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Sample records for modeling respiratory toxicity

  1. Modeling Respiratory Toxicity of Authentic Lunar Dust

    Science.gov (United States)

    Santana, Patricia A.; James, John T.; Lam, Chiu-Wing

    2010-01-01

    The lunar expeditions of the Apollo operations from the 60 s and early 70 s have generated awareness about lunar dust exposures and their implication towards future lunar explorations. Critical analyses on the reports from the Apollo crew members suggest that lunar dust is a mild respiratory and ocular irritant. Currently, NASA s space toxicology group is functioning with the Lunar Airborne Dust Toxicity Assessment Group (LADTAG) and the National Institute for Occupational Safety and Health (NIOSH) to investigate and examine toxic effects to the respiratory system of rats in order to establish permissible exposure levels (PELs) for human exposure to lunar dust. In collaboration with the space toxicology group, LADTAG and NIOSH the goal of the present research is to analyze dose-response curves from rat exposures seven and twenty-eight days after intrapharyngeal instillations, and model the response using BenchMark Dose Software (BMDS) from the Environmental Protection Agency (EPA). Via this analysis, the relative toxicities of three types of Apollo 14 lunar dust samples and two control dust samples, titanium dioxide (TiO2) and quartz will be determined. This will be executed for several toxicity endpoints such as cell counts and biochemical markers in bronchoaveolar lavage fluid (BALF) harvested from the rats.

  2. Respiratory Toxicity of Lunar Highland Dust

    Science.gov (United States)

    James, John T.; Lam, Chiu-wing; Wallace, William T.

    2009-01-01

    Lunar dust exposures occurred during the Apollo missions while the crew was on the lunar surface and especially when microgravity conditions were attained during rendezvous in lunar orbit. Crews reported that the dust was irritating to the eyes and in some cases respiratory symptoms were elicited. NASA s vision for lunar exploration includes stays of 6 months on the lunar surface hence the health effects of periodic exposure to lunar dust need to be assessed. NASA has performed this assessment with a series of in vitro and in vivo tests on authentic lunar dust. Our approach is to "calibrate" the intrinsic toxicity of lunar dust by comparison to a nontoxic dust (TiO2) and a highly toxic dust (quartz) using intratrachael instillation of the dusts in mice. A battery of indices of toxicity is assessed at various time points after the instillations. Cultures of selected cells are exposed to test dusts to assess the adverse effects on the cells. Finally, chemical systems are used to assess the nature of the reactivity of various dusts and to determine the persistence of reactivity under various environmental conditions that are relevant to a space habitat. Similar systems are used to assess the dissolution of the dust. From these studies we will be able to set a defensible inhalation exposure standard for aged dust and predict whether we need a separate standard for reactive dust. Presently-available data suggest that aged lunar highland dust is slightly toxic, that it can adversely affect cultured cells, and that the surface reactivity induced by grinding the dust persists for a few hours after activation.

  3. A Review on the Respiratory System Toxicity of Carbon Nanoparticles.

    Science.gov (United States)

    Pacurari, Maricica; Lowe, Kristine; Tchounwou, Paul B; Kafoury, Ramzi

    2016-03-15

    The respiratory system represents the main gateway for nanoparticles' entry into the human body. Although there is a myriad of engineered nanoparticles, carbon nanoparticles/nanotubes (CNPs/CNTs) have received much attention mainly due to their light weight, very high surface area, durability, and their diverse applications. Since their discovery and manufacture over two decades ago, much has been learned about nanoparticles' interactions with diverse biological system models. In particular, the respiratory system has been of great interest because various natural and man-made fibrous particles are known to be responsible for chronic and debilitating lung diseases. In this review, we present up-to-date the literature regarding the effects of CNTs or carbon nanofibers (CNFs) on the human respiratory system with respect to respiratory toxicity pathways and associated pathologies. This article is intended to emphasize the potentially dangerous effects to the human respiratory system if inadequate measures are used in the manufacture, handling, and preparation and applications of CNP or CNP-based products.

  4. The Respiratory Toxicities of Mustard Gas

    Directory of Open Access Journals (Sweden)

    Mostafa Ghanei

    2010-12-01

    Full Text Available Sulfur mustard is one of the major potent chemical warfareagents. It was widely used against not only military personnelbut also civilian people of Iran during the last years (1984–1988 of the Iraq–Iran war. A number of studies were performedregarding the acute and long-term consequences ofsulfur mustard on respiratory system. Currently, many aspectsof leading respiratory disorder that was prescribed as “mustardlung” have been revealed. However, there is growing concernabout pathophysiological mechanisms behind the mustardlung. Herein available published materials about mustard lungare summarized, and it has been tried to highlight practicalpoints relevant to the diagnosis and treatment of the disease.Iran J Med Sci 2010; 35(4: 273-280.

  5. Inhalation method for delivery of nanoparticles to the Drosophila respiratory system for toxicity testing

    International Nuclear Information System (INIS)

    Posgai, Ryan; Ahamed, Maqusood; Hussain, Saber M.; Rowe, John J.; Nielsen, Mark G.

    2009-01-01

    The growth of the nanotechnology industry and subsequent proliferation of nanoparticle types present the need to rapidly assess nanoparticle toxicity. We present a novel, simple and cost-effective nebulizer-based method to deliver nanoparticles to the Drosophila melanogaster respiratory system, for the purpose of toxicity testing. FluoSpheres (registered) , silver, and CdSe/ZnS nanoparticles of different sizes were effectively aerosolized, showing the system is capable of functioning with a wide range of nanoparticle types and sizes. Red fluorescent CdSe/ZnS nanoparticles were successfully delivered to the fly respiratory system, as visualized by fluorescent microscopy. Silver coated and uncoated nanoparticles were delivered in a toxicity test, and induced Hsp70 expression in flies, confirming the utility of this model in toxicity testing. This is the first method developed capable of such delivery, provides the advantage of the Drosophila health model, and can serve as a link between tissue culture and more expensive mammalian models in a tiered toxicity testing strategy.

  6. Inhalation method for delivery of nanoparticles to the Drosophila respiratory system for toxicity testing

    Energy Technology Data Exchange (ETDEWEB)

    Posgai, Ryan; Ahamed, Maqusood [Department of Biology, University of Dayton, Dayton, OH, 45469-2320 (United States); Hussain, Saber M. [Applied Biotechnology Branch, Human Effectiveness Directorate Air Force Research Laboratory/RHBP, Wright-Patterson Air Force Base, OH, 45433 (United States); Rowe, John J. [Department of Biology, University of Dayton, Dayton, OH, 45469-2320 (United States); Nielsen, Mark G., E-mail: Mark.Nielsen@notes.udayton.edu [Department of Biology, University of Dayton, Dayton, OH, 45469-2320 (United States)

    2009-12-20

    The growth of the nanotechnology industry and subsequent proliferation of nanoparticle types present the need to rapidly assess nanoparticle toxicity. We present a novel, simple and cost-effective nebulizer-based method to deliver nanoparticles to the Drosophila melanogaster respiratory system, for the purpose of toxicity testing. FluoSpheres (registered) , silver, and CdSe/ZnS nanoparticles of different sizes were effectively aerosolized, showing the system is capable of functioning with a wide range of nanoparticle types and sizes. Red fluorescent CdSe/ZnS nanoparticles were successfully delivered to the fly respiratory system, as visualized by fluorescent microscopy. Silver coated and uncoated nanoparticles were delivered in a toxicity test, and induced Hsp70 expression in flies, confirming the utility of this model in toxicity testing. This is the first method developed capable of such delivery, provides the advantage of the Drosophila health model, and can serve as a link between tissue culture and more expensive mammalian models in a tiered toxicity testing strategy.

  7. A Review on Human Respiratory Modeling.

    Science.gov (United States)

    Ghafarian, Pardis; Jamaati, Hamidreza; Hashemian, Seyed Mohammadreza

    2016-01-01

    Input impedance of the respiratory system is measured by forced oscillation technique (FOT). Multiple prior studies have attempted to match the electromechanical models of the respiratory system to impedance data. Since the mechanical behavior of airways and the respiratory system as a whole are similar to an electrical circuit in a combination of series and parallel formats some theories were introduced according to this issue. It should be noted that, the number of elements used in these models might be less than those required due to the complexity of the pulmonary-chest wall anatomy. Various respiratory models have been proposed based on this idea in order to demonstrate and assess the different parts of respiratory system related to children and adults data. With regard to our knowledge, some of famous respiratory models in related to obstructive, restrictive diseases and also Acute Respiratory Distress Syndrome (ARDS) are reviewed in this article.

  8. Staphylococcal toxic shock syndrome presenting as acute respiratory distress and cor pulmonale.

    Science.gov (United States)

    Zaki, S A; Shanbag, P; Chavan, V; Shenoy, P

    2010-01-01

    We describe a 7-year-old boy with staphylococcal toxic shock syndrome who presented with acute respiratory distress and cor pulmonale. We wish to highlight this unusual presentation as the diagnosis of toxic shock syndrome depends chiefly on a high degree of clinical suspicion. Early diagnosis and prompt institution of appropriate therapy will significantly reduce morbidity and mortality.

  9. Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke.

    Science.gov (United States)

    Yeager, R Philip; Kushman, Mary; Chemerynski, Susan; Weil, Roxana; Fu, Xin; White, Marcella; Callahan-Lyon, Priscilla; Rosenfeldt, Hans

    2016-06-01

    This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation. The key mechanisms of acrolein toxicity identified in this proposed MOA include (1) acrolein chemical reactivity with proteins and other macromolecules of cells lining the respiratory tract, (2) cellular oxidative stress, including compromise of the important anti-oxidant glutathione, (3) chronic inflammation, (4) necrotic cell death leading to a feedback loop where necrosis-induced inflammation leads to more necrosis and oxidative damage and vice versa, (5) tissue remodeling and destruction, and (6) loss of lung elasticity and enlarged lung airspaces. From these mechanisms, the proposed MOA analysis identifies the key cellular processes in acrolein respiratory toxicity that consistently occur with the development of COPD: inflammation and necrosis in the middle and lower regions of the respiratory tract. Moreover, the acrolein exposures that occur as a result of smoking are well above exposures that induce both inflammation and necrosis in laboratory animals, highlighting the importance of the role of acrolein in smoking-related respiratory disease. Published by Oxford University Press on behalf of the Society of Toxicology 2016. This work is written by US Government employees and is in the public domain in the US.

  10. Toxic effect of naphta exposure on respiratory system among ...

    African Journals Online (AJOL)

    A cross-sectional study was carried out on workers in a tyre manufacturing industry in Malaysia to determine the effects of naphtha exposure on lung functions and respiratory symptoms. Sixty male workers exposed to naphtha and 42 unexposed workers were selected for this study. Personal air monitoring carried out using ...

  11. Toxic effect of naphta exposure on respiratory system among ...

    African Journals Online (AJOL)

    EJIRO

    The animal tests showed that exposure to these organic solvents can cause serious problem to the respiratory system. (Cakmak et al., 2004).There are several organic solvents that can cause the effects and one of .... The measurements were classified according to the standard percentage as carried out by (Miller et al., ...

  12. Biological monitoring of toxic metals - steel workers respiratory health survey

    International Nuclear Information System (INIS)

    Pinheiro, T.; Almeida, A. Bugalho de; Alves, L.; Freitas, M.C.; Moniz, D.; Alvarez, E.; Monteiro, P.; Reis, M.

    1999-01-01

    The aim of this work is to search for respiratory system aggressors to which workers are submitted in their labouring activity. Workers from one sector of a steel plant in Portugal, Siderurgia Nacional (SN), were selected according to the number of years of exposure and labouring characteristics. The work reports on blood elemental content alterations and lung function tests to determine an eventual bronchial hyper-reactivity. Aerosol samples collected permit an estimate of indoor air quality and airborne particulate matter characterisation to further check whether the elemental associations and alterations found in blood may derive from exposure. Blood and aerosol elemental composition was determined by PIXE and INAA. Respiratory affections were verified for 24% of the workers monitored. There are indications that the occurrence of affections can be associated with the total working years. The influence of long-term exposure, health status parameters, and lifestyle factors in blood elemental variations found was investigated

  13. Environmental and anthropogenic factors affecting the respiratory toxicity of volcanic ash in vitro

    Science.gov (United States)

    Tomašek, Ines; Horwell, Claire J.; Damby, David E.; Ayris, Paul M.; Barošová, Hana; Geers, Christoph; Petri-Fink, Alke; Rothen-Rutishauser, Barbara; Clift, Martin J. D.

    2016-04-01

    Human exposure to inhalable volcanic ash particles following an eruption is a health concern, as respirable-sized particles can potentially contribute towards adverse respiratory health effects, such as the onset or exacerbation of respiratory and cardiovascular diseases. Although there is substantial information on the mineralogical properties of volcanic ash that may influence its biological reactivity, knowledge as to how external factors, such as air pollution, contribute to and augment the potential reactivity is limited. To determine the respiratory effects of volcanic particle interactions with anthropogenic pollution and volcanic gases we will experimentally assess: (i) physicochemical characteristics of volcanic ash relevant to respiratory toxicity; (ii) the effects of simultaneously inhaling anthropogenic pollution (i.e. diesel exhaust particles (DEP)) and volcanic ash (of different origins); (iii) alteration of volcanic ash toxicity following interaction with volcanic gases. In order to gain a first understanding of the biological impact of the respirable fraction of volcanic ash when inhaled with DEP in vitro, we used a sophisticated 3D triple cell co-culture model of the human alveolar epithelial tissue barrier. The multi-cellular system was exposed to DEP [0.02 mg/mL] and then exposed to either a single or repeated dose of well-characterised respirable volcanic ash (0.26 ± 0.09 or 0.89 ± 0.29 μg/cm2, respectively) from the Soufrière Hills volcano, Montserrat for a period of 24 hours using a pseudo-air liquid interface approach. Cultures were subsequently assessed for adverse biological endpoints including cytotoxicity, oxidative stress and (pro)-inflammatory responses. Results indicated that the combination of DEP and respirable volcanic ash at sub-lethal concentrations incited a significant release of pro-inflammatory markers that was greater than the response for either DEP or volcanic ash, independently. Further work is planned, to determine if

  14. [Fatal toxic respiratory epitheliolysis. Subacute tracheo-bronchial desquamation in Stevens-Johnson syndrome].

    Science.gov (United States)

    Martin, L; Hazouard, E; Michalak-Provost, S; Maurage, C; Machet, L

    2001-09-01

    Acute bronchial mucosal sloughing related to Toxic Epidermal Necrolysis (Lyell syndrome) is widely reported in literature. On the contrary severe respiratory involvement is rare in post-infectious or toxic Epitheliolysis (Stevens-Johnson syndrome). There is no well-known predictive sign of bronchial epithelium involvement. An 18-year-old patient was admitted for Stevens-Johnson syndrome related to sulfasalazine (salazosulfapyridine). There were no respiratory signs. An acute respiratory failure occurred 36 hours after from admission due to an obstructive and desquamative necrosis of the tracheobronchial epithelium. We purpose that a fiberoptic laryngoscopy should be performed even in non-dyspneic patients suffering from Stevens-Johnson syndrome if hypersecretion is present. Fiberoptic bronchoscopy can be helpful in these cases.

  15. Estimation of oil toxicity using an additive toxicity model

    International Nuclear Information System (INIS)

    French, D.

    2000-01-01

    The impacts to aquatic organisms resulting from acute exposure to aromatic mixtures released from oil spills can be modeled using a newly developed toxicity model. This paper presented a summary of the model development for the toxicity of monoaromatic and polycyclic aromatic hydrocarbon mixtures. This is normally difficult to quantify because oils are mixtures of a variety of hydrocarbons with different toxicities and environmental fates. Also, aromatic hydrocarbons are volatile, making it difficult to expose organism to constant concentrations in bioassay tests. This newly developed and validated model corrects toxicity for time and temperature of exposure. In addition, it estimates the toxicity of each aromatic in the oil-derived mixture. The toxicity of the mixture can be estimated by the weighted sum of the toxicities of the individual compounds. Acute toxicity is estimated as LC50 (lethal concentration to 50 per cent of exposed organisms). Sublethal effects levels are estimated from LC50s. The model was verified with available oil bioassay data. It was concluded that oil toxicity is a function of the aromatic content and composition in the oil as well as the fate and partitioning of those components in the environment. 81 refs., 19 tabs., 1 fig

  16. Salicylate toxicity model of tinnitus

    Science.gov (United States)

    Stolzberg, Daniel; Salvi, Richard J.; Allman, Brian L.

    2012-01-01

    Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs, or aging, which affects ∼14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed. PMID:22557950

  17. Salicylate toxicity model of tinnitus

    Directory of Open Access Journals (Sweden)

    Daniel eStolzberg

    2012-04-01

    Full Text Available Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs or aging which affects ~14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed.

  18. Biophysical Modeling of Respiratory Organ Motion

    Science.gov (United States)

    Werner, René

    Methods to estimate respiratory organ motion can be divided into two groups: biophysical modeling and image registration. In image registration, motion fields are directly extracted from 4D ({D}+{t}) image sequences, often without concerning knowledge about anatomy and physiology in detail. In contrast, biophysical approaches aim at identification of anatomical and physiological aspects of breathing dynamics that are to be modeled. In the context of radiation therapy, biophysical modeling of respiratory organ motion commonly refers to the framework of continuum mechanics and elasticity theory, respectively. Underlying ideas and corresponding boundary value problems of those approaches are described in this chapter, along with a brief comparison to image registration-based motion field estimation.

  19. Early-life Exposure to Widespread Environmental Toxicants and Health Risk : A Focus on the Immune and Respiratory Systems

    NARCIS (Netherlands)

    Cao, Jun Jun; Xu, Xijin; Hylkema, Machteld N.; Zeng, Eddy Y.; Sly, Peter D.; Suk, William A.; Bergman, Ake; Huo, Xia

    2016-01-01

    Evidence has accumulated that exposure to widespread environmental toxicants, such as heavy metals, persistent organic pollutants, and tobacco smoke adversely affect fetal development and organ maturation, even after birth. The developing immune and respiratory systems are more sensitive to

  20. Respiratory

    Science.gov (United States)

    The words "respiratory" and "respiration" refer to the lungs and breathing. ... Boron WF. Organization of the respiratory system. In: Boron WF, Boulpaep EL, eds. Medical Physiology . 3rd ed. Philadelphia, PA: Elsevier; 2017:chap 26.

  1. Modeling Aquatic Toxicity through Chromatographic Systems.

    Science.gov (United States)

    Fernández-Pumarega, Alejandro; Amézqueta, Susana; Farré, Sandra; Muñoz-Pascual, Laura; Abraham, Michael H; Fuguet, Elisabet; Rosés, Martí

    2017-08-01

    Environmental risk assessment requires information about the toxicity of the growing number of chemical products coming from different origins that can contaminate water and become toxicants to aquatic species or other living beings via the trophic chain. Direct toxicity measurements using sensitive aquatic species can be carried out but they may become expensive and ethically questionable. Literature refers to the use of chromatographic measurements that correlate to the toxic effect of a compound over a specific aquatic species as an alternative to get toxicity information. In this work, we have studied the similarity in the response of the toxicity to different species and we have selected eight representative aquatic species (including tadpoles, fish, water fleas, protozoan, and bacteria) with known nonspecific toxicity to chemical substances. Next, we have selected four chromatographic systems offering good perspectives for surrogation of the eight selected aquatic systems, and thus prediction of toxicity from the chromatographic measurement. Then toxicity has been correlated to the chromatographic retention factor. Satisfactory correlation results have been obtained to emulate toxicity in five of the selected aquatic species through some of the chromatographic systems. Other aquatic species with similar characteristics to these five representative ones could also be emulated by using the same chromatographic systems. The final aim of this study is to model chemical products toxicity to aquatic species by means of chromatographic systems to reduce in vivo testing.

  2. Acute inhalation toxicity of 3-methylfuran in the mouse: pathology, cell kinetics, and respiratory rate effects

    Energy Technology Data Exchange (ETDEWEB)

    Haschek, W.M.; Boyd, M.R.; Hakkinen, P.J.; Owenby, C.S.; Witschi, H.

    1984-01-01

    The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in male BALB/c mice by morphologic examination of animals killed at varying timepoints following a 1-hr exposure to an initial chamber concentration of 14 to 37 mumol/liter (343 to 906 ppm). In addition, respiratory rate measurements and cell kinetics were used to assess quantitatively pulmonary damage and repair. Necrosis of nonciliated bronchiolar epithelial (Clara) cells was seen 1 day following exposure and was followed by regeneration, which was virtually complete, within 21 days. Cell kinetic studies showed peak bronchiolar cell proliferation at 3 days with a labeling index (LI) of 5.0% compared to 0.4% in controls. An increase in parenchymal cell proliferation was also noted coincident with a mild interstitial pneumonitis. This parenchymal proliferation, peaking at 10 days with an LI of 1.4% compared to 0.2% in controls, consisted primarily of type II epithelial and endothelial cell proliferation indicating possible delayed damage and repair of type I epithelial and endothelial cells. The respiratory rate showed an initial transient increase followed by a more prolonged decrease with eventual return to control levels. 3MF toxicity was also evidenced by a necrotizing suppurative rhinitis, centrilobular hepatic necrosis, lymphocyte necrosis in the thymus and spleen, sialoadenitis, and otitis media.

  3. Predictive Model of Systemic Toxicity (SOT)

    Science.gov (United States)

    In an effort to ensure chemical safety in light of regulatory advances away from reliance on animal testing, USEPA and L’Oréal have collaborated to develop a quantitative systemic toxicity prediction model. Prediction of human systemic toxicity has proved difficult and remains a ...

  4. Respiratory trace deposition models. Final report

    International Nuclear Information System (INIS)

    Yeh, H.C.

    1980-03-01

    Respiratory tract characteristics of four mammalian species (human, dog, rat and Syrian hamster) were studied, using replica lung casts. An in situ casting techniques was developed for making the casts. Based on an idealized branch model, over 38,000 records of airway segment diameters, lengths, branching angles and gravity angles were obtained from measurements of two humans, two Beagle dogs, two rats and one Syrian hamster. From examination of the trimmed casts and morphometric data, it appeared that the structure of the human airway is closer to a dichotomous structure, whereas for dog, rat and hamster, it is monopodial. Flow velocity in the trachea and major bronchi in living Beagle dogs was measured using an implanted, subminiaturized, heated film anemometer. A physical model was developed to simulate the regional deposition characteristics proposed by the Task Group on Lung Dynamics of the ICRP. Various simulation modules for the nasopharyngeal (NP), tracheobronchial (TB) and pulmonary (P) compartments were designed and tested. Three types of monodisperse aerosols were developed for animal inhalation studies. Fifty Syrian hamsters and 50 rats were exposed to five different sizes of monodisperse fused aluminosilicate particles labeled with 169 Yb. Anatomical lung models were developed for four species (human, Beagle dog, rat and Syrian hamster) that were based on detailed morphometric measurements of replica lung casts. Emphasis was placed on developing a lobar typical-path lung model and on developing a modeling technique which could be applied to various mammalian species. A set of particle deposition equations for deposition caused by inertial impaction, sedimentation, and diffusion were developed. Theoretical models of particle deposition were developed based on these equations and on the anatomical lung models

  5. Toxicity of single walled carbon nanotubes to rainbow trout (Oncorhynchus mykiss): Respiratory toxicity, organ pathologies, and other physiological effects

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Catherine J. [Ecotoxicology and Stress Biology Research Group, School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA (United Kingdom); Shaw, Benjamin J. [Ecotoxicology and Stress Biology Research Group, School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA (United Kingdom); Handy, Richard D. [Ecotoxicology and Stress Biology Research Group, School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA (United Kingdom)]. E-mail: rhandy@plymouth.ac.uk

    2007-05-01

    division. Overt fatty change or wide spread lipidosis was absent in the liver. Fish ingested water containing SWCNT during exposure (presumably stress-induced drinking) which resulted in precipitated SWCNT in the gut lumen and intestinal pathology. Aggressive behaviour and fin nipping caused some mortalities at the end of the experiment, which may be associated with the gill irritation and brain injury, although the solvent may also partly contributed to aggression. Overall we conclude that SWCNTs are a respiratory toxicant in trout, the fish are able to manage oxidative stress and osmoregulatory disturbances, but other cellular pathologies raise concerns about cell cycle defects, neurotoxicity, and as yet unidentified blood borne factors that possibly mediate systemic pathologies.

  6. Toxicity of single walled carbon nanotubes to rainbow trout (Oncorhynchus mykiss): Respiratory toxicity, organ pathologies, and other physiological effects

    International Nuclear Information System (INIS)

    Smith, Catherine J.; Shaw, Benjamin J.; Handy, Richard D.

    2007-01-01

    spread lipidosis was absent in the liver. Fish ingested water containing SWCNT during exposure (presumably stress-induced drinking) which resulted in precipitated SWCNT in the gut lumen and intestinal pathology. Aggressive behaviour and fin nipping caused some mortalities at the end of the experiment, which may be associated with the gill irritation and brain injury, although the solvent may also partly contributed to aggression. Overall we conclude that SWCNTs are a respiratory toxicant in trout, the fish are able to manage oxidative stress and osmoregulatory disturbances, but other cellular pathologies raise concerns about cell cycle defects, neurotoxicity, and as yet unidentified blood borne factors that possibly mediate systemic pathologies

  7. Acute respiratory toxicity following inhalation exposure to soman in guinea pigs

    International Nuclear Information System (INIS)

    Perkins, Michael W.; Pierre, Zdenka; Rezk, Peter; Sabnekar, Praveena; Kabra, Kareem; Chanda, Soma; Oguntayo, Samuel; Sciuto, Alfred M.; Doctor, Bhupendra P.; Nambiar, Madhusoodana P.

    2010-01-01

    Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m 3 concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m 3 soman survived, while animals exposed to 841, and 1121 mg/m 3 resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt 50 for soman determined by probit analysis was 827.2 mg/m 3 . A majority of the animals that died at 1121 mg/m 3 developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.

  8. Animal models of human respiratory syncytial virus disease

    NARCIS (Netherlands)

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

    2011-01-01

    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

  9. Computational Models and Emergent Properties of Respiratory Neural Networks

    Science.gov (United States)

    Lindsey, Bruce G.; Rybak, Ilya A.; Smith, Jeffrey C.

    2012-01-01

    Computational models of the neural control system for breathing in mammals provide a theoretical and computational framework bringing together experimental data obtained from different animal preparations under various experimental conditions. Many of these models were developed in parallel and iteratively with experimental studies and provided predictions guiding new experiments. This data-driven modeling approach has advanced our understanding of respiratory network architecture and neural mechanisms underlying generation of the respiratory rhythm and pattern, including their functional reorganization under different physiological conditions. Models reviewed here vary in neurobiological details and computational complexity and span multiple spatiotemporal scales of respiratory control mechanisms. Recent models describe interacting populations of respiratory neurons spatially distributed within the Bötzinger and pre-Bötzinger complexes and rostral ventrolateral medulla that contain core circuits of the respiratory central pattern generator (CPG). Network interactions within these circuits along with intrinsic rhythmogenic properties of neurons form a hierarchy of multiple rhythm generation mechanisms. The functional expression of these mechanisms is controlled by input drives from other brainstem components, including the retrotrapezoid nucleus and pons, which regulate the dynamic behavior of the core circuitry. The emerging view is that the brainstem respiratory network has rhythmogenic capabilities at multiple levels of circuit organization. This allows flexible, state-dependent expression of different neural pattern-generation mechanisms under various physiological conditions, enabling a wide repertoire of respiratory behaviors. Some models consider control of the respiratory CPG by pulmonary feedback and network reconfiguration during defensive behaviors such as cough. Future directions in modeling of the respiratory CPG are considered. PMID:23687564

  10. Reference respiratory waveforms by minimum jerk model analysis

    Energy Technology Data Exchange (ETDEWEB)

    Anetai, Yusuke, E-mail: anetai@radonc.med.osaka-u.ac.jp; Sumida, Iori; Takahashi, Yutaka; Yagi, Masashi; Mizuno, Hirokazu; Ogawa, Kazuhiko [Department of Radiation Oncology, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita-shi, Osaka 565-0871 (Japan); Ota, Seiichi [Department of Medical Technology, Osaka University Hospital, Yamadaoka 2-15, Suita-shi, Osaka 565-0871 (Japan)

    2015-09-15

    Purpose: CyberKnife{sup ®} robotic surgery system has the ability to deliver radiation to a tumor subject to respiratory movements using Synchrony{sup ®} mode with less than 2 mm tracking accuracy. However, rapid and rough motion tracking causes mechanical tracking errors and puts mechanical stress on the robotic joint, leading to unexpected radiation delivery errors. During clinical treatment, patient respiratory motions are much more complicated, suggesting the need for patient-specific modeling of respiratory motion. The purpose of this study was to propose a novel method that provides a reference respiratory wave to enable smooth tracking for each patient. Methods: The minimum jerk model, which mathematically derives smoothness by means of jerk, or the third derivative of position and the derivative of acceleration with respect to time that is proportional to the time rate of force changed was introduced to model a patient-specific respiratory motion wave to provide smooth motion tracking using CyberKnife{sup ®}. To verify that patient-specific minimum jerk respiratory waves were being tracked smoothly by Synchrony{sup ®} mode, a tracking laser projection from CyberKnife{sup ®} was optically analyzed every 0.1 s using a webcam and a calibrated grid on a motion phantom whose motion was in accordance with three pattern waves (cosine, typical free-breathing, and minimum jerk theoretical wave models) for the clinically relevant superior–inferior directions from six volunteers assessed on the same node of the same isocentric plan. Results: Tracking discrepancy from the center of the grid to the beam projection was evaluated. The minimum jerk theoretical wave reduced the maximum-peak amplitude of radial tracking discrepancy compared with that of the waveforms modeled by cosine and typical free-breathing model by 22% and 35%, respectively, and provided smooth tracking for radial direction. Motion tracking constancy as indicated by radial tracking discrepancy

  11. Mucosal inflammation at the respiratory interface: a zebrafish model.

    Science.gov (United States)

    Progatzky, Fränze; Cook, H Terence; Lamb, Jonathan R; Bugeon, Laurence; Dallman, Margaret J

    2016-03-15

    Inflammatory diseases of the respiratory system such as asthma and chronic obstructive pulmonary disease are increasing globally and remain poorly understood conditions. Although attention has long focused on the activation of type 1 and type 2 helper T cells of the adaptive immune system in these diseases, it is becoming increasingly apparent that there is also a need to understand the contributions and interactions between innate immune cells and the epithelial lining of the respiratory system. Cigarette smoke predisposes the respiratory tissue to a higher incidence of inflammatory disease, and here we have used zebrafish gills as a model to study the effect of cigarette smoke on the respiratory epithelium. Zebrafish gills fulfill the same gas-exchange function as the mammalian airways and have a similar structure. Exposure to cigarette smoke extracts resulted in an increase in transcripts of the proinflammatory cytokines TNF-α, IL-1β, and MMP9 in the gill tissue, which was at least in part mediated via NF-κB activation. Longer term exposure of fish for 6 wk to cigarette smoke extract resulted in marked structural changes to the gills with lamellar fusion and mucus cell formation, while signs of inflammation or fibrosis were absent. This shows, for the first time, that zebrafish gills are a relevant model for studying the effect of inflammatory stimuli on a respiratory epithelium, since they mimic the immunopathology involved in respiratory inflammatory diseases of humans. Copyright © 2016 the American Physiological Society.

  12. Computational 3-D Model of the Human Respiratory System

    Science.gov (United States)

    We are developing a comprehensive, morphologically-realistic computational model of the human respiratory system that can be used to study the inhalation, deposition, and clearance of contaminants, while being adaptable for age, race, gender, and health/disease status. The model ...

  13. Assaying environmental nickel toxicity using model nematodes

    Science.gov (United States)

    Rudel, David; Douglas, Chandler; Huffnagle, Ian; Besser, John M.; Ingersoll, Christopher G.

