed. Photon S-values for several radionuclides which have been administered intraperitoneally are shown. Dose conversion factors for electrons irradiating the peritoneal cavity wall, from either a thin plane or volume source of activity within the cavity, are also given for several nuclides.

  1. Epidemiology-driven neurodevelopmental animal models of schizophrenia.

    PubMed

    Meyer, Urs; Feldon, Joram

    2010-03-01

    Human epidemiological studies have provided compelling evidence that the risk of developing schizophrenia is significantly enhanced following prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infection and/or immune activation, nutritional deficiencies and obstetric complications. Based on these associations, a great deal of interest has been centered upon the establishment of neurodevelopmental animal models which are based on prenatal and/or perinatal exposure to such environmental stimuli. In the present review, we describe this relatively novel class of epidemiology-based animal models in relation to the etiology, neurobiology and psychopharmacology of schizophrenia. Thereby, we discuss the general design and practical implementation of these models, and we provide an integrative summary of experimental findings derived from diverse epidemiology-based models, including models of maternal exposure to psychological stress, glucocorticoid treatment, viral infection, immune activating agents, protein deprivation, vitamin D deficiency, as well as models of obstetric complications in the form of birth by Caesarian section and perinatal/postnatal hypoxia. We highlight that the long-term consequences of prenatal exposure to these environmental challenges in animals successfully capture a broad spectrum of structural and functional brain abnormalities implicated in schizophrenia, some of which can be normalized by acute and/or chronic antipsychotic drug treatment. We thus conclude that epidemiology-driven neurodevelopmental models of schizophrenia are characterized by a high level of face, construct and predictive validity, including intrinsic etiological significance to the disorder. They also fulfill the expectation of the neurodevelopmental theory, such that the effects of prenatal environmental insults often only emerge after puberty. Epidemiologically based animal models not only provide indispensable

  2. Establishing a clinically meaningful predictive model of hematologic toxicity in nonmyeloablative targeted radiotherapy: practical aspects and limitations of red marrow dosimetry.

    PubMed

    Siegel, Jeffry A

    2005-04-01

    In either heavily pretreated or previously untreated patient populations, dosimetry holds the promise of playing an integral role in the physician's ability to adjust therapeutic activity prescriptions to limit excessive hematologic toxicity in individual patients. However, red marrow absorbed doses have not been highly predictive of hematopoietic toxicity. Although the accuracy of red marrow dose estimates is expected to improve as more patient-specific models are implemented, these model-calculated absorbed doses more than likely will have to be adjusted by parameters that adequately characterize bone marrow tolerance in the heavily pretreated patients most likely to receive nonmyeloablative radiolabeled antibody therapy. Models need to be established that consider not only absorbed dose but also parameters that are indicative of pretherapy bone marrow reserve and radiosensitivity so that a clinically meaningful predictive model of hematologic toxicity can be established.

  3. Functional GI disorders: from animal models to drug development

    PubMed Central

    Mayer, E A; Bradesi, S; Chang, L; Spiegel, B M R; Bueller, J A; Naliboff, B D

    2014-01-01

    Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, the empirical basis for this process is reviewed, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, in both animals and humans, as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man. PMID:17965064

  4. Peripheral biomarkers in animal models of major depressive disorder.

    PubMed

    Carboni, Lucia

    2013-01-01

    Investigations of preclinical biomarkers for major depressive disorder (MDD) encompass the quantification of proteins, peptides, mRNAs, or small molecules in blood or urine of animal models. Most studies aim at characterising the animal model by including the assessment of analytes or hormones affected in depressive patients. The ultimate objective is to validate the model to better understand the neurobiological basis of MDD. Stress hormones or inflammation-related analytes associated with MDD are frequently measured. In contrast, other investigators evaluate peripheral analytes in preclinical models to translate the results in clinical settings afterwards. Large-scale, hypothesis-free studies are performed in MDD models to identify candidate biomarkers. Other studies wish to propose new targets for drug discovery. Animal models endowed with predictive validity are investigated, and the assessment of peripheral analytes, such as stress hormones or immune molecules, is comprised to increase the confidence in the target. Finally, since the mechanism of action of antidepressants is incompletely understood, studies investigating molecular alterations associated with antidepressant treatment may include peripheral analyte levels. In conclusion, preclinical biomarker studies aid the identification of new candidate analytes to be tested in clinical trials. They also increase our understanding of MDD pathophysiology and help to identify new pharmacological targets.