    2013-01-01

    Although nickel exposure results in allergic reactions, respiratory conditions, and cancer in humans and rodents, the ramifications of excess nickel in the environment for animal and human health remain largely undescribed. Nickel and other cationic metals travel through waterways and bind to soils and sediments. To evaluate the potential toxic effects of nickel at environmental contaminant levels (8.9-7,600 µg Ni/g dry weight of sediment and 50-800 µg NiCl2/L of water), we conducted assays using two cosmopolitan nematodes, Caenorhabditis elegans and Pristionchus pacificus. We assayed the effects of both sediment-bound and aqueous nickel upon animal growth, developmental survival, lifespan, and fecundity. Uncontaminated sediments were collected from sites in the Midwestern United States and spiked with a range of nickel concentrations. We found that nickel-spiked sediment substantially impairs both survival from larval to adult stages and adult longevity in a concentration-dependent manner. Further, while aqueous nickel showed no adverse effects on either survivorship or longevity, we observed a significant decrease in fecundity, indicating that aqueous nickel could have a negative impact on nematode physiology. Intriguingly, C. elegansand P. pacificus exhibit similar, but not identical, responses to nickel exposure. Moreover, P. pacificus could be tested successfully in sediments inhospitable to C. elegans. Our results add to a growing body of literature documenting the impact of nickel on animal physiology, and suggest that environmental toxicological studies could gain an advantage by widening their repertoire of nematode species.

  14. Assaying environmental nickel toxicity using model nematodes.

    Directory of Open Access Journals (Sweden)

    David Rudel

    Full Text Available Although nickel exposure results in allergic reactions, respiratory conditions, and cancer in humans and rodents, the ramifications of excess nickel in the environment for animal and human health remain largely undescribed. Nickel and other cationic metals travel through waterways and bind to soils and sediments. To evaluate the potential toxic effects of nickel at environmental contaminant levels (8.9-7,600 µg Ni/g dry weight of sediment and 50-800 µg NiCl2/L of water, we conducted assays using two cosmopolitan nematodes, Caenorhabditis elegans and Pristionchus pacificus. We assayed the effects of both sediment-bound and aqueous nickel upon animal growth, developmental survival, lifespan, and fecundity. Uncontaminated sediments were collected from sites in the Midwestern United States and spiked with a range of nickel concentrations. We found that nickel-spiked sediment substantially impairs both survival from larval to adult stages and adult longevity in a concentration-dependent manner. Further, while aqueous nickel showed no adverse effects on either survivorship or longevity, we observed a significant decrease in fecundity, indicating that aqueous nickel could have a negative impact on nematode physiology. Intriguingly, C. elegans and P. pacificus exhibit similar, but not identical, responses to nickel exposure. Moreover, P. pacificus could be tested successfully in sediments inhospitable to C. elegans. Our results add to a growing body of literature documenting the impact of nickel on animal physiology, and suggest that environmental toxicological studies could gain an advantage by widening their repertoire of nematode species.

  15. Assaying environmental nickel toxicity using model nematodes.

    Science.gov (United States)

    Rudel, David; Douglas, Chandler D; Huffnagle, Ian M; Besser, John M; Ingersoll, Christopher G

    2013-01-01

    Although nickel exposure results in allergic reactions, respiratory conditions, and cancer in humans and rodents, the ramifications of excess nickel in the environment for animal and human health remain largely undescribed. Nickel and other cationic metals travel through waterways and bind to soils and sediments. To evaluate the potential toxic effects of nickel at environmental contaminant levels (8.9-7,600 µg Ni/g dry weight of sediment and 50-800 µg NiCl2/L of water), we conducted assays using two cosmopolitan nematodes, Caenorhabditis elegans and Pristionchus pacificus. We assayed the effects of both sediment-bound and aqueous nickel upon animal growth, developmental survival, lifespan, and fecundity. Uncontaminated sediments were collected from sites in the Midwestern United States and spiked with a range of nickel concentrations. We found that nickel-spiked sediment substantially impairs both survival from larval to adult stages and adult longevity in a concentration-dependent manner. Further, while aqueous nickel showed no adverse effects on either survivorship or longevity, we observed a significant decrease in fecundity, indicating that aqueous nickel could have a negative impact on nematode physiology. Intriguingly, C. elegans and P. pacificus exhibit similar, but not identical, responses to nickel exposure. Moreover, P. pacificus could be tested successfully in sediments inhospitable to C. elegans. Our results add to a growing body of literature documenting the impact of nickel on animal physiology, and suggest that environmental toxicological studies could gain an advantage by widening their repertoire of nematode species.

  16. An Improved Dynamic Model for the Respiratory Response to Exercise

    Directory of Open Access Journals (Sweden)

    Leidy Y. Serna

    2018-02-01

    Full Text Available Respiratory system modeling has been extensively studied in steady-state conditions to simulate sleep disorders, to predict its behavior under ventilatory diseases or stimuli and to simulate its interaction with mechanical ventilation. Nevertheless, the studies focused on the instantaneous response are limited, which restricts its application in clinical practice. The aim of this study is double: firstly, to analyze both dynamic and static responses of two known respiratory models under exercise stimuli by using an incremental exercise stimulus sequence (to analyze the model responses when step inputs are applied and experimental data (to assess prediction capability of each model. Secondly, to propose changes in the models' structures to improve their transient and stationary responses. The versatility of the resulting model vs. the other two is shown according to the ability to simulate ventilatory stimuli, like exercise, with a proper regulation of the arterial blood gases, suitable constant times and a better adjustment to experimental data. The proposed model adjusts the breathing pattern every respiratory cycle using an optimization criterion based on minimization of work of breathing through regulation of respiratory frequency.

  17. Chemosensory TRP channels in the respiratory tract: role in toxic lung injury and potential as "sweet spots" for targeted therapies.

    Science.gov (United States)

    Büch, Thomas; Schäfer, Eva; Steinritz, Dirk; Dietrich, Alexander; Gudermann, Thomas

    2013-01-01

    Acute toxic lung injury by reactive inhalational compounds is an important and still unresolved medical problem. Hazardous gases or vapors, e. g. chlorine, phosgene, sulfur mustard or methyl isocyanate, are released during occupational accidents or combustion processes and also represent a potential threat in terroristic scenarios. According to their broad-range chemical reactivity, the mechanism of lung injury evoked by these agents has long been described as rather unspecific. Consequently, therapeutic options are still restricted to symptomatic treatment. However, in recent years, ion channels of the transient receptor potential (TRP) family have been identified to act as specific sensor molecules expressed in the respiratory tract and to engage defined signaling pathways upon inhalational exposure to toxic challenges. These pulmonary receptor molecules have been primarily characterized in sensory neurons of the lung. However, chemosensory molecules are also expressed in non-neuronal cells, e.g. in the lung epithelium as well as in the pulmonary vasculature. Thus, activation of respiratory chemosensors by toxic inhalants promotes a complex signaling network directly or indirectly regulating pulmonary blood flow, the integrity of the epithelial lining, and the mucociliary clearance of the bronchial system. This review gives a synopsis on reactive lung-toxic agents and their specific target molecules in the lung and summarizes the current knowledge about the pathophysiological role of chemosensory signaling in neuronal and non-neuronal cells in toxic lung injury. Finally, we describe possible future strategies for a causal, specifically tailored treatment option based on the mechanistic understanding of molecular events ensuing inhalation of lung-toxic agents.

  18. Respiratory toxicity of cyanobacterial aphantoxins from Aphanizomenon flos-aquae DC-1 in the zebrafish gill

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, De Lu, E-mail: deluzh@163.com [Department of Lifescience and Biotechnology, College of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070 (China); Liu, Si Yi [Department of Lifescience and Biotechnology, College of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070 (China); Zhang, Jing [College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 (China); Zhang, Jian Kun [Department of Lifescience and Biotechnology, College of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070 (China); Hu, Chun Xiang, E-mail: cxhu@ihb.ac.cn [Key Laboratory of Algal Biology, Institute of Hydrobiology, The Chinese Academy of Sciences, Wuhan 430072 (China); Liu, Yong Ding [Key Laboratory of Algal Biology, Institute of Hydrobiology, The Chinese Academy of Sciences, Wuhan 430072 (China)

    2016-07-15

    aphantoxins or PSPs lead to structural damage and altered function in the gills of zebrafish, including changes in histological structure and increases in the activities of AST and ALT. The inhibition of the activities of AChE and MAO suggest that aphantoxins or PSPs could induce respiratory toxicity in the zebrafish gill. Furthermore, these parameters may be used as bioindicators for investigating aphantoxin exposure and cyanobacterial blooms in nature.

  19. 3-D Model of the Human Respiratory System

    Science.gov (United States)

    The U.S. EPA’s Office of Research and Development (ORD) has developed a 3-D computational fluid dynamics (CFD) model of the human respiratory system that allows for the simulation of particulate based contaminant deposition and clearance, while being adaptable for age, ethn...

  20. Mathematical modeling of respiratory system mechanics in the newborn lamb.

    Science.gov (United States)

    Le Rolle, Virginie; Samson, Nathalie; Praud, Jean-Paul; Hernández, Alfredo I

    2013-03-01

    In this paper, a mathematical model of the respiratory mechanics is used to reproduce experimental signal waveforms acquired from three newborn lambs. As the main challenge is to determine specific lamb parameters, a sensitivity analysis has been realized to find the most influent parameters, which are identified using an evolutionary algorithm. Results show a close match between experimental and simulated pressure and flow waveforms obtained during spontaneous ventilation and pleural pressure variations acquired during the application of positive pressure, since root mean square errors equal to 0.0119, 0.0052 and 0.0094. The identified parameters were discussed in light of previous knowledge of respiratory mechanics in the newborn.

  1. Sublethal toxicant effects with dynamic energy budget theory: model formulation

    OpenAIRE

    Muller, Erik B.; Nisbet, Roger M.; Berkley, Heather A.

    2009-01-01

    We develop and test a general modeling framework to describe the sublethal effects of pollutants by adding toxicity modules to an established dynamic energy budget (DEB) model. The DEB model describes the rates of energy acquisition and expenditure by individual organisms; the toxicity modules describe how toxicants affect these rates by changing the value of one or more DEB parameters, notably the parameters quantifying the rates of feeding and maintenance. We investigate four toxicity modul...

  2. Deterministic and stochastic models for middle east respiratory syndrome (MERS)

    Science.gov (United States)

    Suryani, Dessy Rizki; Zevika, Mona; Nuraini, Nuning

    2018-03-01

    World Health Organization (WHO) data stated that since September 2012, there were 1,733 cases of Middle East Respiratory Syndrome (MERS) with 628 death cases that occurred in 27 countries. MERS was first identified in Saudi Arabia in 2012 and the largest cases of MERS outside Saudi Arabia occurred in South Korea in 2015. MERS is a disease that attacks the respiratory system caused by infection of MERS-CoV. MERS-CoV transmission occurs directly through direct contact between infected individual with non-infected individual or indirectly through contaminated object by the free virus. Suspected, MERS can spread quickly because of the free virus in environment. Mathematical modeling is used to illustrate the transmission of MERS disease using deterministic model and stochastic model. Deterministic model is used to investigate the temporal dynamic from the system to analyze the steady state condition. Stochastic model approach using Continuous Time Markov Chain (CTMC) is used to predict the future states by using random variables. From the models that were built, the threshold value for deterministic models and stochastic models obtained in the same form and the probability of disease extinction can be computed by stochastic model. Simulations for both models using several of different parameters are shown, and the probability of disease extinction will be compared with several initial conditions.

  3. Assessing the in vitro toxicity of the lunar dust environment using respiratory cells exposed to Al(2)O(3) or SiO(2) fine dust particles.

    Science.gov (United States)

    Jordan, Jacqueline A; Verhoff, Ashley M; Morgan, Julie E; Fischer, David G

    2009-12-01

    Prior chemical and physical analysis of lunar soil suggests a composition of dust particles that may contribute to the development of acute and chronic respiratory disorders. In this study, fine Al(2)O(3) (0.7 μm) and fine SiO(2) (mean 1.6 μm) were used to assess the cellular uptake and cellular toxicity of lunar dust particle analogs. Respiratory cells, murine alveolar macrophages (RAW 264.7) and human type II epithelial (A549), were cultured as the in vitro model system. The phagocytic activity of both cell types using ultrafine (0.1 μm) and fine (0.5 μm) fluorescent polystyrene beads was determined. Following a 6-h exposure, RAW 264.7 cells had extended pseudopods with beads localized in the cytoplasmic region of cells. After 24 h, the macrophage cells were rounded and clumped and lacked pseudopods, which suggest impairment of phagocytosis. A549 cells did not contain beads, and after 24 h, the majority of the beads appeared to primarily coat the surface of the cells. Next, we investigated the cellular response to fine SiO(2) and Al(2)O(3) (up to 5 mg/ml). RAW 264.7 cells exposed to 1.0 mg/ml of fine SiO(2) for 6 h demonstrated pseudopods, cellular damage, apoptosis, and necrosis. A549 cells showed slight toxicity when exposed to fine SiO(2) for the same time and dose. A549 cells had particles clustered on the surface of the cells. Only a higher dose (5.0 mg/ml) of fine SiO(2) resulted in a significant cytotoxicity to A549 cells. Most importantly, both cell types showed minimal cytotoxicity following exposure to fine Al(2)O(3). Overall, this study suggests differential cellular toxicity associated with exposure to fine mineral dust particles.

  4. ASSISTED MODELLING OF MOBILE MEDICAL TREATMENT EQUIPMENT, UPPER RESPIRATORY AFFECTIONS

    Directory of Open Access Journals (Sweden)

    GOANTA Adrian Mihai

    2012-09-01

    Full Text Available The paper aims to present some aspects of parametric modelling application in medical engineering, specifically in the design of medical instruments for ENT diseases. The work also contains both stages, how to obtain all parts parametrically and related accessories that are part of a mobile aerosol -generating medical equipment intended for the treatment of the upper respiratory diseases. Also photorealistic visualization capabilities are highlighted with NX Software from Siemens as well as how to obtain the corresponding 2D documentation.

  5. Toxic Chemical from Plastics Attenuates Phenylbiguanide-induced Cardio-respiratory Reflexes in Anaesthetized Rats.

    Science.gov (United States)

    Pant, Jayanti; Pant, Mahendra K; Chouhan, Shikha; Singh, Surya P; Deshpande, Shripad B

    2015-01-01

    Bisphenol A (BPA) attenuated phenylbiguanide (PBG)-induced cardio-respiratory reflexes involving decreased vagal afferent activity. BPA leaches out from plastics thus it is expected that chronic exposure to plastic boiled (PBW) water will also produce similar changes. Therefore, the present study was undertaken to evaluate the effects of chronic ingestion of PBW on PBG evoked reflexes and were compared with BPA. Adult female rats were ingested BPA containing pellets (2 µg/kg body weight)/PBW/tap water (ad libitum) for 30 days. On day 30, the animals were anaesthetized and BP, ECG and respiratory excursions were recorded. Further, PBG was injected intravenously to evoke cardio-respiratory reflexes and at the end lungs were excised for histopathological examination. BPA concentration in PBW was 6.6 µg/ml estimated by HPLC. In rats receiving tap water, PBG produced bradycardia, hypotension and tachypnoea. In PBW/BPA treated groups, PBG-induced reflexes were attenuated significantly along with emphysematous and consolidative changes in lungs. The present results indicate that PBW attenuates the protective cardio-respiratory reflexes and also produces histopathological changes in lungs.

  6. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX

    International Nuclear Information System (INIS)

    Nambiar, Madhusoodana P.; Gordon, Richard K.; Rezk, Peter E.; Katos, Alexander M.; Wajda, Nikolai A.; Moran, Theodore S.; Steele, Keith E.; Doctor, Bhupendra P.; Sciuto, Alfred M.

    2007-01-01

    To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m 3 of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure

  7. Assessment of Geographical Variation in the Respiratory Toxicity of Desert Dust Particles

    Science.gov (United States)

    2013-01-01

    toxicity in rats following intratracheal administration. Assessments included biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung...research staff for 5 days after the procedure to document clinical abnormalities. Bronchoalveolar lavage fluid and lung tissue collection The right lung...and placed in sample collection tubes. Following bronchoalveolar lavage fluid (BALF) collection, the right lung lobes were severed away from the

  8. Assessing the toxic effects of ethylene glycol ethers using Quantitative Structure Toxicity Relationship models

    International Nuclear Information System (INIS)

    Ruiz, Patricia; Mumtaz, Moiz; Gombar, Vijay

    2011-01-01

    Experimental determination of toxicity profiles consumes a great deal of time, money, and other resources. Consequently, businesses, societies, and regulators strive for reliable alternatives such as Quantitative Structure Toxicity Relationship (QSTR) models to fill gaps in toxicity profiles of compounds of concern to human health. The use of glycol ethers and their health effects have recently attracted the attention of international organizations such as the World Health Organization (WHO). The board members of Concise International Chemical Assessment Documents (CICAD) recently identified inadequate testing as well as gaps in toxicity profiles of ethylene glycol mono-n-alkyl ethers (EGEs). The CICAD board requested the ATSDR Computational Toxicology and Methods Development Laboratory to conduct QSTR assessments of certain specific toxicity endpoints for these chemicals. In order to evaluate the potential health effects of EGEs, CICAD proposed a critical QSTR analysis of the mutagenicity, carcinogenicity, and developmental effects of EGEs and other selected chemicals. We report here results of the application of QSTRs to assess rodent carcinogenicity, mutagenicity, and developmental toxicity of four EGEs: 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, and 2-butoxyethanol and their metabolites. Neither mutagenicity nor carcinogenicity is indicated for the parent compounds, but these compounds are predicted to be developmental toxicants. The predicted toxicity effects were subjected to reverse QSTR (rQSTR) analysis to identify structural attributes that may be the main drivers of the developmental toxicity potential of these compounds.

  9. The Linear Model Research on Tibetan Six-Character Poetry's Respiratory Signal

    Science.gov (United States)

    Yonghong, Li; Yangrui, Yang; Lei, Guo; Hongzhi, Yu

    In this paper, we studied the Tibetan six-character pomes' respiratory signal during reading from the perspective of the physiological. Main contents include: 1) Selected 40 representative Tibetan six-character and four lines pomes from ldquo; The Love-songs of 6th Dalai Lama Tshang•yangGya•tsho ", and recorded speech sounds, voice and respiratory signals; 2) Designed a set of respiratory signal parameters for the study of poetry; 3) Extracted the relevant parameters of poetry respiratory signal by using the well-established respiratory signal processing platform; 4) Studied the type of breathing pattern, established the linear model of poetry respiratory signal.

  10. The Acute Toxicity of Major Ion Salts to Ceriodaphnia dubia. III. Mathematical models for mixture toxicity

    Data.gov (United States)

    U.S. Environmental Protection Agency — This dataset concerns the development of models for describing the acute toxicity of major ions to Ceriodaphnia dubia using data from single salt tests and binary...

  11. Comparative study of respiratory tract immune toxicity induced by three sterilisation nanoparticles: silver, zinc oxide and titanium dioxide.

    Science.gov (United States)

    Liu, Huanliang; Yang, Danfeng; Yang, Honglian; Zhang, Huashan; Zhang, Wei; Fang, Yanjun; Lin, Zhiqing; Tian, Lei; Lin, Bencheng; Yan, Jun; Xi, Zhuge

    2013-03-15

    Silver, zinc oxide, and titanium dioxide nanoparticles are used as sterilisation materials to enhance the performance of disinfectants. We investigated the respiratory tract immune toxicity ("immunotoxicity") of these nanoparticles in vivo and in vitro, and we explored the relationships between particle size, particle shape, chemical composition, chemical stability and the toxicological effects of these typical nanoparticles in rats. In vivo, the rats were exposed to nanoparticles by intratracheal instillation. Exposure to nanoparticles caused an increase in oxidative injury to the lungs and disorders in regulating the cytokine network, which were detected in the bronchoalveolar lavage fluid, suggesting that oxidative stress might be important for inducing the respiratory immunotoxicity of nanoparticles. In vitro, the phagocytic function of alveolar macrophages (AMs) was dose-dependently reduced by nanoparticles, and ZnO nanoparticles induced greater cytotoxicity than the silver and titanium-dioxide nanoparticles, which were coincident with the results of multiple measurements, such as a cell viability assay by WST-8 and LDH measurements. Comparative analyses demonstrated that particle composition and chemical stability most likely had a primary role in the biological effects of different nanoparticles. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. A Novel Parametric Model For The Human Respiratory System

    Directory of Open Access Journals (Sweden)

    Clara Mihaela IONESCU

    2003-12-01

    Full Text Available The purpose of this work is to present some recent results in an ongoing research project between Ghent University and Chess Medical Technology Company Belgium. The overall aim of the project is to provide a fast method for identification of the human respiratory system in order to allow for an instantaneously diagnosis of the patient by the medical staff. A novel parametric model of the human respiratory system as well as the obtained experimental results is presented in this paper. A prototype apparatus developed by the company, based on the forced oscillation technique is used to record experimental data from 4 patients in this paper. Signal processing is based on spectral analysis and is followed by the parametric identification of a non-linear mechanistic model. The parametric model is equivalent to the structure of a simple electrical RLC-circuit, containing a non-linear capacitor. These parameters have a useful and easy-to-interpret physical meaning for the medical staff members.

  13. The acute toxicity of major ion salts to Ceriodaphnia dubia. III. Mathematical models for mixture toxicity.

    Science.gov (United States)

    Erickson, Russell J; Mount, David R; Highland, Terry L; Hockett, J Russell; Hoff, Dale J; Jenson, Correne T; Norberg-King, Teresa J; Peterson, Kira N

    2018-01-01

    Based on previous research on the acute toxicity of major ions (Na + , K + , Ca 2+ , Mg 2+ , Cl - , SO 4 2- , and HCO 3 - /CO 3 2- ) to Ceriodaphnia dubia, a mathematical model was developed for predicting the median lethal concentration (LC50) for any ion mixture, excepting those dominated by K-specific toxicity. One component of the model describes a mechanism of general ion toxicity to which all ions contribute and predicts LC50s as a function of osmolarity and Ca activity. The other component describes Mg/Ca-specific toxicity to apply when such toxicity exceeds the general ion toxicity and predicts LC50s as a function of Mg and Ca activities. This model not only tracks well the observed LC50s from past research used for model development but also successfully predicts LC50s from new toxicity tests on synthetic mixtures of ions emulating chemistries of various ion-enriched effluents and receiving waters. It also performs better than a previously published model for major ion toxicity. Because of the complexities of estimating chemical activities and osmolarity, a simplified model based directly on ion concentrations was also developed and found to provide useful predictions. Environ Toxicol Chem 2018;37:247-259. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

  14. COPD management as a model for all chronic respiratory conditions: report of the 4th Consensus Conference in Respiratory Medicine.

    Science.gov (United States)

    Nardini, Stefano; De Benedetto, Fernando; Sanguinetti, Claudio M; Bellofiore, Salvatore; Carlone, Stefano; Privitera, Salvatore; Sagliocca, Luciano; Tupputi, Emmanuele; Baccarani, Claudio; Caiffa, Gennaro; Calabrese, Maria Consiglia; Capuozzo, Antonio; Cauchi, Salvatore; Conio, Valentina; Coratella, Giuseppe; Crismancich, Franco; Dal Negro, Roberto W; Dellarole, Franco; Delucchi, Maurizio; Favaretti, Carlo; Forte, Silvia; Gallo, Franca Matilde; Giuliano, Riccardo; Grandi, Marco; Grillo, Antonino; Gualano, Maria Rosaria; Guffanti, Enrico; Locicero, Salvatore; Lombardo, Francesco Paolo; Mantero, Marco; Marasso, Roberto; Martino, Laura; Mastroberardino, Michele; Mereu, Carlo; Messina, Roberto; Neri, Margherita; Novelletto, Bruno Franco; Parente, Paolo; Pasquinucci, Sergio; Pistolesi, Massimo; Polverino, Mario; Posca, Agnese; Richeldi, Luca; Roccia, Fernando; Giustini, Ettore Saffi; Salemi, Michelangelo; Santacroce, Salvatore; Schisano, Mario; Schisano, Matteo; Selvi, Eleonora; Silenzi, Andrea; Soverina, Patrizio; Taranto, Claudio; Ugolini, Marta; Visaggi, Piero; Zanasi, Alessandro

    2017-01-01

    Non-communicable diseases (NCDs) kill 40 million people each year. The management of chronic respiratory NCDs such as chronic obstructive pulmonary disease (COPD) is particularly critical in Italy, where they are widespread and represent a heavy burden on healthcare resources. It is thus important to redefine the role and responsibility of respiratory specialists and their scientific societies, together with that of the whole healthcare system, in order to create a sustainable management of COPD, which could become a model for other chronic respiratory conditions. These issues were divided into four main topics (Training, Organization, Responsibilities, and Sustainability) and discussed at a Consensus Conference promoted by the Research Center of the Italian Respiratory Society held in Rome, Italy, 3-4 November 2016. Regarding training, important inadequacies emerged regarding specialist training - both the duration of practical training courses and teaching about chronic diseases like COPD. A better integration between university and teaching hospitals would improve the quality of specialization. A better organizational integration between hospital and specialists/general practitioners (GPs) in the local community is essential to improve the diagnostic and therapeutic pathways for chronic respiratory patients. Improving the care pathways is the joint responsibility of respiratory specialists, GPs, patients and their caregivers, and the healthcare system. The sustainability of the entire system depends on a better organization of the diagnostic-therapeutic pathways, in which also other stakeholders such as pharmacists and pharmaceutical companies can play an important role.

  15. Toxic response of occupational exposure to ethylene oxide, with particular reference to its respiratory effects

    Directory of Open Access Journals (Sweden)

    E. Soleimani

    2011-04-01

    Full Text Available Background and Aims Ethylene oxide is used as a sterilizing agent in health care industries. The present study aimed to assess and recognize the nature of pulmonary reactions, if any, associated with occupational exposure to ethylene oxide and to investigate the prevalence of dermal, visual, neurologic, reproductive, hematologic, hepatic and renal disorders .   Methods  Forty exposed and 47 unexposed employees were evaluated . Subjects were interviewed and standard respiratory symptom questionnaire as well as a questionnaire pertaining to symptoms of intoxication with this chemical were administered to them. Furthermore, parameters of pulmonary function were measured during exposure and a few days after exposure ceased Additionally, blood samples were taken for CBC, liver and kidney function tests . Moreover, atmospheric concentrations of ethylene oxide were determined by gas detector tubes .   Results  Respiratory symptoms such as cough and phlegm as well as dermal, visual and neurologic symptoms in exposed workers were significantly more prevalent P≤0.05 . Furthermore, significant decrements in some parameters of pulmonary function during exposure as compared with the values measured after exposure ceased, were noted . Results of biochemical tests were similar in both groups. Mean atmospheric concentration of ethylene oxide was evaluated to be 1.24±1.5 ppm.   Conclusion  The findings of this study indicate that exposure to ethylene oxide even at low concentrations is associated with significant decreases in pulmonary parameters. However, this effect is acute, temporary and reversible. Conversely, exposure to ethylene oxide was not associated with hematotoxic, hepatotoxic and nephrotoxic response, although, dermal, visual and neurologic symptoms were observed.

  16. Assessing reproductive toxicity of two environmental toxicants with a novel in vitro human spermatogenic model

    Directory of Open Access Journals (Sweden)

    Charles A. Easley, IV

    2015-05-01

    Full Text Available Environmental influences and insults by reproductive toxicant exposure can lead to impaired spermatogenesis or infertility. Understanding how toxicants disrupt spermatogenesis is critical for determining how environmental factors contribute to impaired fertility. While current animal models are available, understanding of the reproductive toxic effects on human fertility requires a more robust model system. We recently demonstrated that human pluripotent stem cells can differentiate into spermatogonial stem cells/spermatogonia, primary and secondary spermatocytes, and haploid spermatids; a model that mimics many aspects of human spermatogenesis. Here, using this model system, we examine the effects of 2-bromopropane (2-BP and 1,2,dibromo-3-chloropropane (DBCP on in vitro human spermatogenesis. 2-BP and DBCP are non-endocrine disrupting toxicants that are known to impact male fertility. We show that acute treatment with either 2-BP or DBCP induces a reduction in germ cell viability through apoptosis. 2-BP and DBCP affect viability of different cell populations as 2-BP primarily reduces spermatocyte viability, whereas DBCP exerts a much greater effect on spermatogonia. Acute treatment with 2-BP or DBCP also reduces the percentage of haploid spermatids. Both 2-BP and DBCP induce reactive oxygen species (ROS formation leading to an oxidized cellular environment. Taken together, these results suggest that acute exposure with 2-BP or DBCP causes human germ cell death in vitro by inducing ROS formation. This system represents a unique platform for assessing human reproductive toxicity potential of various environmental toxicants in a rapid, efficient, and unbiased format.

  17. Respiratory toxicity of repeated exposure to particles produced by traffic and sugar cane burning.

    Science.gov (United States)

    Mazzoli-Rocha, Flavia; Carvalho, Giovanna M C; Lanzetti, Manuella; Valença, Samuel S; Silva, Luiz F F; Saldiva, Paulo H N; Zin, Walter A; Faffe, Débora S

    2014-01-15

    We compared the toxicity of subchronic exposure to equivalent masses of particles from sugar cane burning and traffic. BALB/c mice received 3 intranasal instillations/week during 1, 2 or 4 weeks of either distilled water (C1, C2, C4) or particles (15μg) from traffic (UP1, UP2, UP4) or biomass burning (BP1, BP2, BP4). Lung mechanics, histology and oxidative stress were analyzed 24h after the last instillation. In all instances UP and BP groups presented worse pulmonary elastance, airway and tissue resistance, alveolar collapse, bronchoconstriction and macrophage influx into the lungs than controls. UP4, BP2 and BP4 presented more alveolar collapse than UP1 and BP1, respectively. UP and BP had worse bronchial and alveolar lesion scores than their controls; BP4 had greater bronchial lesion scores than UP4. Catalase was higher in UP4 and BP4 than in C4. In conclusion, biomass particles were more toxic than those from traffic after repeated exposures. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Metabolism related toxicity of diclofenac in yeast as model system

    NARCIS (Netherlands)

    van Leeuwen, J.S.; Vredenburg, G.; Dragovic, S.; Tjong, T.F.; Vos, J.C.; Vermeulen, N.P.E.

    2010-01-01

    Diclofenac is a widely used drug that can cause serious hepatotoxicity, which has been linked to metabolism by cytochrome P450s (P450). To investigate the role of oxidative metabolites in diclofenac toxicity, a model for P450-related toxicity was set up in Saccharomyces cerevisiae. We expressed a

  19. Velocity profiles in idealized model of human respiratory tract

    Directory of Open Access Journals (Sweden)

    Jicha M.

    2013-04-01

    Full Text Available This article deals with numerical simulation focused on velocity profiles in idealized model of human upper airways during steady inspiration. Three r gimes of breathing were investigated: Resting condition, Deep breathing and Light activity which correspond to most common regimes used for experiments and simulations. Calculation was validated with experimental data given by Phase Doppler Anemometry performed on the model with same geometry. This comparison was made in multiple points which form one cross-section in trachea near first bifurcation of bronchial tree. Development of velocity profile in trachea during steady inspiration was discussed with respect for common phenomenon formed in trachea and for future research of transport of aerosol particles in human respiratory tract.

  20. Detection of Severe Respiratory Disease Epidemic Outbreaks by CUSUM-Based Overcrowd-Severe-Respiratory-Disease-Index Model

    Directory of Open Access Journals (Sweden)

    Carlos Polanco

    2013-01-01

    Full Text Available A severe respiratory disease epidemic outbreak correlates with a high demand of specific supplies and specialized personnel to hold it back in a wide region or set of regions; these supplies would be beds, storage areas, hemodynamic monitors, and mechanical ventilators, as well as physicians, respiratory technicians, and specialized nurses. We describe an online cumulative sum based model named Overcrowd-Severe-Respiratory-Disease-Index based on the Modified Overcrowd Index that simultaneously monitors and informs the demand of those supplies and personnel in a healthcare network generating early warnings of severe respiratory disease epidemic outbreaks through the interpretation of such variables. A post hoc historical archive is generated, helping physicians in charge to improve the transit and future allocation of supplies in the entire hospital network during the outbreak. The model was thoroughly verified in a virtual scenario, generating multiple epidemic outbreaks in a 6-year span for a 13-hospital network. When it was superimposed over the H1N1 influenza outbreak census (2008–2010 taken by the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City, it showed that it is an effective algorithm to notify early warnings of severe respiratory disease epidemic outbreaks with a minimal rate of false alerts.

  1. Detection of Severe Respiratory Disease Epidemic Outbreaks by CUSUM-Based Overcrowd-Severe-Respiratory-Disease-Index Model

    Science.gov (United States)

    Castañón-González, Jorge Alberto; Macías, Alejandro E.; Samaniego, José Lino; Buhse, Thomas; Villanueva-Martínez, Sebastián

    2013-01-01

    A severe respiratory disease epidemic outbreak correlates with a high demand of specific supplies and specialized personnel to hold it back in a wide region or set of regions; these supplies would be beds, storage areas, hemodynamic monitors, and mechanical ventilators, as well as physicians, respiratory technicians, and specialized nurses. We describe an online cumulative sum based model named Overcrowd-Severe-Respiratory-Disease-Index based on the Modified Overcrowd Index that simultaneously monitors and informs the demand of those supplies and personnel in a healthcare network generating early warnings of severe respiratory disease epidemic outbreaks through the interpretation of such variables. A post hoc historical archive is generated, helping physicians in charge to improve the transit and future allocation of supplies in the entire hospital network during the outbreak. The model was thoroughly verified in a virtual scenario, generating multiple epidemic outbreaks in a 6-year span for a 13-hospital network. When it was superimposed over the H1N1 influenza outbreak census (2008–2010) taken by the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City, it showed that it is an effective algorithm to notify early warnings of severe respiratory disease epidemic outbreaks with a minimal rate of false alerts. PMID:24069063

  2. Mathematical modelling of a human external respiratory system

    Science.gov (United States)

    1977-01-01

    A closed system of algebraic and common differential equations solved by computer is investigated. It includes equations which describe the activity pattern of the respiratory center, the phrenic nerve, the thrust produced by the diaphragm as a function of the lung volume and discharge frequency of the phrenic nerve, as well as certain relations of the lung stretch receptors and chemoreceptors on various lung and blood characteristics, equations for lung biomechanics, pulmonary blood flow, alveolar gas exchange and capillary blood composition equations to determine various air and blood flow and gas exchange parameters, and various gas mixing and arterial and venous blood composition equations, to determine other blood, air and gas mixing characteristics. Data are presented by means of graphs and tables, and some advantages of this model over others are demonstrated by test results.

  3. Use of the zebrafish larvae as a model to study cigarette smoke condensate toxicity.

    Science.gov (United States)

    Ellis, Lee D; Soo, Evelyn C; Achenbach, John C; Morash, Michael G; Soanes, Kelly H

    2014-01-01

    The smoking of tobacco continues to be the leading cause of premature death worldwide and is linked to the development of a number of serious illnesses including heart disease, respiratory diseases, stroke and cancer. Currently, cell line based toxicity assays are typically used to gain information on the general toxicity of cigarettes and other tobacco products. However, they provide little information regarding the complex disease-related changes that have been linked to smoking. The ethical concerns and high cost associated with mammalian studies have limited their widespread use for in vivo toxicological studies of tobacco. The zebrafish has emerged as a low-cost, high-throughput, in vivo model in the study of toxicology. In this study, smoke condensates from 2 reference cigarettes and 6 Canadian brands of cigarettes with different design features were assessed for acute, developmental, cardiac, and behavioural toxicity (neurotoxicity) in zebrafish larvae. By making use of this multifaceted approach we have developed an in vivo model with which to compare the toxicity profiles of smoke condensates from cigarettes with different design features. This model system may provide insights into the development of smoking related disease and could provide a cost-effective, high-throughput platform for the future evaluation of tobacco products.

  4. Ranking of aquatic toxicity of esters modelled by QSAR.

    Science.gov (United States)

    Papa, Ester; Battaini, Francesca; Gramatica, Paola

    2005-02-01

    Alternative methods like predictions based on Quantitative Structure-Activity Relationships (QSARs) are now accepted to fill data gaps and define priority lists for more expensive and time consuming assessments. A heterogeneous data set of 74 esters was studied for their aquatic toxicity, and available experimental toxicity data on algae, Daphnia and fish were used to develop statistically validated QSAR models, obtained using multiple linear regression (MLR) by the OLS (Ordinary Least Squares) method and GA-VSS (Variable Subset Selection by Genetic Algorithms) to predict missing values. An ESter Aquatic Toxicity INdex (ESATIN) was then obtained by combining, by PCA, experimental and predicted toxicity data, from which model outliers and esters highly influential due to their structure had been eliminated. Finally this integrated aquatic toxicity index, defined by the PC1 score, was modelled using only a few theoretical molecular descriptors. This last QSAR model, statistically validated for its predictive power, could be proposed as a preliminary evaluative method for screening/prioritising esters according to their integrated aquatic toxicity, just starting from their molecular structure.

  5. A review of toxicity models for realistic atmospheric applications

    Science.gov (United States)

    Gunatilaka, Ajith; Skvortsov, Alex; Gailis, Ralph

    2014-02-01

    There are many applications that need to study human health effects caused by exposure to toxic chemicals. Risk analysis for industrial sites, study of population health impacts of atmospheric pollutants, and operations research for assessing the potential impacts of chemical releases in military contexts are some examples. Because of safety risks and the high cost of field trials involving hazardous chemical releases, computer simulations are widely used for such studies. Modelling of atmospheric transport and dispersion of chemicals released into the atmosphere to determine the toxic chemical concentrations to which individuals will be exposed is one main component of these simulations, and there are well established atmospheric dispersion models for this purpose. Estimating the human health effects caused by the exposure to these predicted toxic chemical concentrations is the other main component. A number of different toxicity models for assessing the health effects of toxic chemical exposure are found in the literature. Because these different models have been developed based on different assumptions about the plume characteristics, chemical properties, and physiological response, there is a need to review and compare these models to understand their applicability. This paper reviews several toxicity models described in the literature. The paper also presents results of applying different toxicity models to simulated concentration time series data. These results show that the use of ensemble mean concentrations, which are what atmospheric dispersion models typically provide, to estimate human health effects of exposure to hazardous chemical releases may underestimate their impact when toxic exponent, n, of the chemical is greater than one; the opposite phenomenon appears to hold when n biological recovery processes may predict greater toxicity than the explicitly parameterised models. Despite the wide variety of models of varying degrees of complexity that is

  6. A Bidirectional Coupling Procedure Applied to Multiscale Respiratory Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Kuprat, Andrew P.; Kabilan, Senthil; Carson, James P.; Corley, Richard A.; Einstein, Daniel R.

    2013-07-01

    In this study, we present a novel multiscale computational framework for efficiently linking multiple lower-dimensional models describing the distal lung mechanics to imaging-based 3D computational fluid dynamics (CFD) models of the upper pulmonary airways in order to incorporate physiologically appropriate outlet boundary conditions. The framework is an extension of the Modified Newton’s Method with nonlinear Krylov accelerator developed by Carlson and Miller [1, 2, 3]. Our extensions include the retention of subspace information over multiple timesteps, and a special correction at the end of a timestep that allows for corrections to be accepted with verified low residual with as little as a single residual evaluation per timestep on average. In the case of a single residual evaluation per timestep, the method has zero additional computational cost compared to uncoupled or unidirectionally coupled simulations. We expect these enhancements to be generally applicable to other multiscale coupling applications where timestepping occurs. In addition we have developed a “pressure-drop” residual which allows for stable coupling of flows between a 3D incompressible CFD application and another (lower-dimensional) fluid system. We expect this residual to also be useful for coupling non-respiratory incompressible fluid applications, such as multiscale simulations involving blood flow. The lower-dimensional models that are considered in this study are sets of simple ordinary differential equations (ODEs) representing the compliant mechanics of symmetric human pulmonary airway trees. To validate the method, we compare the predictions of hybrid CFD-ODE models against an ODE-only model of pulmonary airflow in an idealized geometry. Subsequently, we couple multiple sets of ODEs describing the distal lung to an imaging-based human lung geometry. Boundary conditions in these models consist of atmospheric pressure at the mouth and intrapleural pressure applied to the multiple

  7. A bidirectional coupling procedure applied to multiscale respiratory modeling

    Energy Technology Data Exchange (ETDEWEB)

    Kuprat, A.P., E-mail: andrew.kuprat@pnnl.gov [Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA (United States); Kabilan, S., E-mail: senthil.kabilan@pnnl.gov [Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA (United States); Carson, J.P., E-mail: james.carson@pnnl.gov [Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA (United States); Corley, R.A., E-mail: rick.corley@pnnl.gov [Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA (United States); Einstein, D.R., E-mail: daniel.einstein@pnnl.gov [Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA (United States)

    2013-07-01

    In this study, we present a novel multiscale computational framework for efficiently linking multiple lower-dimensional models describing the distal lung mechanics to imaging-based 3D computational fluid dynamics (CFDs) models of the upper pulmonary airways in order to incorporate physiologically appropriate outlet boundary conditions. The framework is an extension of the modified Newton’s method with nonlinear Krylov accelerator developed by Carlson and Miller [1], Miller [2] and Scott and Fenves [3]. Our extensions include the retention of subspace information over multiple timesteps, and a special correction at the end of a timestep that allows for corrections to be accepted with verified low residual with as little as a single residual evaluation per timestep on average. In the case of a single residual evaluation per timestep, the method has zero additional computational cost compared to uncoupled or unidirectionally coupled simulations. We expect these enhancements to be generally applicable to other multiscale coupling applications where timestepping occurs. In addition we have developed a “pressure-drop” residual which allows for stable coupling of flows between a 3D incompressible CFD application and another (lower-dimensional) fluid system. We expect this residual to also be useful for coupling non-respiratory incompressible fluid applications, such as multiscale simulations involving blood flow. The lower-dimensional models that are considered in this study are sets of simple ordinary differential equations (ODEs) representing the compliant mechanics of symmetric human pulmonary airway trees. To validate the method, we compare the predictions of hybrid CFD–ODE models against an ODE-only model of pulmonary airflow in an idealized geometry. Subsequently, we couple multiple sets of ODEs describing the distal lung to an imaging-based human lung geometry. Boundary conditions in these models consist of atmospheric pressure at the mouth and intrapleural

  8. A bidirectional coupling procedure applied to multiscale respiratory modeling

    International Nuclear Information System (INIS)

    Kuprat, A.P.; Kabilan, S.; Carson, J.P.; Corley, R.A.; Einstein, D.R.

    2013-01-01

    In this study, we present a novel multiscale computational framework for efficiently linking multiple lower-dimensional models describing the distal lung mechanics to imaging-based 3D computational fluid dynamics (CFDs) models of the upper pulmonary airways in order to incorporate physiologically appropriate outlet boundary conditions. The framework is an extension of the modified Newton’s method with nonlinear Krylov accelerator developed by Carlson and Miller [1], Miller [2] and Scott and Fenves [3]. Our extensions include the retention of subspace information over multiple timesteps, and a special correction at the end of a timestep that allows for corrections to be accepted with verified low residual with as little as a single residual evaluation per timestep on average. In the case of a single residual evaluation per timestep, the method has zero additional computational cost compared to uncoupled or unidirectionally coupled simulations. We expect these enhancements to be generally applicable to other multiscale coupling applications where timestepping occurs. In addition we have developed a “pressure-drop” residual which allows for stable coupling of flows between a 3D incompressible CFD application and another (lower-dimensional) fluid system. We expect this residual to also be useful for coupling non-respiratory incompressible fluid applications, such as multiscale simulations involving blood flow. The lower-dimensional models that are considered in this study are sets of simple ordinary differential equations (ODEs) representing the compliant mechanics of symmetric human pulmonary airway trees. To validate the method, we compare the predictions of hybrid CFD–ODE models against an ODE-only model of pulmonary airflow in an idealized geometry. Subsequently, we couple multiple sets of ODEs describing the distal lung to an imaging-based human lung geometry. Boundary conditions in these models consist of atmospheric pressure at the mouth and intrapleural

  9. QSAR Models for Reproductive Toxicity and Endocrine Disruption Activity

    Directory of Open Access Journals (Sweden)

    Marjan Vračko

    2010-03-01

    Full Text Available Reproductive toxicity is an important regulatory endpoint, which is required in registration procedures of chemicals used for different purposes (for example pesticides. The in vivo tests are expensive, time consuming and require large numbers of animals, which must be sacrificed. Therefore an effort is ongoing to develop alternative In vitro and in silico methods to evaluate reproductive toxicity. In this review we describe some modeling approaches. In the first example we describe the CAESAR model for prediction of reproductive toxicity; the second example shows a classification model for endocrine disruption potential based on counter propagation artificial neural networks; the third example shows a modeling of relative binding affinity to rat estrogen receptor, and the fourth one shows a receptor dependent modeling experiment.

  10. Mucosal inflammation at the respiratory interface: a zebrafish model

    OpenAIRE

    Progatzky, Fr?nze; Cook, H. Terence; Lamb, Jonathan R.; Bugeon, Laurence; Dallman, Margaret J.

    2015-01-01

    Inflammatory diseases of the respiratory system such as asthma and chronic obstructive pulmonary disease are increasing globally and remain poorly understood conditions. Although attention has long focused on the activation of type 1 and type 2 helper T cells of the adaptive immune system in these diseases, it is becoming increasingly apparent that there is also a need to understand the contributions and interactions between innate immune cells and the epithelial lining of the respiratory sys...

  11. Toxicity of Nanoparticles and an Overview of Current Experimental Models.

    Science.gov (United States)

    Bahadar, Haji; Maqbool, Faheem; Niaz, Kamal; Abdollahi, Mohammad

    2016-01-01

    Nanotechnology is a rapidly growing field having potential applications in many areas. Nanoparticles (NPs) have been studied for cell toxicity, immunotoxicity, and genotoxicity. Tetrazolium-based assays such as MTT, MTS, and WST-1 are used to determine cell viability. Cell inflammatory response induced by NPs is checked by measuring inflammatory biomarkers, such as IL-8, IL-6, and tumor necrosis factor, using ELISA. Lactate dehydrogenase (LDH) assay is used for cell membrane integrity. Different types of cell cultures, including cancer cell lines have been employed as in vitro toxicity models. It has been generally agreed that NPs interfere with either assay materials or with detection systems. So far, toxicity data generated by employing such models are conflicting and inconsistent. Therefore, on the basis of available experimental models, it may be difficult to judge and list some of the more valuable NPs as more toxic to biological systems and vice versa. Considering the potential applications of NPs in many fields and the growing apprehensions of FDA about the toxic potential of nanoproducts, it is the need of the hour to look for new internationally agreed free of bias toxicological models by focusing more on in vivo studies.

  12. Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish.

    Science.gov (United States)

    Byrnes, James; Ganetzky, Rebecca; Lightfoot, Richard; Tzeng, Michael; Nakamaru-Ogiso, Eiko; Seiler, Christoph; Falk, Marni J

    2017-07-18

    Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days

  13. Endangered species toxicity extrapolation using ICE models

    Science.gov (United States)

    The National Research Council’s (NRC) report on assessing pesticide risks to threatened and endangered species (T&E) included the recommendation of using interspecies correlation models (ICE) as an alternative to general safety factors for extrapolating across species. ...

  14. The influence of a fentanyl and dexmedetomidine combination on external respiratory functions in acute hemorrhage model

    Directory of Open Access Journals (Sweden)

    Nikolay G. Vengerovich

    2017-01-01

    Full Text Available Background. The synthetic opioid analgesic fentanyl is widely used for prophylaxis and therapy of traumatic shock associated with massive bleeding. Its side effects – skeletal muscle rigidity and respiratory center depression – are especially pronounced with repeated administration. It is rational to apply fentanyl in diminished doses in combination with non-opioid analgesics in order to reduce respiratory disturbances risk.Aim. The aim of the work is to justify the influence of opioid analgesic fentanyl and α2 -adrenomimetic dexmedetomidine combination on external respiratory functions in acute hemorrhage model.Materials and methods. Acute loss of 35–40% of circulating blood volume was modeled in experiments on 75 white mongrel male rats. The external respiratory functions (respiratory rate, respiratory volume, breath volume per minute were estimated in animals of 5 groups: 1 – rats without analgesic help (controls; 2–3 – rats receiving a single fentanyl intramuscular injection (ED99 98,96 mcg/kg or fentanyl together with dexme detomidine (ED99 of combination 67,94 mcg/kg 15 min after acute blood loss; 4–5 – rats receiving the same drugs 15 min, 30, 45 and 60 min later.Results. In experimental acute loss of 35–40% of circulating blood volume, 15 min later a secondary acute respiratory failure developed with a drop of respiratory rate, respiratory volume and volume of breath per minute by 30%, 21 and 47% (p < 0,05. The external respiratory functions recoverеd after 4 h mainly due to the increase of respiratory volume. A single intramuscular injection of fentanyl caused respiratory depression 15 min after experimental blood loss which resulted in the decrease of breath volume per minute to 30–61% (p < 0,05 for 90 min. Four intramuscular injections of fentanyl 15 min, 30, 45 and 60 min after hemorrhage caused a severe respiratory dysfunction, accompanied by apnea periods and Biot’s respiration. Respiratory rate was reduced

  15. Respiratory muscle dysfunction in animal models of hypoxic disease: antioxidant therapy goes from strength to strength

    Directory of Open Access Journals (Sweden)

    O'Halloran KD

    2017-07-01

    Full Text Available Ken D O’Halloran,1 Philip Lewis2 1Department of Physiology, School of Medicine, University College Cork, Cork, Ireland; 2Institute and Policlinic for Occupational Medicine, Environmental Medicine and Preventative Research, University Hospital of Cologne, Germany Abstract: The striated muscles of breathing play a critical role in respiratory homeostasis governing blood oxygenation and pH regulation. Upper airway dilator and thoracic pump muscles retain a remarkable capacity for plasticity throughout life, both in health and disease states. Hypoxia, whatever the cause, is a potent driver of respiratory muscle remodeling with evidence of adaptive and maladaptive outcomes for system performance. The pattern, duration, and intensity of hypoxia are key determinants of respiratory muscle structural-, metabolic-, and functional responses and adaptation. Age and sex also influence respiratory muscle tolerance of hypoxia. Redox stress emerges as the principal protagonist driving respiratory muscle malady in rodent models of hypoxic disease. There is a growing body of evidence demonstrating that antioxidant intervention alleviates hypoxia-induced respiratory muscle dysfunction, and that N-acetyl cysteine, approved for use in humans, is highly effective in preventing hypoxia-induced respiratory muscle weakness and fatigue. We posit that oxygen homeostasis is a key driver of respiratory muscle form and function. Hypoxic stress is likely a major contributor to respiratory muscle malaise in diseases of the lungs and respiratory control network. Animal studies provide an evidence base in strong support of the need to explore adjunctive antioxidant therapies for muscle dysfunction in human respiratory disease. Keywords: respiratory muscle, diaphragm, upper airway, hypoxia, antioxidants, N-acetyl-cysteine, OSA, COPD

  16. Modelling interactions of toxicants and density dependence in wildlife populations

    Science.gov (United States)

    Schipper, Aafke M.; Hendriks, Harrie W.M.; Kauffman, Matthew J.; Hendriks, A. Jan; Huijbregts, Mark A.J.

    2013-01-01

    1. A major challenge in the conservation of threatened and endangered species is to predict population decline and design appropriate recovery measures. However, anthropogenic impacts on wildlife populations are notoriously difficult to predict due to potentially nonlinear responses and interactions with natural ecological processes like density dependence. 2. Here, we incorporated both density dependence and anthropogenic stressors in a stage-based matrix population model and parameterized it for a density-dependent population of peregrine falcons Falco peregrinus exposed to two anthropogenic toxicants [dichlorodiphenyldichloroethylene (DDE) and polybrominated diphenyl ethers (PBDEs)]. Log-logistic exposure–response relationships were used to translate toxicant concentrations in peregrine falcon eggs to effects on fecundity. Density dependence was modelled as the probability of a nonbreeding bird acquiring a breeding territory as a function of the current number of breeders. 3. The equilibrium size of the population, as represented by the number of breeders, responded nonlinearly to increasing toxicant concentrations, showing a gradual decrease followed by a relatively steep decline. Initially, toxicant-induced reductions in population size were mitigated by an alleviation of the density limitation, that is, an increasing probability of territory acquisition. Once population density was no longer limiting, the toxicant impacts were no longer buffered by an increasing proportion of nonbreeders shifting to the breeding stage, resulting in a strong decrease in the equilibrium number of breeders. 4. Median critical exposure concentrations, that is, median toxicant concentrations in eggs corresponding with an equilibrium population size of zero, were 33 and 46 μg g−1 fresh weight for DDE and PBDEs, respectively. 5. Synthesis and applications. Our modelling results showed that particular life stages of a density-limited population may be relatively insensitive to

  17. Combinatorial QSAR modeling of chemical toxicants tested against Tetrahymena pyriformis.

    Science.gov (United States)

    Zhu, Hao; Tropsha, Alexander; Fourches, Denis; Varnek, Alexandre; Papa, Ester; Gramatica, Paola; Oberg, Tomas; Dao, Phuong; Cherkasov, Artem; Tetko, Igor V

    2008-04-01

    Selecting most rigorous quantitative structure-activity relationship (QSAR) approaches is of great importance in the development of robust and predictive models of chemical toxicity. To address this issue in a systematic way, we have formed an international virtual collaboratory consisting of six independent groups with shared interests in computational chemical toxicology. We have compiled an aqueous toxicity data set containing 983 unique compounds tested in the same laboratory over a decade against Tetrahymena pyriformis. A modeling set including 644 compounds was selected randomly from the original set and distributed to all groups that used their own QSAR tools for model development. The remaining 339 compounds in the original set (external set I) as well as 110 additional compounds (external set II) published recently by the same laboratory (after this computational study was already in progress) were used as two independent validation sets to assess the external predictive power of individual models. In total, our virtual collaboratory has developed 15 different types of QSAR models of aquatic toxicity for the training set. The internal prediction accuracy for the modeling set ranged from 0.76 to 0.93 as measured by the leave-one-out cross-validation correlation coefficient ( Q abs2). The prediction accuracy for the external validation sets I and II ranged from 0.71 to 0.85 (linear regression coefficient R absI2) and from 0.38 to 0.83 (linear regression coefficient R absII2), respectively. The use of an applicability domain threshold implemented in most models generally improved the external prediction accuracy but at the same time led to a decrease in chemical space coverage. Finally, several consensus models were developed by averaging the predicted aquatic toxicity for every compound using all 15 models, with or without taking into account their respective applicability domains. We find that consensus models afford higher prediction accuracy for the

  18. Activity of the Respiratory Chain Enzymes of Blood Leucocytes’ Mitochondria Under the Conditions of Toxic Hepatitis Induced Against the Background Alimentary Deprivation of Protein

    Directory of Open Access Journals (Sweden)

    O.N. Voloshchuk

    2015-12-01

    Full Text Available Full functioning of the leucocytes’ energy supply system is one of the essential factors for the immune surveillance system effective work. The pivotal enzymes of the leucocytes’ energy biotransformation system are NADH-ubiquitin reductase, a marker of the Complex I of respiratory chain activity, and succinate dehydrogenase, key enzyme of the Complex II of respiratory chain. The aim of research – to study the NADH-ubiquitin reductase and succinate dehydrogenase activity of the blood leucocytes’ mitochondria under the conditions of toxic hepatitis induced against the background alimentary deprivation of protein. It is shown, that under the conditions of acetaminophen-induced hepatitis a reduction of the NADH-ubiquitin reductase enzymatic activity is observed on the background activation of the succinate-dependent way of the mitochondrial oxidation. Conclusion was made that alimentary deprivation or protein is a factor, aggravating the misbalance of the energy biotransformation system in the leucocytes of rats with toxic hepatitis. Established activity changes of the leucocytes’ mitochondria respiratory chain key enzymes may be considered as one of the mechanisms, directed on the maintenance of leucocytes energy supply on a level, sufficient for their functioning. Research results may be used for the biochemical rationale of the therapeutic approaches to the elimination and correction of the leucocytes’ energy metabolism disturbances consequences under the conditions of acetaminophen-induced hepatitis, aggravated by the alimentary protein deprivation.

  19. A Model of Locomotor-Respiratory Coupling in Quadrupeds

    Science.gov (United States)

    Giuliodori,, Mauricio J.; Lujan, Heidi L.; Briggs, Whitney S.; DiCarlo, Stephen E.

    2009-01-01

    Locomotion and respiration are not independent phenomena in running mammals because locomotion and respiration both rely on cyclic movements of the ribs, sternum, and associated musculature. Thus, constraints are imposed on locomotor and respiratory function by virtue of their linkage. Specifically, locomotion imposes mechanical constraints on…

  20. Time-varying respiratory system elastance: a physiological model for patients who are spontaneously breathing.

    Science.gov (United States)

    Chiew, Yeong Shiong; Pretty, Christopher; Docherty, Paul D; Lambermont, Bernard; Shaw, Geoffrey M; Desaive, Thomas; Chase, J Geoffrey

    2015-01-01

    Respiratory mechanics models can aid in optimising patient-specific mechanical ventilation (MV), but the applications are limited to fully sedated MV patients who have little or no spontaneously breathing efforts. This research presents a time-varying elastance (E(drs)) model that can be used in spontaneously breathing patients to determine their respiratory mechanics. A time-varying respiratory elastance model is developed with a negative elastic component (E(demand)), to describe the driving pressure generated during a patient initiated breathing cycle. Data from 22 patients who are partially mechanically ventilated using Pressure Support (PS) and Neurally Adjusted Ventilatory Assist (NAVA) are used to investigate the physiology relevance of the time-varying elastance model and its clinical potential. E(drs) of every breathing cycle for each patient at different ventilation modes are presented for comparison. At the start of every breathing cycle initiated by patient, E(drs) is 25 cmH2Os/l and thus can be used as an acute respiratory distress syndrome (ARDS) severity indicator. The E(drs) model captures unique dynamic respiratory mechanics for spontaneously breathing patients with respiratory failure. The model is fully general and is applicable to both fully controlled and partially assisted MV modes.

  1. Time-varying respiratory system elastance: a physiological model for patients who are spontaneously breathing.

    Directory of Open Access Journals (Sweden)

    Yeong Shiong Chiew

    Full Text Available BACKGROUND: Respiratory mechanics models can aid in optimising patient-specific mechanical ventilation (MV, but the applications are limited to fully sedated MV patients who have little or no spontaneously breathing efforts. This research presents a time-varying elastance (E(drs model that can be used in spontaneously breathing patients to determine their respiratory mechanics. METHODS: A time-varying respiratory elastance model is developed with a negative elastic component (E(demand, to describe the driving pressure generated during a patient initiated breathing cycle. Data from 22 patients who are partially mechanically ventilated using Pressure Support (PS and Neurally Adjusted Ventilatory Assist (NAVA are used to investigate the physiology relevance of the time-varying elastance model and its clinical potential. E(drs of every breathing cycle for each patient at different ventilation modes are presented for comparison. RESULTS: At the start of every breathing cycle initiated by patient, E(drs is 25 cmH2Os/l and thus can be used as an acute respiratory distress syndrome (ARDS severity indicator. CONCLUSION: The E(drs model captures unique dynamic respiratory mechanics for spontaneously breathing patients with respiratory failure. The model is fully general and is applicable to both fully controlled and partially assisted MV modes.

  2. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity.

    Science.gov (United States)

    Thistlethwaite, Fiona C; Gilham, David E; Guest, Ryan D; Rothwell, Dominic G; Pillai, Manon; Burt, Deborah J; Byatte, Andrea J; Kirillova, Natalia; Valle, Juan W; Sharma, Surinder K; Chester, Kerry A; Westwood, Nigel B; Halford, Sarah E R; Nabarro, Stephen; Wan, Susan; Austin, Eric; Hawkins, Robert E

    2017-11-01

    The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5 + malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5 + -specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies.

  3. A new approach to modeling of selected human respiratory system diseases, directed to computer simulations.

    Science.gov (United States)

    Redlarski, Grzegorz; Jaworski, Jacek

    2013-10-01

    This paper presents a new versatile approach to model severe human respiratory diseases via computer simulation. The proposed approach enables one to predict the time histories of various diseases via information accessible in medical publications. This knowledge is useful to bioengineers involved in the design and construction of medical devices that are employed for monitoring of respiratory condition. The approach provides the data that are crucial for testing diagnostic systems. This can be achieved without the necessity of probing the physiological details of the respiratory system as well as without identification of parameters that are based on measurement data. © 2013 Elsevier Ltd. All rights reserved.

  4. In silico assessment of the acute toxicity of chemicals: recent advances and new model for multitasking prediction of toxic effect.

    Science.gov (United States)

    Kleandrova, Valeria V; Luan, Feng; Speck-Planche, Alejandro; Cordeiro, M Natália D S

    2015-01-01

    The assessment of acute toxicity is one of the most important stages to ensure the safety of chemicals with potential applications in pharmaceutical sciences, biomedical research, or any other industrial branch. A huge and indiscriminate number of toxicity assays have been carried out on laboratory animals. In this sense, computational approaches involving models based on quantitative-structure activity/toxicity relationships (QSAR/QSTR) can help to rationalize time and financial costs. Here, we discuss the most significant advances in the last 6 years focused on the use of QSAR/QSTR models to predict acute toxicity of drugs/chemicals in laboratory animals, employing large and heterogeneous datasets. The advantages and drawbacks of the different QSAR/QSTR models are analyzed. As a contribution to the field, we introduce the first multitasking (mtk) QSTR model for simultaneous prediction of acute toxicity of compounds by considering different routes of administration, diverse breeds of laboratory animals, and the reliability of the experimental conditions. The mtk-QSTR model was based on artificial neural networks (ANN), allowing the classification of compounds as toxic or non-toxic. This model correctly classified more than 94% of the 1646 cases present in the whole dataset, and its applicability was demonstrated by performing predictions of different chemicals such as drugs, dietary supplements, and molecules which could serve as nanocarriers for drug delivery. The predictions given by the mtk-QSTR model are in very good agreement with the experimental results.

  5. Effects of hypothyroidism on the respiratory system and control of breathing: Human studies and animal models.

    Science.gov (United States)

    Schlenker, Evelyn H

    2012-04-30

    Hypothyroidism, subclinical hypothyroidism and euthyroid sick syndrome, are prevalent disorders that affect all body systems including the respiratory system and control of breathing. The purpose of this review article is to discuss the regulation of thyroid hormone production and their function at the cellular level; the many causes of hypothyroidism; the effects of hypothyroidism on the respiratory system and on control of ventilation in hypothyroid patients; the variety of ways animal models of hypothyroidism are induced; and how in animal models hypothyroidism affects the respiratory system and control of breathing including neurotransmitters that influence breathing. Finally, this review will present controversies that exist in the field and thus encourage new research directions. Because of the high prevalence of hypothyroidism and subclinical forms of hypothyroidism and their influence on ventilation and the respiratory system, understanding underlying molecular mechanisms is necessary to ascertain how and sometimes why not thyroid replacement may normalize function. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Equation Discovery for Model Identification in Respiratory Mechanics of the Mechanically Ventilated Human Lung

    Science.gov (United States)

    Ganzert, Steven; Guttmann, Josef; Steinmann, Daniel; Kramer, Stefan

    Lung protective ventilation strategies reduce the risk of ventilator associated lung injury. To develop such strategies, knowledge about mechanical properties of the mechanically ventilated human lung is essential. This study was designed to develop an equation discovery system to identify mathematical models of the respiratory system in time-series data obtained from mechanically ventilated patients. Two techniques were combined: (i) the usage of declarative bias to reduce search space complexity and inherently providing the processing of background knowledge. (ii) A newly developed heuristic for traversing the hypothesis space with a greedy, randomized strategy analogical to the GSAT algorithm. In 96.8% of all runs the applied equation discovery system was capable to detect the well-established equation of motion model of the respiratory system in the provided data. We see the potential of this semi-automatic approach to detect more complex mathematical descriptions of the respiratory system from respiratory data.

  7. Integrative approaches for modeling regulation and function of the respiratory system.

    Science.gov (United States)

    Ben-Tal, Alona; Tawhai, Merryn H

    2013-01-01

    Mathematical models have been central to understanding the interaction between neural control and breathing. Models of the entire respiratory system-which comprises the lungs and the neural circuitry that controls their ventilation-have been derived using simplifying assumptions to compartmentalize each component of the system and to define the interactions between components. These full system models often rely-through necessity-on empirically derived relationships or parameters, in addition to physiological values. In parallel with the development of whole respiratory system models are mathematical models that focus on furthering a detailed understanding of the neural control network, or of the several functions that contribute to gas exchange within the lung. These models are biophysically based, and rely on physiological parameters. They include single-unit models for a breathing lung or neural circuit, through to spatially distributed models of ventilation and perfusion, or multicircuit models for neural control. The challenge is to bring together these more recent advances in models of neural control with models of lung function, into a full simulation for the respiratory system that builds upon the more detailed models but remains computationally tractable. This requires first understanding the mathematical models that have been developed for the respiratory system at different levels, and which could be used to study how physiological levels of O2 and CO2 in the blood are maintained. Copyright © 2013 Wiley Periodicals, Inc.