  5. Large animal model for osteoporosis in humans: the ewe.

    PubMed

    Oheim, R; Amling, M; Ignatius, A; Pogoda, P

    2012-11-12

    Osteoporosis is a chronic systemic disease characterised by bone loss and microarchitectural deterioration. Since the underlying regulatory mechanisms are still not fully understood and treatment options are not satisfactorily resolved, massive efforts are underway to further investigate this critical illness. Large animal models are stipulated, e.g. by the Food and Drug Administration, for preclinical prevention and intervention studies related to osteoporosis research; in this context, the ewe has already proven its value for orthopaedic research. Although oestrogen deficiency doubtless influences bone metabolism in sheep, the ovariectomised ewe seems unsuitable as a model for postmenopausal osteoporosis and bone loss induction due to its unreliable impact on bone mass and structure. In contrast, glucocorticoid treatment has a major impact on bone turnover and leads to bone conditions comparable to those found in steroid-treated humans. However, adverse side effects can be dramatic resulting in unacceptable discomfort and illness of the experimental animals. Further improvements are therefore essential to judge this model as ethically appropriate. Additionally, models for osteoporosis induced by surgical interventions of central regulatory mechanisms seem to be attractive, as remarkable bone loss is induced by only one surgical procedure without any further treatment. Taken together, different ewe models for osteoporosis have been successfully established and are invaluable for orthopaedic research. However, the search for a 'perfect' large remodelling animal model - in terms of mimicking the human disease and compatibility of bone loss, and without ethical concerns - is still on-going.

  6. Modeling the Heterogeneity of Multiple Sclerosis in Animals

    PubMed Central

    Simmons, Sarah B.; Pierson, Emily R.; Lee, Sarah Y.; Goverman, Joan M.

    2013-01-01

    Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system manifested with varying clinical course, pathology, and inflammatory patterns. There are multiple animal models that reflect different aspects of this heterogeneity. Collectively, these models reveal a balance between pathogenic and regulatory CD4+ T cells, CD8+ T cells and B cells that influences the incidence, timing, and severity of central nervous system autoimmunity. In this review we discuss experimental autoimmune encephalomyelitis (EAE) models that have been used to study the pathogenic and regulatory roles of these immune cells, models that recapitulate different aspects of the disease seen in patients with MS, and questions remaining for future studies. PMID:23707039

  7. Field models and numerical dosimetry inside an extremely-low-frequency electromagnetic bioreactor: the theoretical link between the electromagnetically induced mechanical forces and the biological mechanisms of the cell tensegrity.

    PubMed

    Mognaschi, Maria Evelina; Di Barba, Paolo; Magenes, Giovanni; Lenzi, Andrea; Naro, Fabio; Fassina, Lorenzo

    2014-01-01

    We have implemented field models and performed a detailed numerical dosimetry inside our extremely-low-frequency electromagnetic bioreactor which has been successfully used in in vitro Biotechnology and Tissue Engineering researches. The numerical dosimetry permitted to map the magnetic induction field (maximum module equal to about 3.3 mT) and to discuss its biological effects in terms of induced electric currents and induced mechanical forces (compression and traction). So, in the frame of the tensegrity-mechanotransduction theory of Ingber, the study of these electromagnetically induced mechanical forces could be, in our opinion, a powerful tool to understand some effects of the electromagnetic stimulation whose mechanisms remain still elusive.

  8. Review of Nonprimate, Large Animal Models for Osteoporosis Research

    PubMed Central

    Reinwald, Susan; Burr, David

    2008-01-01

    Large animal models are required for preclinical prevention and intervention studies related to osteoporosis research. The challenging aspect of this requirement is that no single animal model exactly mimics the progression of this human-specific chronic condition. There are pros and cons associated with the skeletal, hormonal, and metabolic conditions of each species that influence their relevance and applicability to human physiology. Of all larger mammalian species, nonhuman primates (NHPs) are preeminent in terms of replicating important aspects of human physiology. However, NHPs are very expensive, putting them out of reach of the vast majority of researchers. Practical, cost-effective alternatives to NHPs are sought after among ungulate (porcine, caprine, and ovine) and canine species that are the focus of this review. The overriding caveat to using large lower-order species is to take the time in advance to understand and appreciate the limitations and strengths of each animal model. Under these circumstances, experiments can be strategically designed to optimize the potential of an animal to develop the cardinal features of postmenopausal bone loss and/or yield information of relevance to treatment. PMID:18505374