  8. A semi-Markov chain approach to modeling respiratory patterns prior to extubation in preterm infants.

    Science.gov (United States)

    Onu, Charles C; Kanbar, Lara J; Shalish, Wissam; Brown, Karen A; Sant'Anna, Guilherme M; Kearney, Robert E; Precup, Doina

    2017-07-01

    After birth, extremely preterm infants often require specialized respiratory management in the form of invasive mechanical ventilation (IMV). Protracted IMV is associated with detrimental outcomes and morbidities. Premature extubation, on the other hand, would necessitate reintubation which is risky, technically challenging and could further lead to lung injury or disease. We present an approach to modeling respiratory patterns of infants who succeeded extubation and those who required reintubation which relies on Markov models. We compare the use of traditional Markov chains to semi-Markov models which emphasize cross-pattern transitions and timing information, and to multi-chain Markov models which can concisely represent non-stationarity in respiratory behavior over time. The models we developed expose specific, unique similarities as well as vital differences between the two populations.

  9. Regional Air Toxics Modeling in California's San Francisco Bay Area

    Science.gov (United States)

    Martien, P. T.; Tanrikulu, S.; Tran, C.; Fairley, D.; Jia, Y.; Fanai, A.; Reid, S.; Yarwood, G.; Emery, C.

    2011-12-01

    Regional toxics modeling conducted for California's San Francisco Bay Area (SFBA) estimated potential cancer risk from diesel particulate matter (DPM) and four key reactive toxic gaseous pollutants (1,3-butadiene, benzene, formaldehyde, and acetaldehyde). Concentrations of other non-cancerous gaseous toxic air contaminants, including acrolein, were also generated. In this study, meteorological fields generated from July and December periods in 2000 and emissions from 2005 provided inputs to a three-dimensional air quality model at high spatial resolution (1x1 km^2 grid), from which a baseline set of annual risk values was estimated. Simulated risk maps show highest annual average DPM concentrations and cancer risks were located near and downwind of major freeways and near the Port of Oakland, a major container port in the area. Population weighted risks, using 2000 census data, were found to be highest in highly urbanized areas adjacent to significant DPM sources. For summer, the ratio of mean measured elemental carbon to mean modeled DPM was 0.78, conforming roughly to expectations. But for winter the ratio is 1.13, suggesting other sources of elemental carbon, such as wood smoke, are important. Simulated annual estimates for benzene and 1-3, butadiene compared well to measured annual estimates. Simulated acrolein and formaldehyde significantly under-predicted observed values. Simulations repeated using projected 2015 toxic emissions predicted that potential cancer risk dropped significantly in all areas throughout the SFBA. Emissions estimates for 2015 included the State of California's recently adopted on-road truck rule. Emission estimates of DPM are projected to drop about 70% between 2005 and 2015 in the SFBA, with a commensurate reduction in potential cancer risks. However, due to projected shifts in population during this period, with urban densification close to DPM sources outpacing emission reductions, there are some areas where population-weighted risks

  10. A closed-loop model of the respiratory system: focus on hypercapnia and active expiration.

    Science.gov (United States)

    Molkov, Yaroslav I; Shevtsova, Natalia A; Park, Choongseok; Ben-Tal, Alona; Smith, Jeffrey C; Rubin, Jonathan E; Rybak, Ilya A

    2014-01-01

    Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal "expiratory" muscles become actively involved in breathing. The mechanisms of this transition remain unknown. To study these mechanisms, we developed a computational model of the closed-loop respiratory system that describes the brainstem respiratory network controlling the pulmonary subsystem representing lung biomechanics and gas (O2 and CO2) exchange and transport. The lung subsystem provides two types of feedback to the neural subsystem: a mechanical one from pulmonary stretch receptors and a chemical one from central chemoreceptors. The neural component of the model simulates the respiratory network that includes several interacting respiratory neuron types within the Bötzinger and pre-Bötzinger complexes, as well as the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) representing the central chemoreception module targeted by chemical feedback. The RTN/pFRG compartment contains an independent neural generator that is activated at an increased CO2 level and controls the abdominal motor output. The lung volume is controlled by two pumps, a major one driven by the diaphragm and an additional one activated by abdominal muscles and involved in active expiration. The model represents the first attempt to model the transition from quiet breathing to breathing with active expiration. The model suggests that the closed-loop respiratory control system switches to active expiration via a quantal acceleration of expiratory activity, when increases in breathing rate and phrenic amplitude no longer provide sufficient ventilation. The model

  11. A closed-loop model of the respiratory system: focus on hypercapnia and active expiration.

    Directory of Open Access Journals (Sweden)

    Yaroslav I Molkov

    Full Text Available Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal "expiratory" muscles become actively involved in breathing. The mechanisms of this transition remain unknown. To study these mechanisms, we developed a computational model of the closed-loop respiratory system that describes the brainstem respiratory network controlling the pulmonary subsystem representing lung biomechanics and gas (O2 and CO2 exchange and transport. The lung subsystem provides two types of feedback to the neural subsystem: a mechanical one from pulmonary stretch receptors and a chemical one from central chemoreceptors. The neural component of the model simulates the respiratory network that includes several interacting respiratory neuron types within the Bötzinger and pre-Bötzinger complexes, as well as the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG representing the central chemoreception module targeted by chemical feedback. The RTN/pFRG compartment contains an independent neural generator that is activated at an increased CO2 level and controls the abdominal motor output. The lung volume is controlled by two pumps, a major one driven by the diaphragm and an additional one activated by abdominal muscles and involved in active expiration. The model represents the first attempt to model the transition from quiet breathing to breathing with active expiration. The model suggests that the closed-loop respiratory control system switches to active expiration via a quantal acceleration of expiratory activity, when increases in breathing rate and phrenic amplitude no longer provide sufficient

  12. A finite state model for respiratory motion analysis in image guided radiation therapy

    International Nuclear Information System (INIS)

    Wu Huanmei; Sharp, Gregory C; Salzberg, Betty; Kaeli, David; Shirato, Hiroki; Jiang, Steve B

    2004-01-01

    Effective image guided radiation treatment of a moving tumour requires adequate information on respiratory motion characteristics. For margin expansion, beam tracking and respiratory gating, the tumour motion must be quantified for pretreatment planning and monitored on-line. We propose a finite state model for respiratory motion analysis that captures our natural understanding of breathing stages. In this model, a regular breathing cycle is represented by three line segments, exhale, end-of-exhale and inhale, while abnormal breathing is represented by an irregular breathing state. In addition, we describe an on-line implementation of this model in one dimension. We found this model can accurately characterize a wide variety of patient breathing patterns. This model was used to describe the respiratory motion for 23 patients with peak-to-peak motion greater than 7 mm. The average root mean square error over all patients was less than 1 mm and no patient has an error worse than 1.5 mm. Our model provides a convenient tool to quantify respiratory motion characteristics, such as patterns of frequency changes and amplitude changes, and can be applied to internal or external motion, including internal tumour position, abdominal surface, diaphragm, spirometry and other surrogates

  13. A finite state model for respiratory motion analysis in image guided radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Wu Huanmei [College of Computer and Information Science, Northeastern University, Boston, MA 02115 (United States); Sharp, Gregory C [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 (United States); Salzberg, Betty [College of Computer and Information Science, Northeastern University, Boston, MA 02115 (United States); Kaeli, David [Department of Electrical and Computer Engineering, Northeastern University, Boston, MA 02115 (United States); Shirato, Hiroki [Department of Radiation Medicine, Hokkaido University School of Medicine, Sapporo (Japan); Jiang, Steve B [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 (United States)

    2004-12-07

    Effective image guided radiation treatment of a moving tumour requires adequate information on respiratory motion characteristics. For margin expansion, beam tracking and respiratory gating, the tumour motion must be quantified for pretreatment planning and monitored on-line. We propose a finite state model for respiratory motion analysis that captures our natural understanding of breathing stages. In this model, a regular breathing cycle is represented by three line segments, exhale, end-of-exhale and inhale, while abnormal breathing is represented by an irregular breathing state. In addition, we describe an on-line implementation of this model in one dimension. We found this model can accurately characterize a wide variety of patient breathing patterns. This model was used to describe the respiratory motion for 23 patients with peak-to-peak motion greater than 7 mm. The average root mean square error over all patients was less than 1 mm and no patient has an error worse than 1.5 mm. Our model provides a convenient tool to quantify respiratory motion characteristics, such as patterns of frequency changes and amplitude changes, and can be applied to internal or external motion, including internal tumour position, abdominal surface, diaphragm, spirometry and other surrogates.

  14. Predictive QSAR Models for the Toxicity of Disinfection Byproducts.

    Science.gov (United States)

    Qin, Litang; Zhang, Xin; Chen, Yuhan; Mo, Lingyun; Zeng, Honghu; Liang, Yanpeng

    2017-10-09

    Several hundred disinfection byproducts (DBPs) in drinking water have been identified, and are known to have potentially adverse health effects. There are toxicological data gaps for most DBPs, and the predictive method may provide an effective way to address this. The development of an in-silico model of toxicology endpoints of DBPs is rarely studied. The main aim of the present study is to develop predictive quantitative structure-activity relationship (QSAR) models for the reactive toxicities of 50 DBPs in the five bioassays of X-Microtox, GSH+, GSH-, DNA+ and DNA-. All-subset regression was used to select the optimal descriptors, and multiple linear-regression models were built. The developed QSAR models for five endpoints satisfied the internal and external validation criteria: coefficient of determination ( R ²) > 0.7, explained variance in leave-one-out prediction ( Q ² LOO ) and in leave-many-out prediction ( Q ² LMO ) > 0.6, variance explained in external prediction ( Q ² F1 , Q ² F2 , and Q ² F3 ) > 0.7, and concordance correlation coefficient ( CCC ) > 0.85. The application domains and the meaning of the selective descriptors for the QSAR models were discussed. The obtained QSAR models can be used in predicting the toxicities of the 50 DBPs.

  15. Predictive QSAR Models for the Toxicity of Disinfection Byproducts

    Directory of Open Access Journals (Sweden)

    Litang Qin

    2017-10-01

    Full Text Available Several hundred disinfection byproducts (DBPs in drinking water have been identified, and are known to have potentially adverse health effects. There are toxicological data gaps for most DBPs, and the predictive method may provide an effective way to address this. The development of an in-silico model of toxicology endpoints of DBPs is rarely studied. The main aim of the present study is to develop predictive quantitative structure–activity relationship (QSAR models for the reactive toxicities of 50 DBPs in the five bioassays of X-Microtox, GSH+, GSH−, DNA+ and DNA−. All-subset regression was used to select the optimal descriptors, and multiple linear-regression models were built. The developed QSAR models for five endpoints satisfied the internal and external validation criteria: coefficient of determination (R2 > 0.7, explained variance in leave-one-out prediction (Q2LOO and in leave-many-out prediction (Q2LMO > 0.6, variance explained in external prediction (Q2F1, Q2F2, and Q2F3 > 0.7, and concordance correlation coefficient (CCC > 0.85. The application domains and the meaning of the selective descriptors for the QSAR models were discussed. The obtained QSAR models can be used in predicting the toxicities of the 50 DBPs.

  16. Modeling of respiratory system dysfunction among nuclear workers: a preliminary study.

    Science.gov (United States)

    Belyaeva, Z D; Osovets, S V; Scott, B R; Zhuntova, G V; Grigoryeva, E S

    2008-01-01

    Numerous studies have reported on cancers among Mayak Production Association (PA) nuclear workers. Other studies have reported on serious deterministic effects of large radiation doses for the same population. This study relates to deterministic effects (respiratory system dysfunction) in Mayak workers after relatively small chronic radiation doses (alpha plus gamma). Because cigarette smoke is a confounding factor, we also account for smoking effects. Here we present a new empirical mathematical model that was introduced for simultaneous assessment of radiation and cigarette-smoking-related damage to the respiratory system. The model incorporates absolute thresholds for smoking- and radiation-induced respiratory system dysfunction. As the alpha radiation dose to the lung increased from 0 to 4.36 Gy, respiratory function indices studied decreased, although remaining in the normal range. The data were consistent with the view that alpha radiation doses to the lung above a relatively small threshold (0.15 to 0.39 Gy) cause some respiratory system dysfunction. Respiratory function indices were not found to be influenced by total-body gamma radiation doses in the range 0-3.8 Gy when delivered at low rates over years. However, significant decreases in airway conductance were found to be associated with cigarette smoking. Whether the indicated cigarette smoking and alpha radiation associated dysfunction is debilitating is unclear.

  17. Patient specific respiratory motion modeling using a limited number of 3D lung CT images.

    Science.gov (United States)

    Cui, Xueli; Gao, Xin; Xia, Wei; Liu, Yangchuan; Liang, Zhiyuan

    2014-01-01

    To build a patient specific respiratory motion model with a low dose, a novel method was proposed that uses a limited number of 3D lung CT volumes with an external respiratory signal. 4D lung CT volumes were acquired for patients with in vitro labeling on the upper abdominal surface. Meanwhile, 3D coordinates of in vitro labeling were measured as external respiratory signals. A sequential correspondence between the 4D lung CT and the external respiratory signal was built using the distance correlation method, and a 3D displacement for every registration control point in the CT volumes with respect to time can be obtained by the 4D lung CT deformable registration. A temporal fitting was performed for every registration control point displacements and an external respiratory signal in the anterior-posterior direction respectively to draw their fitting curves. Finally, a linear regression was used to fit the corresponding samples of the control point displacement fitting curves and the external respiratory signal fitting curve to finish the pulmonary respiration modeling. Compared to a B-spline-based method using the respiratory signal phase, the proposed method is highly advantageous as it offers comparable modeling accuracy and target modeling error (TME); while at the same time, the proposed method requires 70% less 3D lung CTs. When using a similar amount of 3D lung CT data, the mean of the proposed method's TME is smaller than the mean of the PCA (principle component analysis)-based methods' TMEs. The results indicate that the proposed method is successful in striking a balance between modeling accuracy and number of 3D lung CT volumes.

  18. A Comparative Data-Based Modeling Study on Respiratory CO2 Gas Exchange during Mechanical Ventilation

    Directory of Open Access Journals (Sweden)

    Chang-Sei eKim

    2016-02-01

    Full Text Available The goal of this study is to derive a minimally complex but credible model of respiratory CO2 gas exchange that may be used in systematic design and pilot testing of closed-loop end-tidal CO2 controllers in mechanical ventilation. We first derived a candidate model that captures the essential mechanisms involved in the respiratory CO2 gas exchange process. Then, we simplified the candidate model to derive two lower-order candidate models. We compared these candidate models for predictive capability and reliability using experimental data collected from 25 pediatric subjects undergoing dynamically varying mechanical ventilation during surgical procedures. A two-compartment model equipped with transport delay to account for CO2 delivery between the lungs and the tissues showed modest but statistically significant improvement in predictive capability over the same model without transport delay. Aggregating the lungs and the tissues into a single compartment further degraded the predictive fidelity of the model. In addition, the model equipped with transport delay demonstrated superior reliability to the one without transport delay. Further, the respiratory parameters derived from the model equipped with transport delay, but not the one without transport delay, were physiologically plausible. The results suggest that gas transport between the lungs and the tissues must be taken into account to accurately reproduce the respiratory CO2 gas exchange process under conditions of wide-ranging and dynamically varying mechanical ventilation conditions.

  19. Validation of statistical models for estimating hospitalization associated with influenza and other respiratory viruses.

    Directory of Open Access Journals (Sweden)

    Lin Yang

    Full Text Available BACKGROUND: Reliable estimates of disease burden associated with respiratory viruses are keys to deployment of preventive strategies such as vaccination and resource allocation. Such estimates are particularly needed in tropical and subtropical regions where some methods commonly used in temperate regions are not applicable. While a number of alternative approaches to assess the influenza associated disease burden have been recently reported, none of these models have been validated with virologically confirmed data. Even fewer methods have been developed for other common respiratory viruses such as respiratory syncytial virus (RSV, parainfluenza and adenovirus. METHODS AND FINDINGS: We had recently conducted a prospective population-based study of virologically confirmed hospitalization for acute respiratory illnesses in persons <18 years residing in Hong Kong Island. Here we used this dataset to validate two commonly used models for estimation of influenza disease burden, namely the rate difference model and Poisson regression model, and also explored the applicability of these models to estimate the disease burden of other respiratory viruses. The Poisson regression models with different link functions all yielded estimates well correlated with the virologically confirmed influenza associated hospitalization, especially in children older than two years. The disease burden estimates for RSV, parainfluenza and adenovirus were less reliable with wide confidence intervals. The rate difference model was not applicable to RSV, parainfluenza and adenovirus and grossly underestimated the true burden of influenza associated hospitalization. CONCLUSION: The Poisson regression model generally produced satisfactory estimates in calculating the disease burden of respiratory viruses in a subtropical region such as Hong Kong.

  20. Quantifying lung morphology with respiratory-gated micro-CT in a murine model of emphysema

    Science.gov (United States)

    Ford, N. L.; Martin, E. L.; Lewis, J. F.; Veldhuizen, R. A. W.; Holdsworth, D. W.; Drangova, M.

    2009-04-01

    Non-invasive micro-CT imaging techniques have been developed to investigate lung structure in free-breathing rodents. In this study, we investigate the utility of retrospectively respiratory-gated micro-CT imaging in an emphysema model to determine if anatomical changes could be observed in the image-derived quantitative analysis at two respiratory phases. The emphysema model chosen was a well-characterized, genetically altered model (TIMP-3 knockout mice) that exhibits a homogeneous phenotype. Micro-CT scans of the free-breathing, anaesthetized mice were obtained in 50 s and retrospectively respiratory sorted and reconstructed, providing 3D images representing peak inspiration and end expiration with 0.15 mm isotropic voxel spacing. Anatomical measurements included the volume and CT density of the lungs and the volume of the major airways, along with the diameters of the trachea, left bronchus and right bronchus. From these measurements, functional parameters such as functional residual capacity and tidal volume were calculated. Significant differences between the wild-type and TIMP-3 knockout groups were observed for measurements of CT density over the entire lung, indicating increased air content in the lungs of TIMP-3 knockout mice. These results demonstrate retrospective respiratory-gated micro-CT, providing images at multiple respiratory phases that can be analyzed quantitatively to investigate anatomical changes in murine models of emphysema.

  1. Visualisation of time-varying respiratory system elastance in experimental ARDS animal models.

    Science.gov (United States)

    van Drunen, Erwin J; Chiew, Yeong Shiong; Pretty, Christopher; Shaw, Geoffrey M; Lambermont, Bernard; Janssen, Nathalie; Chase, J Geoffrey; Desaive, Thomas

    2014-03-02

    Patients with acute respiratory distress syndrome (ARDS) risk lung collapse, severely altering the breath-to-breath respiratory mechanics. Model-based estimation of respiratory mechanics characterising patient-specific condition and response to treatment may be used to guide mechanical ventilation (MV). This study presents a model-based approach to monitor time-varying patient-ventilator interaction to guide positive end expiratory pressure (PEEP) selection. The single compartment lung model was extended to monitor dynamic time-varying respiratory system elastance, Edrs, within each breathing cycle. Two separate animal models were considered, each consisting of three fully sedated pure pietrain piglets (oleic acid ARDS and lavage ARDS). A staircase recruitment manoeuvre was performed on all six subjects after ARDS was induced. The Edrs was mapped across each breathing cycle for each subject. Six time-varying, breath-specific Edrs maps were generated, one for each subject. Each Edrs map shows the subject-specific response to mechanical ventilation (MV), indicating the need for a model-based approach to guide MV. This method of visualisation provides high resolution insight into the time-varying respiratory mechanics to aid clinical decision making. Using the Edrs maps, minimal time-varying elastance was identified, which can be used to select optimal PEEP. Real-time continuous monitoring of in-breath mechanics provides further insight into lung physiology. Therefore, there is potential for this new monitoring method to aid clinicians in guiding MV treatment. These are the first such maps generated and they thus show unique results in high resolution. The model is limited to a constant respiratory resistance throughout inspiration which may not be valid in some cases. However, trends match clinical expectation and the results highlight both the subject-specificity of the model, as well as significant inter-subject variability.

  2. Transcriptomic responses of European flounder (Platichthys flesus) to model toxicants

    International Nuclear Information System (INIS)

    Williams, Tim D.; Diab, Amer; Ortega, Fernando; Sabine, Victoria S.; Godfrey, Rita E.; Falciani, Francesco; Chipman, J. Kevin; George, Stephen G.

    2008-01-01

    The temporal transcriptomic responses in liver of Platichthys flesus to model environmental pollutants were studied over a 16-day time span after intraperitoneal injection with cadmium chloride (50 μg/kg in saline), 3-methylcholanthrene (25 mg/kg in olive oil), Aroclor 1254 (50 mg/kg in olive oil), tert-butyl-hydroperoxide (5 mg/kg in saline), Lindane (25 mg/kg in olive oil), perfluoro-octanoic acid (100 mg/kg in olive oil) and their vehicles, olive oil (1 ml/kg) or saline (0.9%). Statistical, gene ontology and supervised analysis clearly demonstrated the progression from acute effects, biological responses to and recovery from the treatments. Key biological processes disturbed by the individual treatments were characterised by gene ontology analyses and individual toxicant-responsive genes and pathways were identified by supervised analyses. Responses to the polyaromatic and chlorinated aromatic compounds showed a degree of commonality but were distinguishable and they were clearly segregated from the responses to the pro-oxidants cadmium and the organic hydroperoxide, as well as from the peroxisomal proliferator, perfluoro-octanoic acid. This study demonstrated the utility of the microarray technique in the identification of toxicant-responsive genes and in discrimination between modes of toxicant action

  3. Extracorporeal Membrane Oxygenation in a Patient With Refractory Acute Respiratory Distress Syndrome Secondary to Toxic Epidermal Necrolysis.

    Science.gov (United States)

    2014-12-01

    treatment in adults with swine flu (H1N1)3 and publication of the CESAR (conventional ventilation or ECMO for severe adult respiratory failure) trial,4...ing lactate. Prone positioning was considered but not offered because of the low likelihood of success, given her underlying lung pathology...which consisted primarily of silver nitrate dress- ings that require fewer dressing changes than other therapies. Lung -protective ventilator

  4. Variability in respiratory rhythm generation: In vitro and in silico models

    Science.gov (United States)

    Fietkiewicz, Christopher; Shafer, Geoffrey O.; Platt, Ethan A.; Wilson, Christopher G.

    2016-03-01

    The variability inherent in physiological rhythms is disruptive in extremis (too great or too little) but may also serve a functional and important role in homeostatic systems. Here we focus on the neural control of respiration which is critical for survival in many animals. The overall respiratory control system is comprised of multiple nuclei, each of which may have different contributions to rhythm variability. We focused on the pre-Bötzinger complex (preBötC) which is unique in that it can be studied in vitro as an isolated nucleus with autorhythmic behavior. The in vitro results show a bounded range of variability in which the upper and lower limits are functions of the respiratory rate. In addition, the correlation between variability and respiratory rate changes during development. We observed a weaker correlation in younger animals (0-3 days old) as compared to older animals (4-5 days old). Based on experimental observations, we developed a computational model that can be embedded in more comprehensive models of respiratory and cardiovascular autonomic control. Our simulation results successfully reproduce the variability we observed experimentally. The in silico model suggests that age-dependent variability may be due to a developmental increase in mean synaptic conductance between preBötC neurons. We also used simulations to explore the effects of stochastic spiking in sensory relay neurons. Our results suggest that stochastic spiking may actually stabilize modulation of both respiratory rate and its variability when the rate changes due to physiological demand.

  5. Noninvasive evaluation of respiratory muscles in pre-clinical model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Daniela M. Oliveira

    2016-04-01

    Full Text Available Abstract Since respiratory insufficiency is the main cause of death in patients affected by Duchenne Muscular Dystrophy (DMD, the present study aims at establishing a new non-invasive method to evaluate the clinical parameters of respiratory conditions of experimental models affected by DMD. With this purpose in mind, we evaluated the cardiorespiratory clinical conditions, the changes in the intercostal muscles, the diaphragmatic mobility, and the respiratory cycles in Golden Retriever Muscular Dystrophy (GRMD employing ultrasonography (US. A control group consisting of dogs of the same race, but not affected by muscular dystrophy, were used in this study. The results showed that inspiration, expiration and plateau movements (diaphragm mobility were lower in the affected group. Plateau phase in the affected group was practically non-existent and showed that the diaphragm remained in constant motion. Respiratory rate reached 15.5 per minute for affected group and 26.93 per minute for the control group. Expiration and inspiration movements of intercostal muscles reached 8.99mm and 8.79mm, respectively, for control group and 7.42mm and 7.40mm, respectively, for affected group. Methodology used in the present analysis proved to be viable for the follow-up and evaluation of the respiratory model in GRMD and may be adapted to other muscular dystrophy experimental models.

  6. High-throughput gene expression analysis in pigs as model for respiratory infections

    DEFF Research Database (Denmark)

    Skovgaard, Kerstin; Brogaard, Louise; Schou, Kirstine Klitgaard

    for disease and inflammation. Pigs are fully susceptible to human influenza, and have been demonstrated to be involved in influenza evolution and ecology. Pigs share many similarities with humans regarding lung physiology and innate immune cell infiltration of the respiratory system and thus seem...... to be an obvious large animal model for respiratory infections. This study aimed at providing a better understanding of the involvement of circulating non-coding RNA and innate immune factors in porcine blood leukocytes during influenza virus infection. By employing the pig as a model we were able to perform...

  7. The Respiratory Impedance in an Asymmetric Model of the Lung Structure

    Directory of Open Access Journals (Sweden)

    Robin De Keyser

    2011-01-01

    Full Text Available This paper presents a model of the respiratory tree as a recurrent, but asymmetric, structure. The intrinsic properties posed by such a system lead to a multi-fractal structure, i.e. a non-integer order model of the total impedance. The fractional order behavior of the asymmetric tree simulated as a dynamic system is assessed by means of Bode plots, on a wide range of frequencies. The results indicate than in a specific frequency range, both the symmetric
    and asymmetric representation of the respiratory tree lead to similar values in the impedance.

  8. Inverse Modeling of Respiratory System during Noninvasive Ventilation by Maximum Likelihood Estimation

    Directory of Open Access Journals (Sweden)

    Esra Saatci

    2010-01-01

    Full Text Available We propose a procedure to estimate the model parameters of presented nonlinear Resistance-Capacitance (RC and the widely used linear Resistance-Inductance-Capacitance (RIC models of the respiratory system by Maximum Likelihood Estimator (MLE. The measurement noise is assumed to be Generalized Gaussian Distributed (GGD, and the variance and the shape factor of the measurement noise are estimated by MLE and Kurtosis method, respectively. The performance of the MLE algorithm is also demonstrated by the Cramer-Rao Lower Bound (CRLB with artificially produced respiratory signals. Airway flow, mask pressure, and lung volume are measured from patients with Chronic Obstructive Pulmonary Disease (COPD under the noninvasive ventilation and from healthy subjects. Simulations show that respiratory signals from healthy subjects are better represented by the RIC model compared to the nonlinear RC model. On the other hand, the Patient group respiratory signals are fitted to the nonlinear RC model with lower measurement noise variance, better converged measurement noise shape factor, and model parameter tracks. Also, it is observed that for the Patient group the shape factor of the measurement noise converges to values between 1 and 2 whereas for the Control group shape factor values are estimated in the super-Gaussian area.

  9. Respiratory sensitization: toxicological point of view on the available assays.

    Science.gov (United States)

    Chary, Aline; Hennen, Jennifer; Klein, Sebastian G; Serchi, Tommaso; Gutleb, Arno C; Blömeke, Brunhilde

    2018-02-01

    Respiratory sensitization as a consequence of exposure to chemical products has increased over the last decades, leading to an increase of morbidity. The increased use of synthetic compounds resulted in an exponential growth of substances to which we are potentially exposed on a daily basis. Some of them are known to induce respiratory sensitization, meaning that they can trigger the development of allergies. In the past, animal studies provided useful results for the understanding of mechanisms involved in the development of respiratory allergies. However, the mechanistic understanding of the involved cellular effects is still limited. Currently, no in vitro or in vivo models are validated to identify chemical respiratory sensitizers. Nonetheless, chemical respiratory sensitizers elicit a positive response in validated assays for skin sensitization. In this review, we will discuss how these assays could be used for respiratory sensitization and if necessary, what can be learnt from these assays to develop a model to assess the respiratory sensitizing potential of chemicals. In the last decades, much work has been done to study the respiratory toxicity of inhaled compounds especially in developing in vitro assays grown at the air-liquid interface. We will discuss how possibly the tests currently used to investigate general particle toxicity could be transformed to investigate respiratory sensitization. In the present review, we describe the most known mechanism involved in the sensitization process and the experimental in vivo and alternative in vitro models, which are currently available and how to adapt and improve existing models to study respiratory sensitization.

  10. The effects of a single intravenous injection of novel activin A/BMP-2 (AB204) on toxicity and the respiratory and central nervous systems.

    Science.gov (United States)

    Yoon, Byung-Hak; Lee, Jae Hyup; Na, Kyuheum; Ahn, Chihoon; Cho, Jongho; Ahn, Hyun Chan; Choi, Jungyoun; Oh, Hyosun; Kim, Byong Moon; Choe, Senyon

    2016-01-01

    The purpose of this study was to determine the effects of a single intravenous injection of a novel osteoinductive material, activin A/BMP-2 (AB204), to rodents on toxicity and their respiratory functions and central nervous system (CNS). A single intravenous injection of AB204 was given to Sprague-Dawley (SD) rats in doses of 0, 0.625, 2.5 and 10 mg/kg to observe the mortality rate, the general symptoms for 14 days. The experimental groups were also given 0.2, 0.4 and 0.8 mg/kg of AB204, respectively, and the respiration rate, the tidal volume and the minute volume were measured for 240 min. The experimental groups of imprinting control region (ICR) mice were given a single intravenous injection of 0.2, 0.4 and 0.8 mg/kg of AB204, respectively. Their body temperature was taken and general behaviors were observed to evaluate the effect of AB204 on the CNS for 240 min. The study on toxicity of a single intravenous injection found no death or abnormal symptoms, abnormal findings from autopsy, or abnormal body weight gain or loss in all the experimental groups. No abnormal variation associated with the test substance was observed in the respiration rate, the tidal volume, the minute volume, body temperature or the general behaviors. On the basis of these results, the approximate lethal dose of AB204 for a single intravenous injection exceeds 10 mg/kg for SD rats and a single intravenous injection of ≤0.8 mg/kg AB204 has no effect on their respiratory system for SD rat and no effect on their CNS for ICR mice.

  11. Respiratory nanoparticle-based vaccines and challenges associated with animal models and translation.

    Science.gov (United States)

    Renukaradhya, Gourapura J; Narasimhan, Balaji; Mallapragada, Surya K

    2015-12-10

    Vaccine development has had a huge impact on human health. However, there is a significant need to develop efficacious vaccines for several existing as well as emerging respiratory infectious diseases. Several challenges need to be overcome to develop efficacious vaccines with translational potential. This review focuses on two aspects to overcome some barriers - 1) the development of nanoparticle-based vaccines, and 2) the choice of suitable animal models for respiratory infectious diseases that will allow for translation. Nanoparticle-based vaccines, including subunit vaccines involving synthetic and/or natural polymeric adjuvants and carriers, as well as those based on virus-like particles offer several key advantages to help overcome the barriers to effective vaccine development. These include the ability to deliver combinations of antigens, target the vaccine formulation to specific immune cells, enable cross-protection against divergent strains, act as adjuvants or immunomodulators, allow for sustained release of antigen, enable single dose delivery, and potentially obviate the cold chain. While mouse models have provided several important insights into the mechanisms of infectious diseases, they are often a limiting step in translation of new vaccines to the clinic. An overview of different animal models involved in vaccine research for respiratory infections, with advantages and disadvantages of each model, is discussed. Taken together, advances in nanotechnology, combined with the right animal models for evaluating vaccine efficacy, has the potential to revolutionize vaccine development for respiratory infections. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. 4D motion models over the respiratory cycle for use in lung cancer radiotherapy planning

    Science.gov (United States)

    McClelland, J. R.; Chandler, A. G.; Blackall, J. M.; Ahmad, S.; Landau, D. B.; Hawkes, D. J.

    2005-04-01

    Respiratory motion causes problems of tumour localisation in radiotherapy treatment planning for lung cancer patients. We have developed a novel method of building patient specific motion models, which model the movement and non-rigid deformation of a lung tumour and surrounding lung tissue over the respiratory cycle. Free-breathing (FB) CT scans are acquired in cine mode, using 3 couch positions to acquire contiguous 'slabs' of 16 slices covering the region of interest. For each slab, 20 FB volumes are acquired over approx 20s. A reference volume acquired at Breath Hold (BH) and covering the whole lung, is non-rigidly registered to each of the FB volumes. The FB volumes are assigned a position in the respiratory cycle (PRC) calculated from the displacement of the chest wall. A motion model is then constructed for each slab, by fitting functions that temporally interpolate the registration results over the respiratory cycle. This can produce a prediction of the lung and tumour within the slab at any arbitrary PRC. The predictions for each of the slabs are then combined to produce a volume covering the whole region of interest. Results indicate that the motion modelling method shows considerable promise, offering significant improvement over current clinical practice, and potential advantages over alternative 4D CT imaging techniques. Using this framework, we examined and evaluated several different functions for performing the temporal interpolation. We believe the results of these comparisons will aid future model building for this and other applications.

  13. Development of an anesthetized rat model of exercise hyperpnoea: An integrative model of respiratory control using an equilibrium diagram.

    Science.gov (United States)

    Miyamoto, Tadayoshi; Manabe, Kou; Ueda, Shinya; Nakahara, Hidehiro

    2018-03-06

    What is the central question of this study? The lack of useful small animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states. What is the main finding and its importance? We developed an anesthetized rat model for studying exercise hyperpnoea, using respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of the respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiologic basis in various disease models, the lack of integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anesthetized rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data, and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO 2 pressure (P ETCO2 ) and minute ventilation (V E ), and the plant by the hyperbolic relationship between V E and P ETCO2 . During exercise, the controller curve shifted upward without change in controller gain, accompanying

  14. A novel swine model of ricin-induced acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Shahaf Katalan

    2017-02-01

    Full Text Available Pulmonary exposure to the plant toxin ricin leads to respiratory insufficiency and death. To date, in-depth study of acute respiratory distress syndrome (ARDS following pulmonary exposure to toxins is hampered by the lack of an appropriate animal model. To this end, we established the pig as a large animal model for the comprehensive study of the multifarious clinical manifestations of pulmonary ricinosis. Here, we report for the first time, the monitoring of barometric whole body plethysmography for pulmonary function tests in non-anesthetized ricin-treated pigs. Up to 30 h post-exposure, as a result of progressing hypoxemia and to prevent carbon dioxide retention, animals exhibited a compensatory response of elevation in minute volume, attributed mainly to a large elevation in respiratory rate with minimal response in tidal volume. This response was followed by decompensation, manifested by a decrease in minute volume and severe hypoxemia, refractory to oxygen treatment. Radiological evaluation revealed evidence of early diffuse bilateral pulmonary infiltrates while hemodynamic parameters remained unchanged, excluding cardiac failure as an explanation for respiratory insufficiency. Ricin-intoxicated pigs suffered from increased lung permeability accompanied by cytokine storming. Histological studies revealed lung tissue insults that accumulated over time and led to diffuse alveolar damage. Charting the decline in PaO2/FiO2 ratio in a mechanically ventilated pig confirmed that ricin-induced respiratory damage complies with the accepted diagnostic criteria for ARDS. The establishment of this animal model of pulmonary ricinosis should help in the pursuit of efficient medical countermeasures specifically tailored to deal with the respiratory deficiencies stemming from ricin-induced ARDS.

  15. Population pharmacodynamic modeling and simulation of the respiratory effect of acetazolamide in decompensated COPD patients.

    Directory of Open Access Journals (Sweden)

    Nicholas Heming

    Full Text Available Chronic obstructive pulmonary disease (COPD patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis.619 time-respiratory (minute ventilation, tidal volume and respiratory rate and 207 time-PaCO2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug.The effect of acetazolamide on minute ventilation and PaCO2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily was required to significantly increase minute ventilation (P0.75 L min(-1 in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day.Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide.

  16. Research Summary 3-D Computational Fluid Dynamics (CFD) Model Of The Human Respiratory System

    Science.gov (United States)

    The U.S. EPA’s Office of Research and Development (ORD) has developed a 3-D computational fluid dynamics (CFD) model of the human respiratory system that allows for the simulation of particulate based contaminant deposition and clearance, while being adaptable for age, ethn...

  17. Biological effects of desert dust in respiratory epithelial cells and a murine model.

    Science.gov (United States)

    Abstract As a result of the challenge of recent dust storms to public health, we tested the postulate that desert dust collected in the southwestern United States could impact a biological effect in respiratory epithelial cells and an animal model. Two samples of surface sedime...

  18. Respiratory mechanics

    CERN Document Server

    Wilson, Theodore A

    2016-01-01

    This book thoroughly covers each subfield of respiratory mechanics: pulmonary mechanics, the respiratory pump, and flow. It presents the current understanding of the field and serves as a guide to the scientific literature from the golden age of respiratory mechanics, 1960 - 2010. Specific topics covered include the contributions of surface tension and tissue forces to lung recoil, the gravitational deformation of the lung, and the interdependence forces that act on pulmonary airways and blood vessels. The geometry and kinematics of the ribs is also covered in detail, as well as the respiratory action of the external and internal intercostal muscles, the mechanics of the diaphragm, and the quantitative compartmental models of the chest wall is also described. Additionally, flow in the airways is covered thoroughly, including the wave-speed and viscous expiratory flow-limiting mechanisms; convection, diffusion and the stationary front; and the distribution of ventilation. This is an ideal book for respiratory ...

  19. Evaluating humidity recovery efficiency of currently available heat and moisture exchangers: a respiratory system model study

    Directory of Open Access Journals (Sweden)

    Jeanette Janaina Jaber Lucato

    2009-06-01

    Full Text Available OBJECTIVES: To evaluate and compare the efficiency of humidification in available heat and moisture exchanger models under conditions of varying tidal volume, respiratory rate, and flow rate. INTRODUCTION: Inspired gases are routinely preconditioned by heat and moisture exchangers to provide a heat and water content similar to that provided normally by the nose and upper airways. The absolute humidity of air retrieved from and returned to the ventilated patient is an important measurable outcome of the heat and moisture exchangers' humidifying performance. METHODS: Eight different heat and moisture exchangers were studied using a respiratory system analog. The system included a heated chamber (acrylic glass, maintained at 37°C, a preserved swine lung, a hygrometer, circuitry and a ventilator. Humidity and temperature levels were measured using eight distinct interposed heat and moisture exchangers given different tidal volumes, respiratory frequencies and flow-rate conditions. Recovery of absolute humidity (%RAH was calculated for each setting. RESULTS: Increasing tidal volumes led to a reduction in %RAH for all heat and moisture exchangers while no significant effect was demonstrated in the context of varying respiratory rate or inspiratory flow. CONCLUSIONS: Our data indicate that heat and moisture exchangers are more efficient when used with low tidal volume ventilation. The roles of flow and respiratory rate were of lesser importance, suggesting that their adjustment has a less significant effect on the performance of heat and moisture exchangers.

  20. Evaluating humidity recovery efficiency of currently available heat and moisture exchangers: a respiratory system model study.

    Science.gov (United States)

    Lucato, Jeanette Janaina Jaber; Adams, Alexander Bernard; Souza, Rogério; Torquato, Jamili Anbar; Carvalho, Carlos Roberto Ribeiro; Marini, John J

    2009-01-01

    To evaluate and compare the efficiency of humidification in available heat and moisture exchanger models under conditions of varying tidal volume, respiratory rate, and flow rate. Inspired gases are routinely preconditioned by heat and moisture exchangers to provide a heat and water content similar to that provided normally by the nose and upper airways. The absolute humidity of air retrieved from and returned to the ventilated patient is an important measurable outcome of the heat and moisture exchangers' humidifying performance. Eight different heat and moisture exchangers were studied using a respiratory system analog. The system included a heated chamber (acrylic glass, maintained at 37 degrees C), a preserved swine lung, a hygrometer, circuitry and a ventilator. Humidity and temperature levels were measured using eight distinct interposed heat and moisture exchangers given different tidal volumes, respiratory frequencies and flow-rate conditions. Recovery of absolute humidity (%RAH) was calculated for each setting. Increasing tidal volumes led to a reduction in %RAH for all heat and moisture exchangers while no significant effect was demonstrated in the context of varying respiratory rate or inspiratory flow. Our data indicate that heat and moisture exchangers are more efficient when used with low tidal volume ventilation. The roles of flow and respiratory rate were of lesser importance, suggesting that their adjustment has a less significant effect on the performance of heat and moisture exchangers.

  1. A novel modelling approach to energy transport in a respiratory system.

    Science.gov (United States)

    Nithiarasu, Perumal; Sazonov, Igor

    2017-10-01

    In this paper, energy transport in a respiratory tract is modelled using the finite element method for the first time. The upper and lower respiratory tracts are approximated as a 1-dimensional domain with varying cross-sectional and surface areas, and the radial heat conduction in the tissue is approximated using the 1-dimensional cylindrical coordinate system. The governing equations are solved using 1-dimensional linear finite elements with convective and evaporative boundary conditions on the wall. The results obtained for the exhalation temperature of the respiratory system have been compared with the available animal experiments. The study of a full breathing cycle indicates that evaporation is the main mode of heat transfer, and convection plays almost negligible role in the energy transport. This is in-line with the results obtained from animal experiments. Copyright © 2016 John Wiley & Sons, Ltd.

  2. A dynamic population-based model for the development of work-related respiratory health effects among bakery workers.

    NARCIS (Netherlands)

    Warren, N.; Meijster, T.; Heederik, D.; Tielemans, E.

    2009-01-01

    OBJECTIVES: This paper presents a dynamic population-based model for the development of sensitisation and respiratory symptoms in bakery workers. The model simulates a population of individual workers longitudinally and tracks the development of work-related sensitisation and respiratory symptoms in

  3. A dynamic population-based model for the development of work-related respiratory health effects among bakery workers

    NARCIS (Netherlands)

    Warren, N.; Meijster, T.; Heederik, D.; Tielemans, E.

    2009-01-01

    Objectives: This paper presents a dynamic population-based model for the development of sensitisation and respiratory symptoms in bakery workers. The model simulates a population of individual workers longitudinally and tracks the development of work-related sensitisation and respiratory symptoms in

  4. Two new animal models for actinide toxicity studies

    International Nuclear Information System (INIS)

    Taylor, G.N.; Gardner, P.A.; Jones, C.W.; Lloyd, R.D.; Mays, C.W.

    1979-01-01

    Two small rodent species, the grasshopper mouse (Onychomys leucogaster) and the deer mouse (Peromyscus maniculatus) have tenacious retention in the liver and skeleton of plutonium and americium. The retention following intraperitoneal injection of Pu and Am in citrate solution ranged from 20 to 47% (liver) and 19 to 42% (skeleton), relatively independent of post-injection times, varying from 30 to 125 days. Based on observations extended to 125 days post-injection, the biological half-times appeared to be long. Both of these rodents are relatively long-lived (median lifespans of approximately 1400 days), breed well in captivity, and adapt suitably to laboratory conditions. It is suggested that these two species of mice, in which plutonium is partitioned between the skeleton and liver in a manner similar to that of man, may be useful animal models for actinide toxicity studies

  5. Two new rodent models for actinide toxicity studies

    International Nuclear Information System (INIS)

    Taylor, G.N.; Jones, C.W.; Gardner, P.A.; Lloyd, R.D.; Mays, C.W.; Charrier, K.E.

    1981-01-01

    Two small rodent species, the grasshopper mouse (Onychomys leucogaster) and the deer mouse (Peromyscus maniculatus), have tenacious and high retention in the liver and skeleton of plutonium and americium following intraperitoneal injection of Pu and Am in citrate solution. Liver retention of Pu and Am in the grasshopper mouse is higher than liver retention in the deer mouse. Both of these rodents are relatively long-lived, breed well in captivity, and adapt suitably to laboratory conditions. It is suggested that these two species of mice, in which plutonium retention is high and prolonged in both the skeleton and liver, as it is in man, may be useful animal models for actinide toxicity studies

  6. Efficient solvers for coupled models in respiratory mechanics.

    Science.gov (United States)

    Verdugo, Francesc; Roth, Christian J; Yoshihara, Lena; Wall, Wolfgang A

    2017-02-01

    We present efficient preconditioners for one of the most physiologically relevant pulmonary models currently available. Our underlying motivation is to enable the efficient simulation of such a lung model on high-performance computing platforms in order to assess mechanical ventilation strategies and contributing to design more protective patient-specific ventilation treatments. The system of linear equations to be solved using the proposed preconditioners is essentially the monolithic system arising in fluid-structure interaction (FSI) extended by additional algebraic constraints. The introduction of these constraints leads to a saddle point problem that cannot be solved with usual FSI preconditioners available in the literature. The key ingredient in this work is to use the idea of the semi-implicit method for pressure-linked equations (SIMPLE) for getting rid of the saddle point structure, resulting in a standard FSI problem that can be treated with available techniques. The numerical examples show that the resulting preconditioners approach the optimal performance of multigrid methods, even though the lung model is a complex multiphysics problem. Moreover, the preconditioners are robust enough to deal with physiologically relevant simulations involving complex real-world patient-specific lung geometries. The same approach is applicable to other challenging biomedical applications where coupling between flow and tissue deformations is modeled with additional algebraic constraints. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Erythrocytes as a biological model for screening of xenobiotics toxicity.

    Science.gov (United States)

    Farag, Mayada Ragab; Alagawany, Mahmoud

    2018-01-05

    Erythrocytes are the main cells in circulation. They are devoid of internal membrane structures and easy to be isolated and handled providing a good model for different assays. Red blood cells (RBCs) plasma membrane is a multi-component structure that keeps the cell morphology, elasticity, flexibility and deformability. Alteration of membrane structure upon exposure to xenobiotics could induce various cellular abnormalities and releasing of intracellular components. Therefore the morphological changes and extracellular release of haemoglobin [hemolysis] and increased content of extracellular adenosine triphosphate (ATP) [as signs of membrane stability] could be used to evaluate the cytotoxic effects of various molecules. The nucleated RBCs from birds, fish and amphibians can be used to evaluate genotoxicity of different xenobiotics using comet, DNA fragmentation and micronucleus assays. The RBCs could undergo programmed cell death (eryptosis) in response to injury providing a useful model to analyze some mechanisms of toxicity that could be implicated in apoptosis of nucleated cells. Erythrocytes are vulnerable to peroxidation making it a good biological membrane model for analyzing the oxidative stress and lipid peroxidation of various xenobiotics. The RBCs contain a large number of enzymatic and non-enzymatic antioxidants. The changes of the RBCs antioxidant capacity could reflect the capability of xenobiotics to generate reactive oxygen species (ROS) resulting in oxidative damage of tissue. These criteria make RBCs a valuable in vitro model to evaluate the cytotoxicity of different natural or synthetic and organic or inorganic molecules by cellular damage measures. Copyright © 2017. Published by Elsevier B.V.

  8. Interdisciplinary approaches of transcranial magnetic stimulation applied to a respiratory neuronal circuitry model.

    Directory of Open Access Journals (Sweden)

    Stéphane Vinit

    Full Text Available Respiratory related diseases associated with the neuronal control of breathing represent life-threatening issues and to date, no effective therapeutics are available to enhance the impaired function. The aim of this study was to determine whether a preclinical respiratory model could be used for further studies to develop a non-invasive therapeutic tool applied to rat diaphragmatic neuronal circuitry. Transcranial magnetic stimulation (TMS was performed on adult male Sprague-Dawley rats using a human figure-of-eight coil. The largest diaphragmatic motor evoked potentials (MEPdia were recorded when the center of the coil was positioned 6 mm caudal from Bregma, involving a stimulation of respiratory supraspinal pathways. Magnetic shielding of the coil with mu metal reduced magnetic field intensities and improved focality with increased motor threshold and lower amplitude recruitment curve. Moreover, transynaptic neuroanatomical tracing with pseudorabies virus (applied to the diaphragm suggest that connections exist between the motor cortex, the periaqueductal grey cell regions, several brainstem neurons and spinal phrenic motoneurons (distributed in the C3-4 spinal cord. These results reveal the anatomical substrate through which supraspinal stimulation can convey descending action potential volleys to the spinal motoneurons (directly or indirectly. We conclude that MEPdia following a single pulse of TMS can be successfully recorded in the rat and may be used in the assessment of respiratory supraspinal plasticity. Supraspinal non-invasive stimulations aimed to neuromodulate respiratory circuitry will enable new avenues of research into neuroplasticity and the development of therapies for respiratory dysfunction associated with neural injury and disease (e.g. spinal cord injury, amyotrophic lateral sclerosis.

  9. The relation between air pollution and respiratory deaths in Tehran, Iran- using generalized additive models.

    Science.gov (United States)

    Dehghan, Azizallah; Khanjani, Narges; Bahrampour, Abbas; Goudarzi, Gholamreza; Yunesian, Masoud

    2018-03-20

    Some epidemiological evidence has shown a relation between ambient air pollution and adverse health outcomes. The aim of this study was to investigate the effect of air pollution on mortality from respiratory diseases in Tehran, Iran. In this ecological study, air pollution data was inquired from the Tehran Province Environmental Protection Agency and the Tehran Air Quality Control Company. Meteorological data was collected from the Tehran Meteorology Organization and mortality data from the Tehran Cemetery Mortality Registration. Generalized Additive Models (GAM) was used for data analysis with different lags, up to 15 days. A 10-unit increase in all pollutants except CO (1-unit) was used to compute the Relative Risk of deaths. During 2005 until 2014, 37,967 respiratory deaths occurred in Tehran in which 21,913 (57.7%) were male. The strongest relationship between NO 2 and PM 10 and respiratory death was seen on the same day (lag 0), and was respectively (RR = 1.04, 95% CI: 1.02-1.07) and (RR = 1.03, 95% CI: 1.02-1.04). O 3 and PM 2.5 had the strongest relationship with respiratory deaths on lag 2 and 1 respectively, and the RR was equal to 1.03, 95% CI: 1.01-1.05 and 1.06, 95% CI: 1.02-1.10 respectively. NO 2 , O 3 , PM 10 and PM 2.5 also showed significant relations with respiratory deaths in the older age groups. The findings of this study showed that O 3 , NO 2 , PM 10 and PM 2.5 air pollutants were related to respiratory deaths in Tehran. Reducing ambient air pollution can save lives in Tehran.

  10. QSAR models for reproductive toxicity and endocrine disruption in regulatory use – a preliminary investigation

    DEFF Research Database (Denmark)

    Jensen, Gunde Egeskov; Niemelä, Jay Russell; Wedebye, Eva Bay

    2008-01-01

    the new legislation. This article focuses on a screening exercise by use of our own and commercial QSAR models for identification of possible reproductive toxicants. Three QSAR models were used for reproductive toxicity for the endpoints teratogenic risk to humans (based on animal tests, clinical data...... for humans owing to possible developmental toxic effects: Xn (Harmful) and R63 (Possible risk of harm to the unborn child). The chemicals were also screened in three models for endocrine disruption....

  11. Respiratory hazard of Li-ion battery components: elective toxicity of lithium cobalt oxide (LiCoO2) particles in a mouse bioassay.

    Science.gov (United States)

    Sironval, Violaine; Reylandt, Laurence; Chaurand, Perrine; Ibouraadaten, Saloua; Palmai-Pallag, Mihaly; Yakoub, Yousof; Ucakar, Bernard; Rose, Jérôme; Poleunis, Claude; Vanbever, Rita; Marbaix, Etienne; Lison, Dominique; van den Brule, Sybille

    2018-03-17

    Rechargeable Li-ion batteries (LIB) are increasingly produced and used worldwide. LIB electrodes are made of micrometric and low solubility particles, consisting of toxicologically relevant elements. The health hazard of these materials is not known. Here, we investigated the respiratory hazard of three leading LIB components (LiFePO 4 or LFP, Li 4 Ti 5 O 12 or LTO, and LiCoO 2 or LCO) and their mechanisms of action. Particles were characterized physico-chemically and elemental bioaccessibility was documented. Lung inflammation and fibrotic responses, as well as particle persistence and ion bioavailability, were assessed in mice after aspiration of LIB particles (0.5 or 2 mg); crystalline silica (2 mg) was used as reference. Acute inflammatory lung responses were recorded with the 3 LIB particles and silica, LCO being the most potent. Inflammation persisted 2 m after LFP, LCO and silica, in association with fibrosis in LCO and silica lungs. LIB particles persisted in the lungs after 2 m. Endogenous iron co-localized with cobalt in LCO lungs, indicating the formation of ferruginous bodies. Fe and Co ions were detected in the broncho-alveolar lavage fluids of LFP and LCO lungs, respectively. Hypoxia-inducible factor (HIF) -1α, a marker of fibrosis and of the biological activity of Co ions, was upregulated in LCO and silica lungs. This study identified, for the first time, the respiratory hazard of LIB particles. LCO was at least as potent as crystalline silica to induce lung inflammation and fibrosis. Iron and cobalt, but not lithium, ions appear to contribute to LFP and LCO toxicity, respectively.

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

    International Nuclear Information System (INIS)

    Boecker, B.B.

    1993-01-01

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

  13. Diaphragm remodeling and compensatory respiratory mechanics in a canine model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Mead, A F; Petrov, M; Malik, A S; Mitchell, M A; Childers, M K; Bogan, J R; Seidner, G; Kornegay, J N; Stedman, H H

    2014-04-01

    Ventilatory insufficiency remains the leading cause of death and late stage morbidity in Duchenne muscular dystrophy (DMD). To address critical gaps in our knowledge of the pathobiology of respiratory functional decline, we used an integrative approach to study respiratory mechanics in a translational model of DMD. In studies of individual dogs with the Golden Retriever muscular dystrophy (GRMD) mutation, we found evidence of rapidly progressive loss of ventilatory capacity in association with dramatic morphometric remodeling of the diaphragm. Within the first year of life, the mechanics of breathing at rest, and especially during pharmacological stimulation of respiratory control pathways in the carotid bodies, shift such that the primary role of the diaphragm becomes the passive elastic storage of energy transferred from abdominal wall muscles, thereby permitting the expiratory musculature to share in the generation of inspiratory pressure and flow. In the diaphragm, this physiological shift is associated with the loss of sarcomeres in series (∼ 60%) and an increase in muscle stiffness (∼ 900%) compared with those of the nondystrophic diaphragm, as studied during perfusion ex vivo. In addition to providing much needed endpoint measures for assessing the efficacy of therapeutics, we expect these findings to be a starting point for a more precise understanding of respiratory failure in DMD.

  14. Studying human respiratory disease in animals--role of induced and naturally occurring models.

    Science.gov (United States)

    Williams, Kurt; Roman, Jesse

    2016-01-01

    Respiratory disorders like asthma, emphysema, and pulmonary fibrosis affect millions of Americans and many more worldwide. Despite advancements in medical research that have led to improved understanding of the pathophysiology of these conditions and sometimes to new therapeutic interventions, these disorders are for the most part chronic and progressive; current interventions are not curative and do not halt disease progression. A major obstacle to further advancements relates to the absence of animal models that exactly resemble the human condition, which delays the elucidation of relevant mechanisms of action, the unveiling of biomarkers of disease progression, and identification of new targets for intervention in patients. There are currently many induced animal models of human respiratory disease available for study, and even though they mimic features of human disease, discoveries in these models have not always translated into safe and effective treatments in humans. A major obstacle relates to the genetic, anatomical, and functional variations amongst species, which represents the major challenge to overcome when searching for appropriate models of respiratory disease. Nevertheless, rodents, in particular mice, have become the most common species used for experimentation, due to their relatively low cost, size, and adequate understanding of murine genetics, among other advantages. Less well known is the fact that domestic animals also suffer from respiratory illnesses similar to those found in humans. Asthma, bronchitis, pneumonia, and pulmonary fibrosis are among the many disorders occurring naturally in dogs, cats, and horses, among other species. These models might better resemble the human condition and are emphasized here, but further investigations are needed to determine their relevance. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  15. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study.

    Science.gov (United States)

    Iuliano, A Danielle; Roguski, Katherine M; Chang, Howard H; Muscatello, David J; Palekar, Rakhee; Tempia, Stefano; Cohen, Cheryl; Gran, Jon Michael; Schanzer, Dena; Cowling, Benjamin J; Wu, Peng; Kyncl, Jan; Ang, Li Wei; Park, Minah; Redlberger-Fritz, Monika; Yu, Hongjie; Espenhain, Laura; Krishnan, Anand; Emukule, Gideon; van Asten, Liselotte; Pereira da Silva, Susana; Aungkulanon, Suchunya; Buchholz, Udo; Widdowson, Marc-Alain; Bresee, Joseph S

    2017-12-14

    Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000-500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999-2015. We estimated country-specific influenza-associated respiratory excess mortality rates (EMR) for 33 countries using time series log-linear regression models with vital death records and influenza surveillance data. To extrapolate estimates to countries without data, we divided countries into three analytic divisions for three age groups (respiratory infection mortality rates. We calculated mortality rate ratios (MRR) to account for differences in risk of influenza death across countries by comparing GHE respiratory infection mortality rates from countries without EMR estimates with those with estimates. To calculate death estimates for individual countries within each age-specific analytic division, we multiplied randomly selected mean annual EMRs by the country's MRR and population. Global 95% credible interval (CrI) estimates were obtained from the posterior distribution of the sum of country-specific estimates to represent the range of possible influenza-associated deaths in a season or year. We calculated influenza-associated deaths for children younger than 5 years for 92 countries with high rates of mortality due to respiratory infection using the same methods. EMR-contributing countries represented 57% of the global population. The estimated mean annual influenza-associated respiratory EMR ranged from 0·1 to 6·4 per 100 000 individuals for people younger than 65 years, 2·9 to 44·0 per 100 000 individuals for people aged between 65 and 74 years, and 17·9 to 223·5 per 100 000 for people older than 75 years. We estimated that 291 243-645 832 seasonal

  16. Measurement of fractional order model parameters of respiratory mechanical impedance in total liquid ventilation.

    Science.gov (United States)

    Beaulieu, Alexandre; Bossé, Dominick; Micheau, Philippe; Avoine, Olivier; Praud, Jean-Paul; Walti, Hervé

    2012-02-01

    This study presents a methodology for applying the forced-oscillation technique in total liquid ventilation. It mainly consists of applying sinusoidal volumetric excitation to the respiratory system, and determining the transfer function between the delivered flow rate and resulting airway pressure. The investigated frequency range was f ∈ [0.05, 4] Hz at a constant flow amplitude of 7.5 mL/s. The five parameters of a fractional order lung model, the existing "5-parameter constant-phase model," were identified based on measured impedance spectra. The identification method was validated in silico on computer-generated datasets and the overall process was validated in vitro on a simplified single-compartment mechanical lung model. In vivo data on ten newborn lambs suggested the appropriateness of a fractional-order compliance term to the mechanical impedance to describe the low-frequency behavior of the lung, but did not demonstrate the relevance of a fractional-order inertance term. Typical respiratory system frequency response is presented together with statistical data of the measured in vivo impedance model parameters. This information will be useful for both the design of a robust pressure controller for total liquid ventilators and the monitoring of the patient's respiratory parameters during total liquid ventilation treatment. © 2011 IEEE

  17. A Two-Dimensional Human Minilung System (Model for Respiratory Syncytial Virus Infections

    Directory of Open Access Journals (Sweden)

    Esmeralda Magro-Lopez

    2017-12-01

    Full Text Available Human respiratory syncytial virus (HRSV is a major cause of serious pediatric respiratory diseases that lacks effective vaccine or specific therapeutics. Although our understanding about HRSV biology has dramatically increased during the last decades, the need for adequate models of HRSV infection is compelling. We have generated a two-dimensional minilung from human embryonic stem cells (hESCs. The differentiation protocol yielded at least six types of lung and airway cells, although it is biased toward the generation of distal cells. We show evidence of HRSV replication in lung cells, and the induction of innate and proinflammatory responses, thus supporting its use as a model for the study of HRSV–host interactions.

  18. Modeling Respiratory Gas Dynamics in the Aviator’s Breathing System. Volume 1

    Science.gov (United States)

    1994-05-01

    tricuspid valve which is presumed to track intrathoracic pressure. The pressures and flows in the various segments are coupled by their spatial connections...function in clinically significant pulmonary disease or for teaching respiratory physiology.’Ŗ’,13,14,15,16.17 Unfortunately, these were developed for...inspiratory valve model relates the flow and pressures between the mask supply hose and the oronasal cavity during inspiration. The expiratory valve

  19. Mathematical modeling and validation in physiology applications to the cardiovascular and respiratory systems

    CERN Document Server

    Bachar, Mostafa; Kappel, Franz

    2013-01-01

    This volume synthesizes theoretical and practical aspects of both the mathematical and life science viewpoints needed for modeling of the cardiovascular-respiratory system specifically and physiological systems generally.  Theoretical points include model design, model complexity and validation in the light of available data, as well as control theory approaches to feedback delay and Kalman filter applications to parameter identification. State of the art approaches using parameter sensitivity are discussed for enhancing model identifiability through joint analysis of model structure and data. Practical examples illustrate model development at various levels of complexity based on given physiological information. The sensitivity-based approaches for examining model identifiability are illustrated by means of specific modeling  examples. The themes presented address the current problem of patient-specific model adaptation in the clinical setting, where data is typically limited.

  20. Analysis of toxicity produced by inhalation of trichloroethylene within rat and mice`s respiratory epithelium; Comparazione del danno indotto dall`inalazione di tricloroetilene nell`epitelio nasale e tracheobronchiale del ratto e del topo

    Energy Technology Data Exchange (ETDEWEB)

    Mancuso, M.T.; Fravolini, M.E.; Parasacchi, P.; Lombardi, C.C.; Giovanetti, A. [ENEA, Casaccia (Italy). Area Energia Ambiente e Salute

    1994-05-01

    The aim of this study was to define the sites of cytotoxicity within the respiratory tract (nasal cavity and tracheobronchial tree) after acute inhalation of trichloroethylene (TCE), an organic solvent requiring metabolic activation by cytochrome P-450 enzymatic system to exert its toxic effects. Two animals species, rats and mice, were exposed to 3500 and 7000 ppm of TCE for 30 minutes. The morphological analysis of the respiratory epithelium has underlined a species-specific difference in the cellular sensitivity after treatment with TCE. This work is a part of ENEA (Italian Agency for New Technologies, Energy and the Environment) INTO program, environmental department, sector of effects on man and ecosystem.

  1. Anatomy and bronchoscopy of the porcine lung. A model for translational respiratory medicine.

    LENUS (Irish Health Repository)

    Judge, Eoin P

    2014-09-01

    The porcine model has contributed significantly to biomedical research over many decades. The similar size and anatomy of pig and human organs make this model particularly beneficial for translational research in areas such as medical device development, therapeutics and xenotransplantation. In recent years, a major limitation with the porcine model was overcome with the successful generation of gene-targeted pigs and the publication of the pig genome. As a result, the role of this model is likely to become even more important. For the respiratory medicine field, the similarities between pig and human lungs give the porcine model particular potential for advancing translational medicine. An increasing number of lung conditions are being studied and modeled in the pig. Genetically modified porcine models of cystic fibrosis have been generated that, unlike mouse models, develop lung disease similar to human cystic fibrosis. However, the scientific literature relating specifically to porcine lung anatomy and airway histology is limited and is largely restricted to veterinary literature and textbooks. Furthermore, methods for in vivo lung procedures in the pig are rarely described. The aims of this review are to collate the disparate literature on porcine lung anatomy, histology, and microbiology; to provide a comparison with the human lung; and to describe appropriate bronchoscopy procedures for the pig lungs to aid clinical researchers working in the area of translational respiratory medicine using the porcine model.

  2. Adenosine monophosphate is elevated in the bronchoalveolar lavage fluid of mice with acute respiratory toxicity induced by nanoparticles with high surface hydrophobicity.