  9. Animal models of herpes simplex virus immunity and pathogenesis.

    PubMed

    Kollias, Christina M; Huneke, Richard B; Wigdahl, Brian; Jennings, Stephen R

    2015-02-01

    Herpes simplex viruses are ubiquitous human pathogens represented by two distinct serotypes: herpes simplex virus (HSV) type 1 (HSV-1); and HSV type 2 (HSV-2). In the general population, adult seropositivity rates approach 90% for HSV-1 and 20-25% for HSV-2. These viruses cause significant morbidity, primarily as mucosal membrane lesions in the form of facial cold sores and genital ulcers, with much less common but more severe manifestations causing death from encephalitis. HSV infections in humans are difficult to study in many cases because many primary infections are asymptomatic. Moreover, the neurotropic properties of HSV make it much more difficult to study the immune mechanisms controlling reactivation of latent infection within the corresponding sensory ganglia and crossover into the central nervous system of infected humans. This is because samples from the nervous system can only be routinely obtained at the time of autopsy. Thus, animal models have been developed whose use has led to a better understanding of multiple aspects of HSV biology, molecular biology, pathogenesis, disease, and immunity. The course of HSV infection in a spectrum of animal models depends on important experimental parameters including animal species, age, and genotype; route of infection; and viral serotype, strain, and dose. This review summarizes the animal models most commonly used to study HSV pathogenesis and its establishment, maintenance, and reactivation from latency. It focuses particularly on the immune response to HSV during acute primary infection and the initial invasion of the ganglion with comparisons to the events governing maintenance of viral latency.

  10. The Laboratory Rat as an Animal Model for Osteoporosis Research

    PubMed Central

    Lelovas, Pavlos P; Xanthos, Theodoros T; Thoma, Sofia E; Lyritis, George P; Dontas, Ismene A

    2008-01-01

    Osteoporosis is an important systemic disorder, affecting mainly Caucasian women, with a diverse and multifactorial etiology. A large variety of animal species, including rodents, rabbits, dogs, and primates, have been used as animal models in osteoporosis research. Among these, the laboratory rat is the preferred animal for most researchers. Its skeleton has been studied extensively, and although there are several limitations to its similarity to the human condition, these can be overcome through detailed knowledge of its specific traits or with certain techniques. The rat has been used in many experimental protocols leading to bone loss, including hormonal interventions (ovariectomy, orchidectomy, hypophysectomy, parathyroidectomy), immobilization, and dietary manipulations. The aim of the current review is not only to present the ovariectomized rat and its advantages as an appropriate model for the research of osteoporosis, but also to provide information about the most relevant age and bone site selection according to the goals of each experimental protocol. In addition, several methods of bone mass evaluation are assessed, such as biochemical markers, densitometry, histomorphometry, and bone mechanical testing, that are used for monitoring and evaluation of this animal model in preventive or therapeutic strategies for osteoporosis. PMID:19004367

  11. Animal Models for Medical Countermeasures to Radiation Exposure

    PubMed Central

    Williams, Jacqueline P.; Brown, Stephen L.; Georges, George E.; Hauer-Jensen, Martin; Hill, Richard P.; Huser, Amy K.; Kirsch, David G.; MacVittie, Thomas J.; Mason, Kathy A.; Medhora, Meetha M.; Moulder, John E.; Okunieff, Paul; Otterson, Mary F.; Robbins, Michael E.; Smathers, James B.; McBride, William H.

    2011-01-01

    Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the “Animal Rule” from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings. PMID:20334528

  12. NNK-Induced Lung Tumors: A Review of Animal Model

    PubMed Central

    Zheng, Hua-Chuan; Takano, Yasuo

    2011-01-01

    The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models. PMID:21559252

  13. Animal models for Ebola and Marburg virus infections

    PubMed Central

    Nakayama, Eri; Saijo, Masayuki

    2013-01-01

    Ebola and Marburg hemorrhagic fevers (EHF and MHF) are caused by the Filoviridae family, Ebolavirus and Marburgvirus (ebolavirus and marburgvirus), respectively. These severe diseases have high mortality rates in humans. Although EHF and MHF are endemic to sub-Saharan Africa. A novel filovirus, Lloviu virus, which is genetically distinct from ebolavirus and marburgvirus, was recently discovered in Spain where filoviral hemorrhagic fever had never been reported. The virulence of this virus has not been determined. Ebolavirus and marburgvirus are classified as biosafety level-4 (BSL-4) pathogens and Category A agents, for which the US government requires preparedness in case of bioterrorism. Therefore, preventive measures against these viral hemorrhagic fevers should be prepared, not only in disease-endemic regions, but also in disease-free countries. Diagnostics, vaccines, and therapeutics need to be developed, and therefore the establishment of animal models for EHF and MHF is invaluable. Several animal models have been developed for EHF and MHF using non-human primates (NHPs) and rodents, which are crucial to understand pathophysiology and to develop diagnostics, vaccines, and therapeutics. Rhesus and cynomolgus macaques are representative models of filovirus infection as they exhibit remarkably similar symptoms to those observed in humans. However, the NHP models