    Science.gov (United States)

    Dailey, Lea Ann; Hernández-Prieto, Raquel; Casas-Ferreira, Ana Maria; Jones, Marie-Christine; Riffo-Vasquez, Yanira; Rodríguez-Gonzalo, Encarnación; Spina, Domenico; Jones, Stuart A; Smith, Norman W; Forbes, Ben; Page, Clive; Legido-Quigley, Cristina

    2015-02-01

    Inhaled nanomaterials present a challenge to traditional methods and understanding of respiratory toxicology. In this study, a non-targeted metabolomics approach was used to investigate relationships between nanoparticle hydrophobicity, inflammatory outcomes and the metabolic fingerprint in bronchoalveolar fluid. Measures of acute lung toxicity were assessed following single-dose intratracheal administration of nanoparticles with varying surface hydrophobicity (i.e. pegylated lipid nanocapsules, polyvinyl acetate nanoparticles and polystyrene beads; listed in order of increasing hydrophobicity). Broncho-alveolar lavage (BAL) fluid was collected from mice exposed to nanoparticles at a surface area dose of 220 cm(2) and metabolite fingerprints were acquired via ultra pressure liquid chromatography-mass spectrometry-based metabolomics. Particles with high surface hydrophobicity were pro-inflammatory. Multivariate analysis of the resultant small molecule fingerprints revealed clear discrimination between the vehicle control and polystyrene beads (p < 0.05), as well as between nanoparticles of different surface hydrophobicity (p < 0.0001). Further investigation of the metabolic fingerprints revealed that adenosine monophosphate (AMP) concentration in BAL correlated with neutrophilia (p < 0.01), CXCL1 levels (p < 0.05) and nanoparticle surface hydrophobicity (p < 0.001). Our results suggest that extracellular AMP is an intermediary metabolite involved in adenine nucleotide-regulated neutrophilic inflammation as well as tissue damage, and could potentially be used to monitor nanoparticle-induced responses in the lung following pulmonary administration.

  3. Respiratory flows during early childhood: Computational models to examine therapeutic aerosols in the developing airways

    Science.gov (United States)

    Tenenbaum-Katan, Janna; Hofemeier, Philipp; Sznitman, Josué; Janna Tenenbaum-Katan Team

    2015-11-01

    Inhalation therapy is the cornerstone of early-childhood respiratory treatments, as well as a rising potential for systemic drug delivery and pulmonary vaccination. As such, indispensable understanding of respiratory flow phenomena, coupled with particle transport at the deep regions of children's lungs is necessary to attain efficient targeting of aerosol therapy. However, fundamental research of pulmonary transport is overwhelmingly focused on adults. In our study, we have developed an anatomically-inspired computational model of representing pulmonary acinar regions at several age points during a child's development. Our numerical simulations examine respiratory flows and particle deposition maps within the acinar model, accounting for varying age dependant anatomical considerations and ventilation patterns. Resulting deposition maps of aerosols alter with age, such findings might suggest that medication protocols of inhalation therapy in young children should be considered to be accordingly amended with the child's development. Additionally to understanding basic scientific concepts of age effects on aerosol deposition, our research can potentially contribute practical guidelines to therapy protocols, and its' necessary modifications with age. We acknowledge the support of the ISF and the Israeli ministry of Science.

  4. 4D modeling and estimation of respiratory motion for radiation therapy

    CERN Document Server

    Lorenz, Cristian

    2013-01-01

    Respiratory motion causes an important uncertainty in radiotherapy planning of the thorax and upper abdomen. The main objective of radiation therapy is to eradicate or shrink tumor cells without damaging the surrounding tissue by delivering a high radiation dose to the tumor region and a dose as low as possible to healthy organ tissues. Meeting this demand remains a challenge especially in case of lung tumors due to breathing-induced tumor and organ motion where motion amplitudes can measure up to several centimeters. Therefore, modeling of respiratory motion has become increasingly important in radiation therapy. With 4D imaging techniques spatiotemporal image sequences can be acquired to investigate dynamic processes in the patient’s body. Furthermore, image registration enables the estimation of the breathing-induced motion and the description of the temporal change in position and shape of the structures of interest by establishing the correspondence between images acquired at different phases of the br...

  5. NASAL-Geom, a free upper respiratory tract 3D model reconstruction software

    Science.gov (United States)

    Cercos-Pita, J. L.; Cal, I. R.; Duque, D.; de Moreta, G. Sanjuán

    2018-02-01

    The tool NASAL-Geom, a free upper respiratory tract 3D model reconstruction software, is here described. As a free software, researchers and professionals are welcome to obtain, analyze, improve and redistribute it, potentially increasing the rate of development, and reducing at the same time ethical conflicts regarding medical applications which cannot be analyzed. Additionally, the tool has been optimized for the specific task of reading upper respiratory tract Computerized Tomography scans, and producing 3D geometries. The reconstruction process is divided into three stages: preprocessing (including Metal Artifact Reduction, noise removal, and feature enhancement), segmentation (where the nasal cavity is identified), and 3D geometry reconstruction. The tool has been automatized (i.e. no human intervention is required) a critical feature to avoid bias in the reconstructed geometries. The applied methodology is discussed, as well as the program robustness and precision.

  6. The respiratory tract deposition model proposed by the ICRP Task Group

    International Nuclear Information System (INIS)

    James, A.C.; Briant, J.K.; Stahlhofen, W.; Rudolf, G.; Gehr, P.

    1990-11-01

    The Task Group has developed a new model of the deposition of inhaled aerosols in each anatomical region of the respiratory tract. The model is used to evaluate the fraction of airborne activity that is deposited in respiratory regions having distinct retention characteristics and clearance pathways: the anterior nares, the extrathoracic airways of the naso- and oropharynx and larynx, the bronchi, the bronchioles, and the alveolated airways of the lung. Drawn from experimental data on total and regional deposition in human subjects, the model is based on extrapolation of these data by means of a detailed theoretical model of aerosol transport and deposition within the lung. The Task Group model applies to all practical conditions, and for aerosol particles and vapors from atomic size up to very coarse aerosols with an activity median aerodynamic diameter of 100 μm. The model is designed to predict regional deposition in different subjects, including adults of either sex, children of various ages, and infants, and also to account for anatomical differences among Caucasian and non-Caucasian subjects. The Task Group model represents aerosol inhalability and regional deposition in different subjects by algebraic expressions of aerosol size, breathing rates, standard lung volumes, and scaling factors for airway dimensions. 35 refs., 13 figs., 2 tabs

  7. Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy

    Directory of Open Access Journals (Sweden)

    Petrica-Adrian Panaite

    2013-05-01

    Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1. Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding

  8. Chlorine gas inhalation: human clinical evidence of toxicity and experience in animal models.

    Science.gov (United States)

    White, Carl W; Martin, James G

    2010-07-01

    Humans can come into contact with chlorine gas during short-term, high-level exposures due to traffic or rail accidents, spills, or other disasters. By contrast, workplace and public (swimming pools, etc.) exposures are more frequently long-term, low-level exposures, occasionally punctuated by unintentional transient increases. Acute exposures can result in symptoms of acute airway obstruction including wheezing, cough, chest tightness, and/or dyspnea. These findings are fairly nonspecific, and might be present after exposures to a number of inhaled chemical irritants. Clinical signs, including hypoxemia, wheezes, rales, and/or abnormal chest radiographs may be present. More severely affected individuals may suffer acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). Up to 1% of exposed individuals die. Humidified oxygen and inhaled beta-adrenergic agents are appropriate therapies for victims with respiratory symptoms while assessments are underway. Inhaled bicarbonate and systemic or inhaled glucocorticoids also have been reported anecdotally to be beneficial. Chronic sequelae may include increased airways reactivity, which tends to diminish over time. Airways hyperreactivity may be more of a problem among those survivors that are older, have smoked, and/or have pre-existing chronic lung disease. Individuals suffering from irritant-induced asthma (IIA) due to workplace exposures to chlorine also tend to have similar characteristics, such as airways hyperresponsiveness to methacholine, and to be older and to have smoked. Other workplace studies, however, have indicated that workers exposed to chlorine dioxide/sulfur dioxide have tended to have increased risk for chronic bronchitis and/or recurrent wheezing attacks (one or more episodes) but not asthma, while those exposed to ozone have a greater incidence of asthma. Specific biomarkers for acute and chronic exposures to chlorine gas are currently lacking. Animal models for chlorine gas

  9. External Validation of Prediction Models for Pneumonia in Primary Care Patients with Lower Respiratory Tract Infection

    DEFF Research Database (Denmark)

    Schierenberg, Alwin; Minnaard, Margaretha C; Hopstaken, Rogier M

    2016-01-01

    BACKGROUND: Pneumonia remains difficult to diagnose in primary care. Prediction models based on signs and symptoms (S&S) serve to minimize the diagnostic uncertainty. External validation of these models is essential before implementation into routine practice. In this study all published S&S models...... for prediction of pneumonia in primary care were externally validated in the individual patient data (IPD) of previously performed diagnostic studies. METHODS AND FINDINGS: S&S models for diagnosing pneumonia in adults presenting to primary care with lower respiratory tract infection and IPD for validation were...... identified through a systematical search. Six prediction models and IPD of eight diagnostic studies (N total = 5308, prevalence pneumonia 12%) were included. Models were assessed on discrimination and calibration. Discrimination was measured using the pooled Area Under the Curve (AUC) and delta AUC...

  10. Sin-quadratic model for chest tomosynthesis respiratory signal analysis and its application in four dimensional chest tomosynthesis reconstruction.

    Science.gov (United States)

    Tao, Xi; Zhang, Hua; Qin, Genggeng; Ma, Jianhua; Feng, Qianjin; Chen, Wufan

    2018-02-01

    Chest tomosynthesis (CTS) is a newly developed imaging technique which provides pseudo-3D volume anatomical information of thorax from limited-angle projections and contains much less of superimposed anatomy than the chest X-ray radiography. One of the relatively common problems in CTS is the patient respiratory motion during image acquisition, which negatively impacts the detectability. In this work, we propose a sin-quadratic model to analyze the respiratory motion during CTS scan, which is a real time method where the respiratory signal is generated by extracting the motion of diaphragm from projection radiographs. According to the estimated respiratory signal, the CTS projections were then amplitude-based sorted into four to eight phases, and an iterative reconstruction strategy with total variation regularization was adopted to reconstruct the CTS images at each phase. Simulated digital XCAT phantom data and three sets of patient data were adopted for the experiments to validate the performance of the sin-quadratic model and its application in four dimensional (4D) CTS reconstruction. Results of the XCAT phantom simulation study show that the correlation coefficient between the extracted respiratory signal and the originally designed respiratory signal is 0.9964, which suggests that the proposed model could exactly extract the respiratory signal from CTS projections. The 4D CTS reconstructions of both the phantom data and the patient data show clear reduction of motion-induced blur. Copyright © 2018 IPEM. Published by Elsevier Ltd. All rights reserved.

  11. Respiratory acidosis

    Science.gov (United States)

    Ventilatory failure; Respiratory failure; Acidosis - respiratory ... Causes of respiratory acidosis include: Diseases of the airways (such as asthma and COPD ) Diseases of the lung tissue (such as ...

  12. Respiratory explants as a model to investigate early events of contagious bovine pleuropneumonia infection.

    Science.gov (United States)

    Di Teodoro, Giovanni; Marruchella, Giuseppe; Di Provvido, Andrea; Orsini, Gianluca; Ronchi, Gaetano Federico; D'Angelo, Anna Rita; D'Alterio, Nicola; Sacchini, Flavio; Scacchia, Massimo

    2018-01-12

    Contagious bovine pleuropneumonia (CBPP) is a severe disease caused by Mycoplasma mycoides subsp. mycoides (Mmm). Knowledge on CBPP pathogenesis is fragmented and hampered by the limited availability of laboratory animal and in vitro models of investigation. The purpose of the present study is to assess respiratory explants as useful tools to study the early stages of CBPP. Explants were obtained from trachea, bronchi and lungs of slaughtered cattle, tested negative for Mycoplasma spp. and for the major bacterial and viral respiratory pathogens. The interaction of Mmm with explant cells was studied by immunohistochemistry (IHC), double-labelling indirect immunofluorescence (DLIIF) and laser scanning confocal microscopy (LSCM). Mmm capability to survive and proliferate within the explants was evaluated by standard microbiological procedures. Finally, the putative cellular internalization of Mmm was further investigated by the gentamicin invasion assay. IHC and DLIIF indicated that Mmm can colonize explants, showing a marked tropism for lower airways. Specifically, Mmm was detected on/inside the bronchiolar and alveolar epithelial cells, the alveolar macrophages and the endothelial cells. The interaction between Mmm and explant cells was abolished by the pre-incubation of the pathogen with bovine anti-Mmm immune sera. Mmm was able to survive and proliferate in all tracheal, bronchial and lung explants, during the entire time course of the experiments. LSCM and gentamicin invasion assay both confirmed that Mmm can enter non-phagocytic host cells. Taken together, our data supports bovine respiratory explants as a promising tool to investigate CBPP, alternative to cattle experimental infection.

  13. The new ICRP respiratory model for radiation protection (ICRP 66) : applications and comparative evaluations

    International Nuclear Information System (INIS)

    Castellani, C.M.; Luciani, A.

    1996-02-01

    The aim of this report is to present the New ICRP Respiratory Model Tract for Radiological Protection. The model allows considering anatomical and physiological characteristics, giving reference values for children aged 3 months, 1, 5,10, and 15 years for adults; it also takes into account aerosol and gas characteristics. After a general description of the model structure, deposition, clearance and dosimetric models are presented. To compare the new and previous model (ICRP 30), dose coefficients (committed effective dose for unit intake) foe inhalation of radionuclides by workers are calculated considering aerosol granulometries with activity median aerodynamic of 1 and 5 μm, reference values for the respective publications. Dose coefficients and annual limits of intakes concerning respective dose limits (50 and 20 mSv respectively for ICRP 26 and 60) for workers and for members of population in case of dispersion of fission products aerosols, are finally calculated

  14. Evaluation and modeling of the parameters affecting fluoride toxicity level in aquatic environments by bioassay method

    Directory of Open Access Journals (Sweden)

    Hamid Reza Shamsollahi

    2014-04-01

    Full Text Available Background: Fluoride exists in various forms in nature and water resources. , The rising level of fluoride in water resources due to discharge of industrial effluents can cause toxicity in aquatic organisms. To prevent toxicity, it is necessary to determine maximum fluoride toxicity as well as effluent discharge limits. The aim of this study was to determine the maximum fluoride toxicity and the factors affecting fluoride toxicity to provide a model in order to determine the effluent discharge limits. Methods: Daphnia magna bioassay in the absence of confounding factors was used to determine the maximum level of fluoride toxicity. Then, bioassay was repeated in the presence of the confounding factors (hardness, temperature and exposure time to determine their effects. Results: In the absence of intervening factors, fluoride LC50 levels determined after 24, 48 and 72 hours exposure were 4.9, 46.5 and 38.7 mg/l, respectively.. Also, the influence of confounding factors on LC50 values was reported significant by Minitab software. Conclusion: Increasing the water hardness reduced fluoride toxicity, and increasing the water temperature and exposure time increased fluoride toxicity in aquatic environments. Therefore, while determining the wastewater discharge limit in terms of fluoride concentration, it is essential to take the effect of confounding factors on fluoride toxicity into account in order to prevent toxicity in the open water resources.

  15. Potential carcinogenicity predicted by computational toxicity evaluation of thiophosphate pesticides using QSTR/QSCarciAR model.

    Science.gov (United States)

    Petrescu, Alina-Maria; Ilia, Gheorghe

    2017-07-01

    This study presents in silico prediction of toxic activities and carcinogenicity, represented by the potential carcinogenicity DSSTox/DBS, based on vector regression with a new Kernel activity, and correlating the predicted toxicity values through a QSAR model, namely: QSTR/QSCarciAR (quantitative structure toxicity relationship/quantitative structure carcinogenicity-activity relationship) described by 2D, 3D descriptors and biological descriptors. The results showed a connection between carcinogenicity (compared to the structure of a compound) and toxicity, as a basis for future studies on this subject, but each prediction is based on structurally similar compounds and the reactivation of the substructures of these compounds.

  16. A Conceptual Framework for Predicting the Toxicity of Reactive Chemicals: Modeling Soft Electrophilicity

    Science.gov (United States)

    Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point...

  17. EFFECTS OF WATER CHEMISTRY ON COPPER TOXICITY - WHAT'S MISSING FROM CURRENT MODELS?

    Science.gov (United States)

    Current models for the acute toxicity of cationic metals to aquatic organisms focus on the binding of free metal ions to gill surfaces. This binding, and the resultant toxicity, can be reduced by metal-complexing ligands in the exposure water, which lower the activity of the free...

  18. Development of biotic ligand models for chronic manganese toxicity to fish, invertebrates, and algae.

    Science.gov (United States)

    Peters, Adam; Lofts, Stephen; Merrington, Graham; Brown, Bruce; Stubblefield, William; Harlow, Keven

    2011-11-01

    Ecotoxicity tests were performed with fish, invertebrates, and algae to investigate the effect of water quality parameters on Mn toxicity. Models were developed to describe the effects of Mn as a function of water quality. Calcium (Ca) has a protective effect on Mn toxicity for both fish and invertebrates, and magnesium (Mg) also provides a protective effect for invertebrates. Protons have a protective effect on Mn toxicity to algae. The models derived are consistent with models of the toxicity of other metals to aquatic organisms in that divalent cations can act as competitors to Mn toxicity in fish and invertebrates, and protons act as competitors to Mn toxicity in algae. The selected models are able to predict Mn toxicity to the test organisms to within a factor of 2 in most cases. Under low-pH conditions invertebrates are the most sensitive taxa, and under high-pH conditions algae are most sensitive. The point at which algae become more sensitive than invertebrates depends on the Ca concentration and occurs at higher pH when Ca concentrations are low, because of the sensitivity of invertebrates under these conditions. Dissolved organic carbon concentrations have very little effect on the toxicity of Mn to aquatic organisms. Copyright © 2011 SETAC.

  19. Exposure Space: Integrating Exposure Data and Modeling with Toxicity Information

    Science.gov (United States)

    Recent advances have been made in high-throughput (HTP) toxicity testing, e.g. from ToxCast, which will ultimately be combined with HTP predictions of exposure potential to support next-generation chemical safety assessment. Rapid exposure methods are essential in selecting chemi...

  20. Predictive Modeling of Apical Toxicity Endpoints Using Data ...

    Science.gov (United States)

    The US EPA and other regulatory agencies face a daunting challenge of evaluating potential toxicity for tens of thousands of environmental chemicals about which little is currently known. The EPA’s ToxCast program is testing a novel approach to this problem by screening compounds using a variety of in vitro assays and using the results to prioritize chemicals for further, more detailed testing. Phase I of ToxCast is testing 320 chemicals (mainly pesticide active ingredients) against ~400 cell-based and biochemical assays. In order to anchor these studies, we are using in vivo guideline study data for subchronic, chronic, cancer, reproductive and developmental endpoints. This data is compiled in the EPA toxicity reference database, ToxRefDB. The main goal of ToxCast is the discovery and validation of “signatures” linking in vitro assay data to in vivo toxicity endpoints. These signatures will be collections of assays that are correlated with particular endpoints. These assay collections should also help define molecular-and cellular-level mechanisms of toxicity. This talk will discuss our strategy to use a combination of statistical and machine learning methods, coupled with biochemical network or systems biology approaches. Our initial examples will focus signatures for endpoints from 2 year rodent cancer bioassays. Most of the data we have analyzed is in dose or concentration response series, so to effectively use this data we have developed novel appro

  1. Simulation of The ICRP-30 Dosimetric Model for the Respiratory Tract

    International Nuclear Information System (INIS)

    Giaddui, T.; Atia, M. A.

    2004-01-01

    Matlab was used to write a simulation program (ACID1) to simulate the ICRP-30 dosimetric model for the respiratory tract. The program (a new version of the one presented at the sixth Arab conference held in Cairo 2002) calculates a series of dosimetric quantities for the reference man as a result of the inhalation of any radionuclide. The program also plots the variation of activity with time for all organs and provided with a graphical user interface to make it friendly user. The results obtained by this program was compared with similar results obtained by other source and found to be very close. (Authors)

  2. Respiratory compensation in projection imaging using a magnification and displacement model

    International Nuclear Information System (INIS)

    Crawford, C.R.; King, K.F.; Ritchie, C.J.; Godwin, J.D.

    1996-01-01

    Respiratory motion during the collection of computed tomography (CT) projections generates structured artifacts and a loss of resolution that can render the scans unusable. This motion is problematic in scans of those patients who cannot suspend respiration, such as the very young or incubated patients. In this paper, the authors present an algorithm that can be used to reduce motion artifacts in CT scans caused by respiration. An approximate model for the effect of respiration is that the object cross section under interrogation experiences time-varying magnification and displacement along two axes. Using this model an exact filtered backprojection algorithm is derived for the case of parallel projections. The result is extended to generate an approximate reconstruction formula for fan-beam projections. Computer simulations and scans of phantoms on a commercial CT scanner validate the new reconstruction algorithms for parallel and fan-beam projections. Significant reduction in respiratory artifacts is demonstrated clinically when the motion model is satisfied. The method can be applied to projection data used in CT single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI)

  3. Towards Global QSAR Model Building for Acute Toxicity: Munro Database Case Study

    Directory of Open Access Journals (Sweden)

    Swapnil Chavan

    2014-10-01

    Full Text Available A series of 436 Munro database chemicals were studied with respect to their corresponding experimental LD50 values to investigate the possibility of establishing a global QSAR model for acute toxicity. Dragon molecular descriptors were used for the QSAR model development and genetic algorithms were used to select descriptors better correlated with toxicity data. Toxic values were discretized in a qualitative class on the basis of the Globally Harmonized Scheme: the 436 chemicals were divided into 3 classes based on their experimental LD50 values: highly toxic, intermediate toxic and low to non-toxic. The k-nearest neighbor (k-NN classification method was calibrated on 25 molecular descriptors and gave a non-error rate (NER equal to 0.66 and 0.57 for internal and external prediction sets, respectively. Even if the classification performances are not optimal, the subsequent analysis of the selected descriptors and their relationship with toxicity levels constitute a step towards the development of a global QSAR model for acute toxicity.

  4. Cardio-respiratory development in bird embryos: new insights from a venerable animal model

    Directory of Open Access Journals (Sweden)

    Warren W. Burggren

    Full Text Available ABSTRACT The avian embryo is a time-honored animal model for understanding vertebrate development. A key area of extensive study using bird embryos centers on developmental phenotypic plasticity of the cardio-respiratory system and how its normal development can be affected by abiotic factors such as temperature and oxygen availability. Through the investigation of the plasticity of development, we gain a better understanding of both the regulation of the developmental process and the embryo's capacity for self-repair. Additionally, experiments with abiotic and biotic stressors during development have helped delineate not just critical windows for avian cardio-respiratory development, but the general characteristics (e.g., timing and dose-dependence of critical windows in all developing vertebrates. Avian embryos are useful in exploring fetal programming, in which early developmental experiences have implications (usually negative later in life. The ability to experimentally manipulate the avian embryo without the interference of maternal behavior or physiology makes it particularly useful in future studies of fetal programming. The bird embryo is also a key participant in studies of transgenerational epigenetics, whether by egg provisioning or effects on the germline that are transmitted to the F1 generation (or beyond. Finally, the avian embryo is heavily exploited in toxicology, in which both toxicological testing of potential consumer products as well as the consequences of exposure to anthropogenic pollutants are routinely carried out in the avian embryo. The avian embryo thus proves useful on numerous experimental fronts as an animal model that is concurrently both of adequate complexity and sufficient simplicity for probing vertebrate cardio-respiratory development.

  5. High-throughput Gene Expression Analysis In Pigs As Model For Respiratory Infections

    DEFF Research Database (Denmark)

    Skovgaard, Kerstin; Brogaard, Louise; Schou, Kirstine Klitgaard

    (WHO). Animal models are essential in understanding the mechanisms involved in human infectious disease and for the development of effective prevention and treatment strategies. It is increasingly realized that large animal models like the pig are exceptionally human like and serve as an excellent...... pleuropneumoniae causes pneumonia in pigs, a disease which is associated with high morbidity and mortality, as well as impaired animal welfare. The rapidly evolving pneumonia is characterized by large areas of lung necrosis resulting from the combined effect of tissue damage caused by the bacteria, and a strong...... model for disease and inflammation. Pigs are fully susceptible to human influenza, and have been demonstrated to be involved in influenza evolution and ecology. Pigs share many similarities with humans regarding lung physiology and innate immune cell infiltration of the respiratory system and thus seem...

  6. Computational fluid dynamics modeling of Bacillus anthracis spore deposition in rabbit and human respiratory airways

    Energy Technology Data Exchange (ETDEWEB)

    Kabilan, S.; Suffield, S. R.; Recknagle, K. P.; Jacob, R. E.; Einstein, D. R.; Kuprat, A. P.; Carson, J. P.; Colby, S. M.; Saunders, J. H.; Hines, S. A.; Teeguarden, J. G.; Straub, T. M.; Moe, M.; Taft, S. C.; Corley, R. A.

    2016-09-01

    Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived respectively from computed tomography (CT) and µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation–exhalation breathing conditions using average species-specific minute volumes. Two different exposure scenarios were modeled in the rabbit based upon experimental inhalation studies. For comparison, human simulations were conducted at the highest exposure concentration used during the rabbit experimental exposures. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the nasal sinus compared to the human at the same air concentration of anthrax spores. In contrast, higher spore deposition was predicted in the lower conducting airways of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology for deposition.

  7. Computational Fluid Dynamics Modeling of Bacillus anthracis Spore Deposition in Rabbit and Human Respiratory Airways

    Energy Technology Data Exchange (ETDEWEB)

    Kabilan, Senthil; Suffield, Sarah R.; Recknagle, Kurtis P.; Jacob, Rick E.; Einstein, Daniel R.; Kuprat, Andrew P.; Carson, James P.; Colby, Sean M.; Saunders, James H.; Hines, Stephanie; Teeguarden, Justin G.; Straub, Tim M.; Moe, M.; Taft, Sarah; Corley, Richard A.

    2016-09-30

    Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived from computed tomography (CT) or µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditions using average species-specific minute volumes. The highest exposure concentration was modeled in the rabbit based upon prior acute inhalation studies. For comparison, human simulation was also conducted at the same concentration. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the upper conducting airways compared to the human at the same air concentration of anthrax spores. As a result, higher particle deposition was predicted in the conducting airways and deep lung of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology.

  8. Integration into Big Data: First Steps to Support Reuse of Comprehensive Toxicity Model Modules (SOT)

    Science.gov (United States)

    Data surrounding the needs of human disease and toxicity modeling are largely siloed limiting the ability to extend and reuse modules across knowledge domains. Using an infrastructure that supports integration across knowledge domains (animal toxicology, high-throughput screening...

  9. Respiratory Health – Exposure Measurements and Modeling in the Fragrance and Flavour Industry

    Science.gov (United States)

    Angelini, Eric; Camerini, Gerard; Diop, Malick; Roche, Patrice; Rodi, Thomas; Schippa, Christine; Thomas, Thierry

    2016-01-01

    Although the flavor and fragrance industry is about 150 years old, the use of synthetic materials started more than 100 years ago, and the awareness of the respiratory hazard presented by some flavoring substances emerged only recently. In 2001, the US National Institute of Occupational Safety and Health (NIOSH) identified for the first time inhalation exposure to flavoring substances in the workplace as a possible occupational hazard. As a consequence, manufacturers must comply with a variety of workplace safety requirements, and management has to ensure the improvement of health and safety of the employees exposed to hazardous volatile organic compounds. In this sensitive context, MANE opened its facilities to an intensive measuring campaign with the objective to better estimate the real level of hazardous respiratory exposure of workers. In this study, exposure to 27 hazardous volatile substances were measured during several types of handling operations (weighing-mixing, packaging, reconditioning-transferring), 430 measurement results were generated, and were exploited to propose an improved model derived from the well-known ECETOC-TRA model. The quantification of volatile substances in the working atmosphere involved three main steps: adsorption of the chemicals on a solid support, thermal desorption, followed by analysis by gas chromatography-mass spectrometry. Our approach was to examine experimental measures done in various manufacturing workplaces and to define correction factors to reflect more accurately working conditions and habits. Four correction factors were adjusted in the ECETOC-TRA to integrate important exposure variation factors: exposure duration, percentage of the substance in the composition, presence of collective protective equipment and wearing of personal protective equipment. Verification of the validity of the model is based on the comparison of the values obtained after adaptation of the ECETOC-TRA model, according to various exposure

  10. Respiratory Health - Exposure Measurements and Modeling in the Fragrance and Flavour Industry.

    Directory of Open Access Journals (Sweden)

    Eric Angelini

    Full Text Available Although the flavor and fragrance industry is about 150 years old, the use of synthetic materials started more than 100 years ago, and the awareness of the respiratory hazard presented by some flavoring substances emerged only recently. In 2001, the US National Institute of Occupational Safety and Health (NIOSH identified for the first time inhalation exposure to flavoring substances in the workplace as a possible occupational hazard. As a consequence, manufacturers must comply with a variety of workplace safety requirements, and management has to ensure the improvement of health and safety of the employees exposed to hazardous volatile organic compounds. In this sensitive context, MANE opened its facilities to an intensive measuring campaign with the objective to better estimate the real level of hazardous respiratory exposure of workers. In this study, exposure to 27 hazardous volatile substances were measured during several types of handling operations (weighing-mixing, packaging, reconditioning-transferring, 430 measurement results were generated, and were exploited to propose an improved model derived from the well-known ECETOC-TRA model. The quantification of volatile substances in the working atmosphere involved three main steps: adsorption of the chemicals on a solid support, thermal desorption, followed by analysis by gas chromatography-mass spectrometry. Our approach was to examine experimental measures done in various manufacturing workplaces and to define correction factors to reflect more accurately working conditions and habits. Four correction factors were adjusted in the ECETOC-TRA to integrate important exposure variation factors: exposure duration, percentage of the substance in the composition, presence of collective protective equipment and wearing of personal protective equipment. Verification of the validity of the model is based on the comparison of the values obtained after adaptation of the ECETOC-TRA model, according to

  11. Next Generation Respiratory Viral Vaccine System: Advanced and Emerging Bioengineered Human Lung Epithelia Model (HLEM) Organoid Technology

    Science.gov (United States)

    Goodwin, Thomas J.; Schneider, Sandra L.; MacIntosh, Victor; Gibbons, Thomas F.

    2010-01-01

    Acute respiratory infections, including pneumonia and influenza, are the S t" leading cause of United States and worldwide deaths. Newly emerging pathogens signaled the need for an advanced generation of vaccine technology.. Human bronchial-tracheal epithelial tissue was bioengineered to detect, identify, host and study the pathogenesis of acute respiratory viral disease. The 3-dimensional (3D) human lung epithelio-mesechymal tissue-like assemblies (HLEM TLAs) share characteristics with human respiratory epithelium: tight junctions, desmosomes, microvilli, functional markers villin, keratins and production of tissue mucin. Respiratory Syntial Virus (RSV) studies demonstrate viral growth kinetics and membrane bound glycoproteins up to day 20 post infection in the human lung-orgainoid infected cell system. Peak replication of RSV occurred on day 10 at 7 log10 particles forming units per ml/day. HLEM is an advanced virus vaccine model and biosentinel system for emergent viral infectious diseases to support DoD global surveillance and military readiness.

  12. Comparisons of calculated respiratory tract deposition of particles based on the NCRP/ITRI model and the new ICRP66 model

    Energy Technology Data Exchange (ETDEWEB)

    Yeh, Hsu-Chi; Phalen, R.F. [Univ. of California, Irvine, CA (United States); Chang, I. [Lovelace Inst., Albuquerque, NM (United States)] [and others

    1995-12-01

    The National Council on Radiation Protection and Measurements (NCRP) in the United States and the International Commission on Radiological Protection (ICRP) have been independently reviewing and revising respiratory tract dosimetry models for inhaled radioactive aerosols. The newly proposed NCRP respiratory tract dosimetry model represents a significant change in philosophy from the old ICRP Task Group model. The proposed NCRP model describes respiratory tract deposition, clearance, and dosimetry for radioactive substances inhaled by workers and the general public and is expected to be published soon. In support of the NCRP proposed model, ITRI staff members have been developing computer software. Although this software is still incomplete, the deposition portion has been completed and can be used to calculate inhaled particle deposition within the respiratory tract for particle sizes as small as radon and radon progeny ({approximately} 1 nm) to particles larger than 100 {mu}m. Recently, ICRP published their new dosimetric model for the respiratory tract, ICRP66. Based on ICRP66, the National Radiological Protection Board of the UK developed PC-based software, LUDEP, for calculating particle deposition and internal doses. The purpose of this report is to compare the calculated respiratory tract deposition of particles using the NCRP/ITRI model and the ICRP66 model, under the same particle size distribution and breathing conditions. In summary, the general trends of the deposition curves for the two models were similar.

  13. Reassessment of the cardio-respiratory stress response, using the king penguin as a model.

    Science.gov (United States)

    Willener, Astrid S T; Halsey, Lewis G; Strike, Siobhán; Enstipp, Manfred R; Georges, Jean-Yves; Handrich, Yves

    2015-01-01

    Research in to short-term cardio-respiratory changes in animals in reaction to a psychological stressor typically describes increases in rate of oxygen consumption (V̇(O2)) and heart rate. Consequently, the broad consensus is that they represent a fundamental stressor response generalizable across adult species. However, movement levels can also change in the presence of a stressor, yet studies have not accounted for this possible confound on heart rate. Thus the direct effects of psychological stressors on the cardio-respiratory system are not resolved. We used an innovative experimental design employing accelerometers attached to king penguins (Aptenodytes patagonicus) to measure and thus account for movement levels in a sedentary yet free-to-move animal model during a repeated measures stress experiment. As with previous studies on other species, incubating king penguins (N = 6) exhibited significant increases in both V̇(O2) and heart rate when exposed to the stressor. However, movement levels, while still low, also increased in response to the stressor. Once this was accounted for by comparing periods of time during the control and stress conditions when movement levels were similar as recorded by the accelerometers, only V̇(O2) significantly increased; there was no change in heart rate. These findings offer evidence that changing movement levels have an important effect on the measured stress response and that the cardio-respiratory response per se to a psychological stressor (i.e. the response as a result of physiological changes directly attributable to the stressor) is an increase in V̇(O2) without an increase in heart rate.

  14. Modelling the effects of toxic metal mixtures on the reproduction of Eisenia veneta in different types of soil

    OpenAIRE

    Sdepanian, Stephanie

    2011-01-01

    Previously, toxicity studies have mainly focused on the responses of organisms to single toxicants; however the importance of studying mixtures of toxicants is now being recognised, along with the importance of speciation as a modifier of toxic effect. The aim of this study was to improve our understanding of the toxic response of the compost worm Eisenia veneta to cadmium, copper and zinc by integrating understanding of speciation effects into existing mixture models. Adult earthworm tests w...

  15. Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Jeffrey L Woodhead

    2014-11-01

    Full Text Available Inhibition of the bile salt export pump (BSEP has been linked to incidence of drug-induced liver injury (DILI, presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors

  16. Application of morphological and physiological parameters representative of a sample Brazilian population in the human respiratory tract model

    International Nuclear Information System (INIS)

    Reis, A.A.; Cardoso, J.C.S.; Lourenco, M.C.

    2005-01-01

    Full text: The Human Respiratory Tract Model (HRTM) proposed in ICRP Publication 66 account for the morphology and physiology of the respiratory tract. The characteristics of air drawn into the lungs and exhaled are greatly influenced by the morphology of the respiratory tract, which causes numerous changes in pressure, flow rate, direction and humidity as air moves into and out of the lungs. These changing characteristics can influence the rates and the sites of deposition. Concerning the respiratory physiological parameters the breathing characteristics influence the volume, the inhalation rate of air and the portion that enters through the nose and the mouth. These characteristics are important to determine the fractional deposition. The HRTM model uses morphological and physiological parameters from the Caucasian man to establish deposition fractions in the respiratory tract regions. lt is known that the morphology and physiology are influenced by environmental, occupational and economic conditions. The ICRP recommends for a reliable evaluation of the regional deposition the use of parameters from a local population when information is available. The main purpose of this study is to verify the influence in using the morphology and physiology parameters representative of a sample of the Brazilian population on the deposition model of ICRP Publication 66. The morphological and physiological data were obtained from the literature. The software EXCEL for Windows (version 2000) was used in order to implement the deposition model and also to allow the changes in parameters of interest. Initially, the implemented model was checked using the parameters defined in ICRP and the results of the fraction deposition in the respiratory tract compartments were compared. Finally, morphological and physiological parameters from Brazilian adult male were applied and the fractional deposition calculated. The respiratory values at different levels of activity for ages varying from

  17. Reduction of irregular breathing artifacts in respiration-correlated CT images using a respiratory motion model.

    Science.gov (United States)

    Hertanto, Agung; Zhang, Qinghui; Hu, Yu-Chi; Dzyubak, Oleksandr; Rimner, Andreas; Mageras, Gig S

    2012-06-01

    Respiration-correlated CT (RCCT) images produced with commonly used phase-based sorting of CT slices often exhibit discontinuity artifacts between CT slices, caused by cycle-to-cycle amplitude variations in respiration. Sorting based on the displacement of the respiratory signal yields slices at more consistent respiratory motion states and hence reduces artifacts, but missing image data (gaps) may occur. The authors report on the application of a respiratory motion model to produce an RCCT image set with reduced artifacts and without missing data. Input data consist of CT slices from a cine CT scan acquired while recording respiration by monitoring abdominal displacement. The model-based generation of RCCT images consists of four processing steps: (1) displacement-based sorting of CT slices to form volume images at 10 motion states over the cycle; (2) selection of a reference image without gaps and deformable registration between the reference image and each of the remaining images; (3) generation of the motion model by applying a principal component analysis to establish a relationship between displacement field and respiration signal at each motion state; (4) application of the motion model to deform the reference image into images at the 9 other motion states. Deformable image registration uses a modified fast free-form algorithm that excludes zero-intensity voxels, caused by missing data, from the image similarity term in the minimization function. In each iteration of the minimization, the displacement field in the gap regions is linearly interpolated from nearest neighbor nonzero intensity slices. Evaluation of the model-based RCCT examines three types of image sets: cine scans of a physical phantom programmed to move according to a patient respiratory signal, NURBS-based cardiac torso (NCAT) software phantom, and patient thoracic scans. Comparison in physical motion phantom shows that object distortion caused by variable motion amplitude in phase

  18. [Etiological analysis and establishment of a discriminant model for lower respiratory tract infections in hospitalized patients].

    Science.gov (United States)

    Chen, Y S; Lin, X H; Li, H R; Hua, Z D; Lin, M Q; Huang, W S; Yu, T; Lyu, H Y; Mao, W P; Liang, Y Q; Peng, X R; Chen, S J; Zheng, H; Lian, S Q; Hu, X L; Yao, X Q

    2017-12-12

    Objective: To analyze the pathogens of lower respiratory tract infection(LRTI) including bacterial, viral and mixed infection, and to establish a discriminant model based on clinical features in order to predict the pathogens. Methods: A total of 243 hospitalized patients with lower respiratory tract infections were enrolled in Fujian Provincial Hospital from April 2012 to September 2015. The clinical data and airway (sputum and/or bronchoalveolar lavage) samples were collected. Microbes were identified by traditional culture (for bacteria), loop-mediated isothermal amplification(LAMP) and gene sequencing (for bacteria and atypical pathogen), or Real-time quantitative polymerase chain reaction (Real-time PCR)for viruses. Finally, a discriminant model was established by using the discriminant analysis methods to help to predict bacterial, viral and mixed infections. Results: Pathogens were detected in 53.9% (131/243) of the 243 cases.Bacteria accounted for 23.5%(57/243, of which 17 cases with the virus, 1 case with Mycoplasma pneumoniae and virus), mainly Pseudomonas Aeruginosa and Klebsiella Pneumonia. Atypical pathogens for 4.9% (12/243, of which 3 cases with the virus, 1 case of bacteria and viruses), all were mycoplasma pneumonia. Viruses for 34.6% (84/243, of which 17 cases of bacteria, 3 cases with Mycoplasma pneumoniae, 1 case with Mycoplasma pneumoniae and bacteria) of the cases, mainly Influenza A virus and Human Cytomegalovirus, and other virus like adenovirus, human parainfluenza virus, respiratory syncytial virus, human metapneumovirus, human boca virus were also detected fewly. Seven parameters including mental status, using antibiotics prior to admission, complications, abnormal breath sounds, neutrophil alkaline phosphatase (NAP) score, pneumonia severity index (PSI) score and CRUB-65 score were enrolled after univariate analysis, and discriminant analysis was used to establish the discriminant model by applying the identified pathogens as the

  19. Flipped classroom model improves graduate student performance in cardiovascular, respiratory, and renal physiology.

    Science.gov (United States)

    Tune, Johnathan D; Sturek, Michael; Basile, David P

    2013-12-01

    The purpose of this study was to assess the effectiveness of a traditional lecture-based curriculum versus a modified "flipped classroom" curriculum of cardiovascular, respiratory, and renal physiology delivered to first-year graduate students. Students in both courses were provided the same notes and recorded lectures. Students in the modified flipped classroom were required to watch the prerecorded lectures before class and then attend class, where they received a quiz or homework covering material in each lecture (valued at 25% of the final grade) followed by a question and answer/problem-solving period. In the traditional curriculum, attending lectures was optional and there were no quizzes. Evaluation of effectiveness and student performance was achieved by having students in both courses take the same multiple-choice exams. Within a comparable group of graduate students, participants in the flipped course scored significantly higher (P ≤ 0.05) on the cardiovascular, respiratory, and weighted cumulative sections by an average of >12 percentage points. Exam averages for students in the flipped course also tended to be higher on the renal section by ∼11 percentage points (P = 0.06). Based on our experience and responses obtained in blinded student surveys, we propose that the use of homework and in-class quizzes were critical motivating factors that likely contributed to the increase in student exam performance. Taken together, our findings support that the flipped classroom model is a highly effective means in which to disseminate key physiological concepts to graduate students.

  20. Toxicity of chlortetracycline and its metal complexes to model microorganisms in wastewater sludge.

    Science.gov (United States)

    Pulicharla, Rama; Das, Ratul Kumar; Brar, Satinder Kaur; Drogui, Patrick; Sarma, Saurabh Jyoti; Verma, Mausam; Surampalli, Rao Y; Valero, Jose R

    2015-11-01

    Complexation of antibiotics with metals is a well-known phenomenon. Wastewater treatment plants contain metals and antibiotics, thus it is essential to know the effect of these complexes on toxicity towards microorganisms, typically present in secondary treatment processes. In this study, stability constants and toxicity of chlortetracycline (CTC) and metal (Ca, Mg, Cu and Cr) complexes were investigated. The calculated stability constants of CTC-metal complexes followed the order: Mg-CTC>Ca-CTC>Cu-CTC>Cr-CTC. Gram positive Bacillus thuringiensis (Bt) and Gram negative Enterobacter aerogenes (Ea) bacteria were used as model microorganisms to evaluate the toxicity of CTC and its metal complexes. CTC-metal complexes were more toxic than the CTC itself for Bt whereas for Ea, CTC and its metal complexes showed similar toxicity. In contrast, CTC spiked wastewater sludge (WWS) did not show any toxic effect compared to synthetic sewage. This study provides evidence that CTC and its metal complexes are toxic to bacteria when they are biologically available. As for WWS, CTC was adsorbed to solid part and was not biologically available to show measurable toxic effects. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Application of morphological and physiological parameters representative of a Brazilian population sample in the respiratory tract model

    International Nuclear Information System (INIS)

    Dos Reis, A. A.; Cardoso, J. C. S.; Lourenco, M. C.

    2007-01-01

    The human respiratory tract model (HRTM) adopted by ICRP in its Publication 66 accounts for the morphology and physiology of the respiratory tract. The characteristics of air drawn into the lungs and exhaled are greatly influenced by the morphology of the respiratory tract, which causes numerous changes in pressure, flow rate, direction and humidity as air moves into and out of the lungs. These characteristics are important to determine the fractional deposition. It is known that the morphology and physiology are influenced by environmental, occupational and economic conditions. The ICRP recommends, for a reliable evaluation of the regional deposition, the use of parameters from a local population wherever such information is available. The main purpose of this study is to verify the influence of using the morphology and physiology parameters representative of a sample of the Brazilian population on the deposition model of the ICRP Publication 66 model. (authors)

  2. Within-breath arterial PO2 oscillations in an experimental model of acute respiratory distress syndrome.

    Science.gov (United States)

    Williams, E M; Viale, J P; Hamilton, R M; McPeak, H; Sutton, L; Hahn, C E

    2000-09-01

    Tidal ventilation causes within-breath oscillations in alveolar oxygen concentration, with an amplitude which depends on the prevailing ventilator settings. These alveolar oxygen oscillations are transmitted to arterial oxygen tension, PaO2, but with an amplitude which now depends upon the magnitude of venous admixture or true shunt, QS/QT. We investigated the effect of positive end-expiratory pressure (PEEP) on the amplitude of the PaO2 oscillations, using an atelectasis model of shunt. Blood PaO2 was measured on-line with an intravascular PaO2 sensor, which had a 2-4 s response time (10-90%). The magnitude of the time-varying PaO2 oscillation was titrated against applied PEEP while tidal volume, respiratory rate and inspired oxygen concentration were kept constant. The amplitude of the PaO2 oscillation, delta PaO2, and the mean PaO2 value varied with the level of PEEP applied. At zero PEEP, both the amplitude and the mean were at their lowest values. As PEEP was increased to 1.5 kPa, both delta PaO2 and the mean PaO2 increased to a maximum. Thereafter, the mean PaO2 increased but delta PaO2 decreased. Clear oscillations of PaO2 were seen even at the lowest mean PaO2, 9.5 kPa. Conventional respiratory models of venous admixture predict that these PaO2 oscillations will be reduced by the steep part of the oxyhaemoglobin dissociation curve if a constant pulmonary shunt exists throughout the whole respiratory cycle. The facts that the PaO2 oscillations occurred at all mean PaO2 values and that their amplitude increased with increasing PEEP suggest that QS/QT, in the atelectasis model, varies between end-expiration and end-inspiration, having a much lower value during inspiration than during expiration.

  3. 20180311 - Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development (SOT)

    Science.gov (United States)

    Alternative models developed for estimating acute systemic toxicity are generally evaluated using in vivo LD50 values. However, in vivo acute systemic toxicity studies can produce variable results, even when conducted according to accepted test guidelines. This variability can ma...

  4. Estimating the Potential Toxicity of Chemicals Associated with Hydraulic Fracturing Operations Using Quantitative Structure-Activity Relationship Modeling

    Science.gov (United States)

    Researchers facilitated evaluation of chemicals that lack chronic oral toxicity values using a QSAR model to develop estimates of potential toxicity for chemicals used in HF fluids or found in flowback or produced water

  5. Model-based setting of inspiratory pressure and respiratory rate in pressure-controlled ventilation

    International Nuclear Information System (INIS)

    Schranz, C; Möller, K; Becher, T; Schädler, D; Weiler, N

    2014-01-01

    Mechanical ventilation carries the risk of ventilator-induced-lung-injury (VILI). To minimize the risk of VILI, ventilator settings should be adapted to the individual patient properties. Mathematical models of respiratory mechanics are able to capture the individual physiological condition and can be used to derive personalized ventilator settings. This paper presents model-based calculations of inspiration pressure (p I ), inspiration and expiration time (t I , t E ) in pressure-controlled ventilation (PCV) and a retrospective evaluation of its results in a group of mechanically ventilated patients. Incorporating the identified first order model of respiratory mechanics in the basic equation of alveolar ventilation yielded a nonlinear relation between ventilation parameters during PCV. Given this patient-specific relation, optimized settings in terms of minimal p I and adequate t E can be obtained. We then retrospectively analyzed data from 16 ICU patients with mixed pathologies, whose ventilation had been previously optimized by ICU physicians with the goal of minimization of inspiration pressure, and compared the algorithm's ‘optimized’ settings to the settings that had been chosen by the physicians. The presented algorithm visualizes the patient-specific relations between inspiration pressure and inspiration time. The algorithm's calculated results highly correlate to the physician's ventilation settings with r = 0.975 for the inspiration pressure, and r = 0.902 for the inspiration time. The nonlinear patient-specific relations of ventilation parameters become transparent and support the determination of individualized ventilator settings according to therapeutic goals. Thus, the algorithm is feasible for a variety of ventilated ICU patients and has the potential of improving lung-protective ventilation by minimizing inspiratory pressures and by helping to avoid the build-up of clinically significant intrinsic positive end

  6. Online model checking for monitoring surrogate-based respiratory motion tracking in radiation therapy.

    Science.gov (United States)

    Antoni, Sven-Thomas; Rinast, Jonas; Ma, Xintao; Schupp, Sibylle; Schlaefer, Alexander

    2016-11-01

    Correlation between internal and external motion is critical for respiratory motion compensation in radiosurgery. Artifacts like coughing, sneezing or yawning or changes in the breathing pattern can lead to misalignment between beam and tumor and need to be detected to interrupt the treatment. We propose online model checking (OMC), a model-based verification approach from the field of formal methods, to verify that the breathing motion is regular and the correlation holds. We demonstrate that OMC may be more suitable for artifact detection than the prediction error. We established a sinusoidal model to apply OMC to the verification of respiratory motion. The method was parameterized to detect deviations from typical breathing motion. We analyzed the performance on synthetic data and on clinical episodes showing large correlation error. In comparison, we considered the prediction error of different state-of-the-art methods based on least mean squares (LMS; normalized LMS, nLMS; wavelet-based multiscale autoregression, wLMS), recursive least squares (RLSpred) and support vector regression (SVRpred). On synthetic data, OMC outperformed wLMS by at least 30 % and SVRpred by at least 141 %, detecting 70 % of transitions. No artifacts were detected by nLMS and RLSpred. On patient data, OMC detected 23-49 % of the episodes correctly, outperforming nLMS, wLMS, RLSpred and SVRpred by up to 544, 491, 408 and 258 %, respectively. On selected episodes, OMC detected up to 94 % of all events. OMC is able to detect changes in breathing as well as artifacts which previously would have gone undetected, outperforming prediction error-based detection. Synthetic data analysis supports the assumption that prediction is very insensitive to specific changes in breathing. We suggest using OMC as an additional safety measure ensuring reliable and fast stopping of irradiation.

  7. Coupled and reduced dimensional modeling of respiratory mechanics during spontaneous breathing.

    Science.gov (United States)

    Ismail, M; Comerford, A; Wall, W A

    2013-11-01

    In this paper, we develop a total lung model based on a tree of 0D airway and acinar models for studying respiratory mechanics during spontaneous breathing. This model utilizes both computer tomography-based geometries and artificially generated lobe-filling airway trees to model the entire conducting region of the lung. Beyond the conducting airways, we develop an acinar model, which takes into account the alveolar tissue resistance, compliance, and the intrapleural pressure. With this methodology, we compare four different 0D models of airway mechanics and determine the best model based on a comparison with a 3D-0D coupled model of the conducting airways; this methodology is possible because the majority of airway resistance is confined to the lower generations, that is, the trachea and the first few bronchial generations. As an example application of the model, we simulate the flow and pressure dynamics under spontaneous breathing conditions, that is, at flow conditions driven purely by pleural space pressure. The results show good agreement, both qualitatively and quantitatively, with reported physiological values. One of the key advantages of this model is the ability to provide insight into lung ventilation in the peripheral regions. This is often crucial because this is where information, specifically for studying diseases and gas exchange, is needed. Thus, the model can be used as a tool for better understanding local peripheral lung mechanics without excluding the upper portions of the lung. This tool will be also useful for in vitro investigations of lung mechanics in both health and disease. Copyright © 2013 John Wiley & Sons, Ltd.

  8. Per- and polyfluoro toxicity (LC(50) inhalation) study in rat and mouse using QSAR modeling.

    Science.gov (United States)

    Bhhatarai, Barun; Gramatica, Paola

    2010-03-15

    Fully or partially fluorinated compounds, known as per- and polyfluorinated chemicals are widely distributed in the environment and released because of their use in different household and industrial products. Few of these long chain per- and polyfluorinated chemicals are classified as emerging pollutants, and their environmental and toxicological effects are unveiled in the literature. This has diverted the production of long chain compounds, considered as more toxic, to short chains, but concerns regarding the toxicity of both types of per- and polyfluorinated chemicals are alarming. There are few experimental data available on the environmental behavior and toxicity of these compounds, and moreover, toxicity profiles are found to be different for the types of animals and species used. Quantitative structure-activity relationship (QSAR) is applied to a combination of short and long chain per- and polyfluorinated chemicals, for the first time, to model and predict the toxicity on two species of rodents, rat (Rattus) and mouse (Mus), by modeling inhalation (LC(50)) data. Multiple linear regression (MLR) models using the ordinary-least-squares (OLS) method, based on theoretical molecular descriptors selected by genetic algorithm (GA), were used for QSAR studies. Training and prediction sets were prepared a priori, and these sets were used to derive statistically robust and predictive (both internally and externally) models. The structural applicability domain (AD) of the model was verified on a larger set of per- and polyfluorinated chemicals retrieved from different databases and journals. The descriptors involved, the similarities, and the differences observed between models pertaining to the toxicity related to the two species are discussed. Chemometric methods such as principal component analysis (PCA) and multidimensional scaling (MDS) were used to select most toxic compounds from those within the AD of both models, which will be subjected to experimental tests

  9. An optimized in vitro model of the respiratory tract wall to study particle cell interactions.

    Science.gov (United States)

    Blank, Fabian; Rothen-Rutishauser, Barbara M; Schurch, Samuel; Gehr, Peter

    2006-01-01

    As a part of the respiratory tissue barrier, lung epithelial cells play an important role against the penetration of the body by inhaled particulate foreign materials. In most cell culture models, which are designed to study particle-cell interactions, the cells are immersed in medium. This does not reflect the physiological condition of lung epithelial cells which are exposed to air, separated from it only by a very thin liquid lining layer with a surfactant film at the air-liquid interface. In this study, A549 epithelial cells were grown on microporous membranes in a two chamber system. After the formation of a confluent monolayer the cells were exposed to air. The morphology of the cells and the expression of tight junction proteins were studied with confocal laser scanning and transmission electron microscopy. Air-exposed cells maintained monolayer structure for 2 days, expressed tight junctions and developed transepithelial electrical resistance. Surfactant was produced and released at the apical side of the air-exposed epithelial cells. In order to study particle-cell interactions fluorescent 1 microm polystyrene particles were sprayed over the epithelial surface. After 4 h, 8.8% of particles were found inside the epithelium. This fraction increased to 38% after 24 h. During all observations, particles were always found in the cells but never between them. In this study, we present an in vitro model of the respiratory tract wall consisting of air-exposed lung epithelial cells covered by a liquid lining layer with a surfactant film to study particle-cell interactions.

  10. Probing the toxicity of nanoparticles: a unified in silico machine learning model based on perturbation theory.

    Science.gov (United States)

    Concu, Riccardo; Kleandrova, Valeria V; Speck-Planche, Alejandro; Cordeiro, M Natália D S

    2017-09-01

    Nanoparticles (NPs) are part of our daily life, having a wide range of applications in engineering, physics, chemistry, and biomedicine. However, there are serious concerns regarding the harmful effects that NPs can cause to the different biological systems and their ecosystems. Toxicity testing is an essential step for assessing the potential risks of the NPs, but the experimental assays are often very expensive and usually too slow to flag the number of NPs that may cause adverse effects. In silico models centered on quantitative structure-activity/toxicity relationships (QSAR/QSTR) are alternative tools that have become valuable supports to risk assessment, rationalizing the search for safer NPs. In this work, we develop a unified QSTR-perturbation model based on artificial neural networks, aimed at simultaneously predicting general toxicity profiles of NPs under diverse experimental conditions. The model is derived from 54,371 NP-NP pair cases generated by applying the perturbation theory to a set of 260 unique NPs, and showed an accuracy higher than 97% in both training and validation sets. Physicochemical interpretation of the different descriptors in the model are additionally provided. The QSTR-perturbation model is then employed to predict the toxic effects of several NPs not included in the original dataset. The theoretical results obtained for this independent set are strongly consistent with the experimental evidence found in the literature, suggesting that the present QSTR-perturbation model can be viewed as a promising and reliable computational tool for probing the toxicity of NPs.

  11. Are Free Ion Activity Models Sufficient Alternatives to Biotic Ligand Models in Evaluating Metal Toxic Impacts in Terrestrial Environments?

    DEFF Research Database (Denmark)

    Owsianiak, Mikolaj; Rosenbaum, Ralph K.; Larsen, Henrik Fred

    Metal partitioning between solid and aqueous phases and speciation in soil pore water control the bioavailability of toxic forms of metals, while protons and base cations can mitigate metal ecotoxicity by competitive interactions with biotic ligands. e employment of BLMs to evaluate toxicity...... potential of metals in soils results in site-specic toxicity scores due to large variability of soil properties and dierences in ionic composition. Unfortunately, terrestrial BMLs are available only for few metals and few organisms, thus their applicability to hazard ranking or toxic impact assessment...... is low and alternatives must be found. In this study, we compared published terrestrial BLMs and their potential alternatives such as free ion activity models (FIAM), for applicability in addressing metal toxic impacts in terrestrial environments. A set of 1300 soils representative for the whole world...

  12. Ecotoxicity interspecies QAAR models from Daphnia toxicity of pharmaceuticals and personal care products.

    Science.gov (United States)

    Sangion, A; Gramatica, P

    2016-10-01

    Pharmaceutical and Personal Care Products (PPCPs) became a class of contaminants of emerging concern because are ubiquitously detected in surface water and soil, where they can affect wildlife. Ecotoxicological data are only available for a few PPCPs, thus modelling approaches are essential tools to maximize the information contained in the existing data. In silico methods may be helpful in filling data gaps for the toxicity of PPCPs towards various ecological indicator organisms. The good correlation between toxicity toward Daphnia magna and those on two fish species (Pimephales promelas and Oncorhynchus mykiss), improved by the addition of one theoretical molecular descriptor, allowed us to develop predictive models to investigate the relationship between toxicities in different species. The aim of this work is to propose quantitative activity-activity relationship (QAAR) models, developed in QSARINS and validated for their external predictivity. Such models can be used to predict the toxicity of PPCPs to a particular species using available experimental toxicity data from a different species, thus reducing the tests on organisms of higher trophic level. Similarly, good QAAR models, implemented by molecular descriptors to improve the quality, are proposed here for fish interspecies. We also comment on the relevance of autocorrelation descriptors in improving all studied interspecies correlations.

  13. Toxicоlogical evaluation of the plant products using Brine Shrimp (Artemia salina L. model

    Directory of Open Access Journals (Sweden)

    Меntor R. Hamidi

    2014-04-01

    Full Text Available Many natural products could serve as the starting point in the development of modern medicines because of their numerous biological and pharmacological activities. However, some of them are known to carry toxicological properties as well. In order to achieve a safe treatment with plant products, numerous research studies have recently been focused on both pharmacology and toxicity of medicinal plants. Moreover, these studies employed efforts for alternative biological assays. Brine Shrimp Lethality Assay is the most convenient system for monitoring biological activities of various plant species. This method is very useful for preliminary assessment of toxicity of the plant extracts. Rapidness, simplicity and low requirements are several advantages of this assay. However, several conditions need to be completed, especially in the means of standardized experimental conditions (temperature, pH of the medium, salinity, aeration and light. The toxicity of herbal extracts using this assay has been determined in a concentration range of 10, 100 and 1000 µg/ml of the examined herbal extract. Most toxicity studies which use the Brine Shrimp Lethality Assay determine the toxicity after 24 hours of exposure to the tested sample. The median lethal concentration (LC50 of the test samples is obtained by a plot of percentage of the dead shrimps against the logarithm of the sample concentration. LC50 values are estimated using a probit regression analysis and compared with either Meyer’s or Clarkson’s toxicity criteria. Furthermore, the positive correlation between Meyer’s toxicity scale for Artemia salina and Gosselin, Smith and Hodge’s toxicity scale for higher animal models confirmed that the Brine Shrimp Lethality Assay is an excellent predictive tool for the toxic potential of plant extracts in humans.

  14. A Randomized Placebo Controlled Trial of Ibuprofen for Respiratory Syncytial Virus Infection in a Bovine Model

    Science.gov (United States)

    Walsh, Paul; Behrens, Nicole; Carvallo Chaigneau, Francisco R.; McEligot, Heather; Agrawal, Karan; Newman, John W.; Anderson, Mark; Gershwin, Laurel J.

    2016-01-01

    Background Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to the virus. RSV is accompanied by elevated prostaglandin E2 (PGE2) which is followed by neutrophil led inflammation in the lung. Ibuprofen is a prototypical non-steroidal anti-inflammatory drug that decreases PGE2 levels by inhibiting cyclooxygenase. Hypotheses We hypothesized that treatment of RSV with ibuprofen would decrease PGE2 levels, modulate the immune response, decrease clinical illness, and decrease the histopathological lung changes in a bovine model of RSV. We further hypothesized that viral replication would be unaffected. Methods We performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, cyclooxygenase, lipoxygenase and endocannabinoid products in plasma and mediastinal lymph nodes and interleukin (Il)-4, Il-13, Il-17 and interferon-γ in mediastinal lymph nodes. RSV shedding was measured daily and nasal Il-6, Il-8 and Il-17 every other day. The calves were necropsied on Day 10 post inoculation and histology performed. Results One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Clinical scores (pibuprofen group. Ibuprofen decreased cyclooxygenase, lipoxygenase, and cytochrome P450 products, and increased monoacylglycerols in lung lymph nodes. Ibuprofen modulated the immune response as measured by narrowed range of observed Il-13, Il-17 and IFN-γ gene expression in mediastinal lymph nodes. Lung histology was not different between groups, and viral shedding was increased in calves randomized to ibuprofen. Conclusions Ibuprofen decreased PGE2, modulated the immune response, and improved clinical outcomes. However lung

  15. Use of the caco-2 model in the screening of polluting substance toxicity.

    Science.gov (United States)

    Velarde, G; Ait-Aissa, S; Gillet, C; Rogerieux, F; Lambre, C; Vindimian, E; Porcher, J M

    1999-01-01

    The aim of this work was to investigate the oral toxicity of representative chemicals chosen from each class of the list of 132 substances present in industrial effluents after the EEC Directive 76-464. Owing to its characterization as a model of the intestinal epithelium, the CaCo-2 cell line model was chosen. Cytotoxicity was assayed using the tetrazolium blue (MTT) test. For most of the substances, a linear correlation was observed between the octanol/water partition coefficient (log Kw) and the median inhibition concentration (IC(50)). This relationship between lipophilicity and toxicity is the hallmark of a narcotic mechanism of action. However, diethylamine appeared more toxic than the correlation would predict. Other amines were then tested (tert-butylamine, n-butylamine and benzylamine). All of these did not fit into the baseline correlation. The IC(50) were corrected by taking into account only the non-ionized, lipid insoluble, concentration at pH7.3. The amines still did not fit into the correlation, reinforcing the idea of a non-narcotic mechanism. The toxicity of a large number of substances can thus be predicted from their physico-chemical properties only when the substances exert a direct and non-specific effect. The amines appeared more toxic than substances with the same partition coefficient, showing that knowledge of the only lipophilicity is too restrictive to predict toxicity.

  16. Toxicity data for modeling impacts of oil components in an Arctic ecosystem

    NARCIS (Netherlands)

    Olsen, G.H.; Klok, C.; Hendriks, A.J.; Geraudie, P.; Hoop, de L.

    2013-01-01

    Ecological impact assessment modeling systems are valuable support tools for managing impacts from commercial activities on marine habitats and species. The inclusion of toxic effects modeling in these systems is predicated on the availability and quality of ecotoxicology data. Here we report on a

  17. Kinetic models for detection of toxicity in a microbial fuel cell based biosensor

    NARCIS (Netherlands)

    Stein, N.E.; Keesman, K.J.; Hamelers, H.V.M.; Straten, van G.

    2011-01-01

    Currently available models describing microbial fuel cell (MFC) polarization curves, do not describe the effect of the presence of toxic components. A bioelectrochemical model combined with enzyme inhibition kinetics, that describes the polarization curve of an MFC-based biosensor, was modified to

  18. GLOBOX : A spatially differentiated global fate, intake and effect model for toxicity assessment in LCA

    NARCIS (Netherlands)

    Wegener Sleeswijk, Anneke; Heijungs, Reinout

    GLOBOX is a model for the calculation of spatially differentiated LCA toxicity characterisation factors on a global scale. It can also be used for human and environmental risk assessment. The GLOBOX model contains equations for the calculation of fate, intake and effect factors, and equations for

  19. Predicting copper toxicity to different earthworm species using a multicomponent Freundlich model.

    Science.gov (United States)

    Qiu, Hao; Vijver, Martina G; He, Erkai; Peijnenburg, Willie J G M

    2013-05-07

    This study aimed to develop bioavailability models for predicting Cu toxicity to earthworms (Lumbricus rubellus, Aporrectodea longa, and Eisenia fetida) in a range of soils of varying properties. A multicomponent Freundlich model, complying with the basic assumption of the biotic ligands model, was used to relate Cu toxicity to the free Cu(2+) activity and possible protective cations in soil porewater. Median lethal concentrations (LC50s) of Cu based on the total Cu concentration varied in each species from soil to soil, reaching differences of approximately a factor 9 in L. rubellus, 49 in A. longa and 45 in E. fetida. The relative sensitivity of the earthworms to Cu in different soils followed the same order: L. rubellus > A. longa > E. fetida. Only pH not other cations (K(+), Ca(2+), Na(+), and Mg(2+)) were found to exert significant protective effects against Cu toxicity to earthworms. The Freundlich-type model in which the protective effects of pH were included, explained 84%, 94%, and 96% of variations in LC50s of Cu (expressed as free ion activity) for L. rubellus, A. longa, and E. fetida, respectively. Predicted LC50s never differed by a factor of more than 2 from the observed LC50s. External validation of the model showed a similar level of precision, even though toxicity data for other soil organisms and for different endpoints were used. The findings of the present study showed the possibility of extrapolating the developed toxicity models for one earthworm species to another species. Moreover, the Freundlich-type model in which the free Cu(2+) activity and pH in soil porewater are considered can even be used to predict toxicity for other soil invertebrates and plants.

  20. Inhibition of galactosamine cytotoxicity in an in vivo/in vitro hepatocellular toxicity model

    International Nuclear Information System (INIS)

    MacDonald, J.R.; Thayer, K.J.; White, C.

    1987-01-01

    A combined in vivo/in vitro model of galactosamine hepatotoxicity was employed to test whether previously reported cytoprotective actions of cystamine administration on galactosamine-induced hepatic injury in vivo could be attributed to a direct action of cystamine on toxicant-challenged hepatocytes. In this model, male Sprague-Dawley rats received a 400 mg/kg galactosamine challenge via intraperitoneal injection 1 hr prior to portal vein cannulation for hepatocyte isolation. Isolated cells are established in monolayer culture and galactosamine-induced cellular injury is then expressed over the ensuing 24-48 hr in culture. Consistent with the biochemical basis of galactosamine-induced hepatocellular injury in vivo, cytotoxicity could be prevented by in vitro uridine treatments within 3 hr of the in vivo galactosamine challenge, but not when added 12 hr later. Cystamine, in contrast, exhibited a cytoprotective effect even when added to cultures 12 hr after the in vivo toxicant challenge. Post-toxicant cytoprotection by cystamine in vitro was concentration dependent and did not produce an alteration of hepatocyte nonprotein sulfhydryl content. Post-toxicant cytoprotection by uridine and cystamine in this in vivo/in vitro model of toxicity were fully consistent with in vivo protection from galactosamine-induced necrosis by these agents. This model eliminates potential extrahepatic mechanisms for cystamine's hepatoprotective effect and demonstrates a direct cytoprotective action on galactosamine-challenged hepatocytes

  1. Modeling Associations between Principals' Reported Indoor Environmental Quality and Students' Self-Reported Respiratory Health Outcomes Using GLMM and ZIP Models.

    Science.gov (United States)

    Toyinbo, Oluyemi; Matilainen, Markus; Turunen, Mari; Putus, Tuula; Shaughnessy, Richard; Haverinen-Shaughnessy, Ulla

    2016-03-30

    The aim of this paper was to examine associations between school building characteristics, indoor environmental quality (IEQ), and health responses using questionnaire data from both school principals and students. From 334 randomly sampled schools, 4248 sixth grade students from 297 schools participated in a questionnaire. From these schools, 134 principals returned questionnaires concerning 51 IEQ related questions of their school. Generalized linear mixed models (GLMM) were used to study the associations between IEQ indicators and existence of self-reported upper respiratory symptoms, while hierarchical Zero Inflated Poisson (ZIP)-models were used to model the number of symptoms. Significant associations were established between existence of upper respiratory symptoms and unsatisfactory classroom temperature during the heating season (ORs 1.45 for too hot and cold, and 1.27 for too cold as compared to satisfactory temperature) and dampness or moisture damage during the year 2006-2007 (OR: 1.80 as compared to no moisture damage), respectively. The number of upper respiratory symptoms was significantly associated with inadequate ventilation and dampness or moisture damage. A higher number of missed school days due to respiratory infections were reported in schools with inadequate ventilation (RR: 1.16). The school level IEQ indicator variables described in this paper could explain a relatively large part of the school level variation observed in the self-reported upper respiratory symptoms and missed school days due to respiratory infections among students.

  2. Pediatric Specialty Care Model for Management of Chronic Respiratory Failure: Cost and Savings Implications and Misalignment With Payment Models.

    Science.gov (United States)

    Graham, Robert J; McManus, Michael L; Rodday, Angie Mae; Weidner, Ruth Ann; Parsons, Susan K

    2018-02-03

    To describe program design, costs, and savings implications of a critical care-based care coordination model for medically complex children with chronic respiratory failure. All program activities and resultant clinical outcomes were tracked over 4 years using an adapted version of the Care Coordination Measurement Tool. Patient characteristics, program activity, and acute care resource utilization were prospectively documented in the adapted version of the Care Coordination Measurement Tool and retrospectively cross-validated with hospital billing data. Impact on total costs of care was then estimated based on program outcomes and nationally representative administrative data. Tertiary children's hospital. Critical Care, Anesthesia, Perioperative Extension and Home Ventilation Program enrollees. None. The program provided care for 346 patients and families over the study period. Median age at enrollment was 6 years with more than half deriving secondary respiratory failure from a primary neuromuscular disease. There were 11,960 encounters over the study period, including 1,202 home visits, 673 clinic visits, and 4,970 telephone or telemedicine encounters. Half (n = 5,853) of all encounters involved a physician and 45% included at least one care coordination activity. Overall, we estimated that program interventions were responsible for averting 556 emergency department visits and 107 hospitalizations. Conservative monetization of these alone accounted for annual savings of $1.2-2 million or $407/pt/mo net of program costs. Innovative models, such as extension of critical care services, for high-risk, high-cost patients can result in immediate cost savings. Evaluation of financial implications of comprehensive care for high-risk patients is necessary to complement clinical and patient-centered outcomes for alternative care models. When year-to-year cost variability is high and cost persistence is low, these savings can be estimated from documentation within care

  3. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model -

    Directory of Open Access Journals (Sweden)

    Himanshu R Gupta

    2016-12-01

    exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

  4. Automated workflows for modelling chemical fate, kinetics and toxicity.

    Science.gov (United States)

    Sala Benito, J V; Paini, Alicia; Richarz, Andrea-Nicole; Meinl, Thorsten; Berthold, Michael R; Cronin, Mark T D; Worth, Andrew P

    2017-12-01

    Automation is universal in today's society, from operating equipment such as machinery, in factory processes, to self-parking automobile systems. While these examples show the efficiency and effectiveness of automated mechanical processes, automated procedures that support the chemical risk assessment process are still in their infancy. Future human safety assessments will rely increasingly on the use of automated models, such as physiologically based kinetic (PBK) and dynamic models and the virtual cell based assay (VCBA). These biologically-based models will be coupled with chemistry-based prediction models that also automate the generation of key input parameters such as physicochemical properties. The development of automated software tools is an important step in harmonising and expediting the chemical safety assessment process. In this study, we illustrate how the KNIME Analytics Platform can be used to provide a user-friendly graphical interface for these biokinetic models, such as PBK models and VCBA, which simulates the fate of chemicals in vivo within the body and in vitro test systems respectively. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Probabilistic ecological risk assessment of effluent toxicity of a wastewater reclamation plant based on process modeling.

    Science.gov (United States)

    Zeng, Siyu; Huang, Yunqing; Sun, Fu; Li, Dan; He, Miao

    2016-09-01

    The growing use of reclaimed wastewater for environmental purposes such as stream flow augmentation requires comprehensive ecological risk assessment and management. This study applied a system analysis approach, regarding a wastewater reclamation plant (WRP) and its recipient water body as a whole system, and assessed the ecological risk of the recipient water body caused by the WRP effluent. Instead of specific contaminants, two toxicity indicators, i.e. genotoxicity and estrogenicity, were selected to directly measure the biological effects of all bio-available contaminants in the reclaimed wastewater, as well as characterize the ecological risk of the recipient water. A series of physically based models were developed to simulate the toxicity indicators in a WRP through a typical reclamation process, including ultrafiltration, ozonation, and chlorination. After being validated against the field monitoring data from a full-scale WRP in Beijing, the models were applied to simulate the probability distribution of effluent toxicity of the WRP through Latin Hypercube Sampling to account for the variability of influent toxicity and operation conditions. The simulated effluent toxicity was then used to derive the predicted environmental concentration (PEC) in the recipient stream, considering the variations of the toxicity and flow of the upstream inflow as well. The ratio of the PEC of each toxicity indicator to its corresponding predicted no-effect concentration was finally used for the probabilistic ecological risk assessment. Regional sensitivity analysis was also performed with the developed models to identify the critical control variables and strategies for ecological risk management. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Oral LD50 toxicity modeling and prediction of per- and polyfluorinated chemicals on rat and mouse.

    Science.gov (United States)

    Bhhatarai, Barun; Gramatica, Paola

    2011-05-01

    Quantitative structure-activity relationship (QSAR) analyses were performed using the LD(50) oral toxicity data of per- and polyfluorinated chemicals (PFCs) on rodents: rat and mouse. PFCs are studied under the EU project CADASTER which uses the available experimental data for prediction and prioritization of toxic chemicals for risk assessment by using the in silico tools. The methodology presented here applies chemometrical analysis on the existing experimental data and predicts the toxicity of new compounds. QSAR analyses were performed on the available 58 mouse and 50 rat LD(50) oral data using multiple linear regression (MLR) based on theoretical molecular descriptors selected by genetic algorithm (GA). Training and prediction sets were prepared a priori from available experimental datasets in terms of structure and response. These sets were used to derive statistically robust and predictive (both internally and externally) models. The structural applicability domain (AD) of the models were verified on 376 per- and polyfluorinated chemicals including those in REACH preregistration list. The rat and mouse endpoints were predicted by each model for the studied compounds, and finally 30 compounds, all perfluorinated, were prioritized as most important for experimental toxicity analysis under the project. In addition, cumulative study on compounds within the AD of all four models, including two earlier published models on LC(50) rodent analysis was studied and the cumulative toxicity trend was observed using principal component analysis (PCA). The similarities and the differences observed in terms of descriptors and chemical/mechanistic meaning encoded by descriptors to prioritize the most toxic compounds are highlighted.

  7. A zebrafish model for uremic toxicity: role of the complement pathway.

    Science.gov (United States)

    Berman, Nathaniel; Lectura, Melisa; Thurman, Josh; Reinecke, James; Raff, Amanda C; Melamed, Michal L; Reinecke, James; Quan, Zhe; Evans, Todd; Meyer, Timothy W; Hostetter, Thomas H

    2013-01-01

    Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p 50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement. Copyright © 2013 S. Karger AG, Basel.

  8. A hypothetical model for predicting the toxicity of high aspect ratio nanoparticles (HARN)

    Science.gov (United States)

    Tran, C. L.; Tantra, R.; Donaldson, K.; Stone, V.; Hankin, S. M.; Ross, B.; Aitken, R. J.; Jones, A. D.

    2011-12-01

    The ability to predict nanoparticle (dimensional structures which are less than 100 nm in size) toxicity through the use of a suitable model is an important goal if nanoparticles are to be regulated in terms of exposures and toxicological effects. Recently, a model to predict toxicity of nanoparticles with high aspect ratio has been put forward by a consortium of scientists. The High aspect ratio nanoparticles (HARN) model is a platform that relates the physical dimensions of HARN (specifically length and diameter ratio) and biopersistence to their toxicity in biological environments. Potentially, this model is of great public health and economic importance, as it can be used as a tool to not only predict toxicological activity but can be used to classify the toxicity of various fibrous nanoparticles, without the need to carry out time-consuming and expensive toxicology studies. However, this model of toxicity is currently hypothetical in nature and is based solely on drawing similarities in its dimensional geometry with that of asbestos and synthetic vitreous fibres. The aim of this review is two-fold: (a) to present findings from past literature, on the physicochemical property and pathogenicity bioassay testing of HARN (b) to identify some of the challenges and future research steps crucial before the HARN model can be accepted as a predictive model. By presenting what has been done, we are able to identify scientific challenges and research directions that are needed for the HARN model to gain public acceptance. Our recommendations for future research includes the need to: (a) accurately link physicochemical data with corresponding pathogenicity assay data, through the use of suitable reference standards and standardised protocols, (b) develop better tools/techniques for physicochemical characterisation, (c) to develop better ways of monitoring HARN in the workplace, (d) to reliably measure dose exposure levels, in order to support future epidemiological

  9. A Novel Large Animal Model of Acute Respiratory Distress Syndrome Induced by Mitochondrial Products.

    Science.gov (United States)

    Sanchez, Pablo G; Pasrija, Chetan; Mulligan, Matthew J; Wadhwa, Mandheer; Pratt, Diana L; Li, Tieluo; Gammie, James S; Kon, Zachary N; Pham, Si M; Griffith, Bartley P

    2017-12-01

    We aimed to create a reproducible lung injury model utilizing injection of mitochondrial damage-associated molecular products. Our goal was to characterize the pathophysiologic response to damage-associated molecular pattern mediated organ injury. There remain significant gaps in our understanding of acute respiratory distress syndrome, in part due to the lack of clinically applicable animal models of this disease. Animal models of noninfectious, tissue damage-induced lung injury are needed to understand the signals and responses associated with this injury. Ten pigs (35-45 kg) received an intravenous dose of disrupted mitochondrial products and were followed for 6 hours under general anesthesia. These animals were compared to a control group (n = 5) and a model of lung injury induced by bacterial products (lipopolysaccharide n = 5). Heart rate and temperature were significantly elevated in the mitochondrial product (204 ± 12 and 41 ± 1) and lipopolysaccharide groups (178 ± 18 and 42 ± 0.5) compared with controls (100 ± 13 and 38 ± 0.5) (P products and lipopolysaccharide groups compared with controls (170 ± 39, 196 ± 27, and 564 ± 75 mm Hg respectively, P = 0.001). Lung injury scoring of histological sections was significantly worse in mitochondrial and lipopolysaccharide groups compared with controls (mitochondrial-64 ± 6, lipopolysaccharide-54 ± 8, control-14 ± 1.5, P= 0.002). Our data demonstrated that the presence of mitochondrial products in the circulation leads to systemic inflammatory response and lung injury. In its acute phase lung injury induced by tissue or bacterial products is clinically indistinguishable.

  10. A Novel Respiratory Motion Perturbation Model Adaptable to Patient Breathing Irregularities

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Amy [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Wei, Jie [Department of Computer Science, City College of New York, New York, New York (United States); Gaebler, Carl P.; Huang, Hailiang; Olek, Devin [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Li, Guang, E-mail: lig2@mskcc.org [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York (United States)

    2016-12-01

    Purpose: To develop a physical, adaptive motion perturbation model to predict tumor motion using feedback from dynamic measurement of breathing conditions to compensate for breathing irregularities. Methods and Materials: A novel respiratory motion perturbation (RMP) model was developed to predict tumor motion variations caused by breathing irregularities. This model contained 2 terms: the initial tumor motion trajectory, measured from 4-dimensional computed tomography (4DCT) images, and motion perturbation, calculated from breathing variations in tidal volume (TV) and breathing pattern (BP). The motion perturbation was derived from the patient-specific anatomy, tumor-specific location, and time-dependent breathing variations. Ten patients were studied, and 2 amplitude-binned 4DCT images for each patient were acquired within 2 weeks. The motion trajectories of 40 corresponding bifurcation points in both 4DCT images of each patient were obtained using deformable image registration. An in-house 4D data processing toolbox was developed to calculate the TV and BP as functions of the breathing phase. The motion was predicted from the simulation 4DCT scan to the treatment 4DCT scan, and vice versa, resulting in 800 predictions. For comparison, noncorrected motion differences and the predictions from a published 5-dimensional model were used. Results: The average motion range in the superoinferior direction was 9.4 ± 4.4 mm, the average ΔTV ranged from 10 to 248 mm{sup 3} (−26% to 61%), and the ΔBP ranged from 0 to 0.2 (−71% to 333%) between the 2 4DCT scans. The mean noncorrected motion difference was 2.0 ± 2.8 mm between 2 4DCT motion trajectories. After applying the RMP model, the mean motion difference was reduced significantly to 1.2 ± 1.8 mm (P=.0018), a 40% improvement, similar to the 1.2 ± 1.8 mm (P=.72) predicted with the 5-dimensional model. Conclusions: A novel physical RMP model was developed with an average accuracy of 1.2 ± 1.8 mm for

  11. TU-F-17A-03: An Analytical Respiratory Perturbation Model for Lung Motion Prediction

    Energy Technology Data Exchange (ETDEWEB)

    Li, G; Yuan, A [Memorial Sloan Kettering Cancer Center, New York, NY (United States); Wei, J [City College of New York, New York, NY (United States)

    2014-06-15

    Purpose: Breathing irregularity is common, causing unreliable prediction in tumor motion for correlation-based surrogates. Both tidal volume (TV) and breathing pattern (BP=ΔVthorax/TV, where TV=ΔVthorax+ΔVabdomen) affect lung motion in anterior-posterior and superior-inferior directions. We developed a novel respiratory motion perturbation (RMP) model in analytical form to account for changes in TV and BP in motion prediction from simulation to treatment. Methods: The RMP model is an analytical function of patient-specific anatomic and physiologic parameters. It contains a base-motion trajectory d(x,y,z) derived from a 4-dimensional computed tomography (4DCT) at simulation and a perturbation term Δd(ΔTV,ΔBP) accounting for deviation at treatment from simulation. The perturbation is dependent on tumor-specific location and patient-specific anatomy. Eleven patients with simulation and treatment 4DCT images were used to assess the RMP method in motion prediction from 4DCT1 to 4DCT2, and vice versa. For each patient, ten motion trajectories of corresponding points in the lower lobes were measured in both 4DCTs: one served as the base-motion trajectory and the other as the ground truth for comparison. In total, 220 motion trajectory predictions were assessed. The motion discrepancy between two 4DCTs for each patient served as a control. An established 5D motion model was used for comparison. Results: The average absolute error of RMP model prediction in superior-inferior direction is 1.6±1.8 mm, similar to 1.7±1.6 mm from the 5D model (p=0.98). Some uncertainty is associated with limited spatial resolution (2.5mm slice thickness) and temporal resolution (10-phases). Non-corrected motion discrepancy between two 4DCTs is 2.6±2.7mm, with the maximum of ±20mm, and correction is necessary (p=0.01). Conclusion: The analytical motion model predicts lung motion with accuracy similar to the 5D model. The analytical model is based on physical relationships, requires no

  12. A Biological Model of the Effects of Toxic Substances

    Science.gov (United States)

    1991-11-29

    either as a protracted low-level exposure or as a high-level, acute exposure. The Draize rabbit eye test for acute irritancy has come under severe...been tested with the in vivo Draize eye test and because of the necessity of comparing Topical Testing’s in vitro model with the in vivo data, definition...analogous to the Draize eye test in which neurons from the trigeminal ganglion (which normally innervates the ocular surface) are grown in culture with

  13. Transmission of human respiratory syncytial virus in the immunocompromised ferret model

    NARCIS (Netherlands)

    de Waal, L. (Leon); S.L. Smits (Saskia); E.J.B. Veldhuis Kroeze (Edwin); G. van Amerongen (Geert); Pohl, M.O. (Marie O.); Osterhaus, A.D.M.E. (Albert D. M. E.); K.J. Stittelaar (Koert)

    2018-01-01

    textabstractHuman respiratory syncytial virus (HRSV) causes substantial morbidity and mortality in vulnerable patients, such as the very young, the elderly, and immunocompromised individuals of any age. Nosocomial transmission of HRSV remains a serious challenge in hospital settings, with

  14. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015 : A systematic review and modelling study

    NARCIS (Netherlands)

    Shi, Ting; McAllister, David A.; O'Brien, Katherine L.; Simoes, Eric A. F.; Madhi, Shabir A.; Gessner, Bradford D.; Polack, Fernando P.; Balsells, Evelyn; Acacio, Sozinho; Aguayo, Claudia; Alassani, Issifou; Ali, Asad; Antonio, Martin; Awasthi, Shally; Awori, Juliet O.; Azziz-Baumgartner, Eduardo; Baggett, Henry C.; Baillie, Vicky L.; Balmaseda, Angel; Barahona, Alfredo; Basnet, Sudha; Bassat, Quique; Basualdo, Wilma; Bigogo, Godfrey; Bont, Louis; Breiman, Robert F.; Brooks, W. Abdullah; Broor, Shobha; Bruce, Nigel; Bruden, Dana; Buchy, Philippe; Campbell, Stuart; Carosone-Link, Phyllis; Chadha, Mandeep; Chipeta, James; Chou, Monidarin; Clara, Wilfrido; Cohen, Cheryl; de Cuellar, Elizabeth; Dang, Duc Anh; Dash-yandag, Budragchaagiin; Deloria-Knoll, Maria; Dherani, Mukesh; Eap, Tekchheng; Ebruke, Bernard E.; Echavarria, Marcela; de Freitas Lázaro Emediato, Carla Cecília; Fasce, Rodrigo A.; Feikin, Daniel R.; Feng, Luzhao; Gentile, Angela; Gordon, Aubree; Goswami, Doli; Goyet, Sophie; Groome, Michelle J; Halasa, Natasha; Hirve, Siddhivinayak; Homaira, Nusrat; Howie, Stephen R.C.; Jara, Jorge; Jroundi, Imane; Kartasasmita, Cissy B.; Khuri-Bulos, Najwa; Kotloff, Karen L.; Krishnan, Anand; Libster, Romina; Lopez, Olga; Lucero, Marilla G.; Lucion, Florencia; Lupisan, Socorro P.; Marcone, Debora N.; McCracken, John P.; Mejia, Mario; Moisi, Jennifer C.; Montgomery, Joel M.; Moore, David P.; Moraleda, Cinta; Moyes, Jocelyn; Munywoki, Patrick; Mutyara, Kuswandewi; Nicol, Mark P.; Nokes, D. James; Nymadawa, Pagbajabyn; da Costa Oliveira, Maria Tereza; Oshitani, Histoshi; Pandey, Nitin; Paranhos-Baccalà, Gláucia; Phillips, Lia N.; Picot, Valentina Sanchez; Rahman, Mustafizur; Rakoto-Andrianarivelo, Mala; Rasmussen, Zeba A.; Rath, Barbara A.; Robinson, Annick; Romero, Candice; Russomando, Graciela; Salimi, Vahid; Sawatwong, Pongpun; Scheltema, Nienke; Schweiger, Brunhilde; Scott, J. Anthony G.; Seidenberg, Phil; Shen, Kunling; Singleton, Rosalyn; Sotomayor, Viviana; Strand, Tor A.; Sutanto, Agustinus; Sylla, Mariam; Tapia, Milagritos D.; Thamthitiwat, Somsak; Thomas, Elizabeth D.; Tokarz, Rafal; Turner, Claudia; Venter, Marietjie; Waicharoen, Sunthareeya; Wang, Jianwei; Watthanaworawit, Wanitda; Yoshida, Lay Myint; Yu, Hongjie; Zar, Heather J.; Campbell, Harry; Nair, Harish

    2017-01-01

    Background: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on

  15. Modeling Zebrafish Developmental Toxicity using a Concurrent In vitro Assay Battery (SOT)

    Science.gov (United States)

    We describe the development of computational models that predict activity in a repeat-dose zebrafish embryo developmental toxicity assay using a combination of physico-chemical parameters and in vitro (human) assay measurements. The data set covered 986 chemicals including pestic...

  16. Large Dataset of Acute Oral Toxicity Data Created for Testing in Silico Models (ASCCT meeting)

    Science.gov (United States)

    Acute toxicity data is a common requirement for substance registration in the US. Currently only data derived from animal tests are accepted by regulatory agencies, and the standard in vivo tests use lethality as the endpoint. Non-animal alternatives such as in silico models are ...

  17. A bioethical perspective on risk assessment models for managing toxic wastes, radioactive or non-radioactive

    International Nuclear Information System (INIS)

    Maxey, M.N.

    1982-01-01

    In the interest of developing an adequate and consistent bioethical perspective for reflecting on the ethical issues raised by toxic wastes, this brief paper focuses on the question of whether or not public opposition to past and proposed methods for waste management has been induced as much by technical incompetance as by deficiencies in using risk models for bioethical problem definitions

  18. Developing predictive models for toxicity of organic chemicals to green algae based on mode of action.

    Science.gov (United States)

    Bakire, Serge; Yang, Xinya; Ma, Guangcai; Wei, Xiaoxuan; Yu, Haiying; Chen, Jianrong; Lin, Hongjun

    2018-01-01

    Organic chemicals in the aquatic ecosystem may inhibit algae growth and subsequently lead to the decline of primary productivity. Growth inhibition tests are required for ecotoxicological assessments for regulatory purposes. In silico study is playing an important role in replacing or reducing animal tests and decreasing experimental expense due to its efficiency. In this work, a series of theoretical models was developed for predicting algal growth inhibition (log EC 50 ) after 72 h exposure to diverse chemicals. In total 348 organic compounds were classified into five modes of toxic action using the Verhaar Scheme. Each model was established by using molecular descriptors that characterize electronic and structural properties. The external validation and leave-one-out cross validation proved the statistical robustness of the derived models. Thus they can be used to predict log EC 50 values of chemicals that lack authorized algal growth inhibition values (72 h). This work systematically studied algal growth inhibition according to toxic modes and the developed model suite covers all five toxic modes. The outcome of this research will promote toxic mechanism analysis and be made applicable to structural diversity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. QSAR models for predicting in vivo aquatic toxicity of chlorinated alkanes to fish

    NARCIS (Netherlands)

    Zvinavashe, E.; Berg, H. van den; Soffers, A.E.M.F.; Vervoort, J.; Freidig, A.; Murk, A.J.; Rietjens, I.M.C.M.

    2008-01-01

    Quantitative structure-activity relationship (QSAR) models are expected to play a crucial role in reducing the number of animals to be used for toxicity testing resulting from the adoption of the new European Union chemical control system called Registration, Evaluation, and Authorization of

  20. Comprehensive mollusk acute toxicity database improves the use of Interspecies Correlation Estimation (ICE) models to predict toxicity of untested freshwater and endangered mussel species

    Science.gov (United States)

    Interspecies correlation estimation (ICE) models extrapolate acute toxicity data from surrogate test species to untested taxa. A suite of ICE models developed from a comprehensive database is available on the US Environmental Protection Agency’s web-based application, Web-I...

  1. Impaired ecosystem process despite little effects on populations: modeling combined effects of warming and toxicants.

    Science.gov (United States)

    Galic, Nika; Grimm, Volker; Forbes, Valery E

    2017-08-01

    Freshwater ecosystems are exposed to many stressors, including toxic chemicals and global warming, which can impair, separately or in combination, important processes in organisms and hence higher levels of organization. Investigating combined effects of warming and toxicants has been a topic of little research, but neglecting their combined effects may seriously misguide management efforts. To explore how toxic chemicals and warming, alone and in combination, propagate across levels of biological organization, including a key ecosystem process, we developed an individual-based model (IBM) of a freshwater amphipod detritivore, Gammarus pseudolimnaeus, feeding on leaf litter. In this IBM, life history emerges from the individuals' energy budgets. We quantified, in different warming scenarios (+1-+4 °C), the effects of hypothetical toxicants on suborganismal processes, including feeding, somatic and maturity maintenance, growth, and reproduction. Warming reduced mean adult body sizes and population abundance and biomass, but only in the warmest scenarios. Leaf litter processing, a key contributor to ecosystem functioning and service delivery in streams, was consistently enhanced by warming, through strengthened interaction between the detritivorous consumer and its resource. Toxicant effects on feeding and maintenance resulted in initially small adverse effects on consumers, but ultimately led to population extinction and loss of ecosystem process. Warming in combination with toxicants had little effect at the individual and population levels, but ecosystem process was impaired in the warmer scenarios. Our results suggest that exposure to the same amount of toxicants can disproportionately compromise ecosystem processing depending on global warming scenarios; for example, reducing organismal feeding rates by 50% will reduce resource processing by 50% in current temperature conditions, but by up to 200% with warming of 4 °C. Our study has implications for

  2. QSAR models for reproductive toxicity and endocrine disruption in regulatory use - a preliminary investigation

    DEFF Research Database (Denmark)

    Jensen, Gunde Egeskov; Niemela, J.R.; Wedebye, Eva Bay

    2008-01-01

    and epidemiological human studies), dominant lethal effect in rodents (in vivo) and Drosophila melanogaster sex-linked recessive lethal effect. A structure set of 57,014 European Inventory of Existing Chemical Substances (EINECS) chemicals was screened. A total of 5240 EINECS chemicals, corresponding to 9.2%, were...... predicted as reproductive toxicants by one or more of the models. The chemicals predicted positive for reproductive toxicity will be submitted to the Danish Environmental Protection Agency as scientific input for a future updated advisory classification list with advisory classifications for concern...

  3. Modelling uptake and toxicity of nickel in solution to Enchytraeus crypticus with biotic ligand model theory

    NARCIS (Netherlands)

    He, E.; Qiu, Hao; van Gestel, C.A.M.

    2014-01-01

    Protons and other cations may inhibit metal uptake and alleviate metal toxicity in aquatic organisms, but less is known about these interactions in soil organisms. The present study investigated the influence of solution chemistry on uptake and toxicity of Ni in Enchytraeus crypticus after 14 days

  4. Modelling the impact of toxic and disturbance stress on white-tailed eagle (Haliaeetus albicilla) populations.

    Science.gov (United States)

    Korsman, John C; Schipper, Aafke M; Lenders, H J Rob; Foppen, Ruud P B; Hendriks, A Jan

    2012-01-01

    Several studies have related breeding success and survival of sea eagles to toxic or non-toxic stress separately. In the present investigation, we analysed single and combined impacts of both toxic and disturbance stress on populations of white-tailed eagle (Haliaeetus albicilla), using an analytical single-species model. Chemical and eco(toxico)logical data reported from laboratory and field studies were used to parameterise and validate the model. The model was applied to assess the impact of ∑PCB, DDE and disturbance stress on the white-tailed eagle population in The Netherlands. Disturbance stress was incorporated through a 1.6% reduction in survival and a 10-50% reduction in reproduction. ∑PCB contamination from 1950 up to 1987 was found to be too high to allow the return of white-tailed eagle as a breeding species in that period. ∑PCB and population trends simulated for 2006-2050 suggest that future population growth is still reduced. Disturbance stress resulted in a reduced population development. The combination of both toxic and disturbance stress varied from a slower population development to a catastrophical reduction in population size, where the main cause was attributed to the reduction in reproduction of 50%. Application of the model was restricted by the current lack of quantitative dose-response relationships between non-toxic stress and survival and reproduction. Nevertheless, the model provides a first step towards integrating and quantifying the impacts of multiple stressors on white-tailed eagle populations.

  5. Prediction of polycyclic aromatic hydrocarbons toxicity using equilibrium partitioning approach and narcosis model.

    Science.gov (United States)

    Ololade, I A

    2010-09-01

    The study underscores the use of equilibrium partitioning (EqP) to determine bioavailability and the narcosis theory to estimate toxicity of PAHs to benthic invertebrates. Eight PAHs (anthracene, azuleno(2,1-b)thiophene, benz(a)anthracene, carbazole, dibenzothiophene, benz(a)azulene, dibenzo(a,h)anthracene and phenanthrene) were identified with phenanthrene and carbazole recording the highest (6.29 microg/g) and least (0.06 microg/g) concentrations at both seasons. Based on EqP and Narcosis model, the sum of PAHs toxic unit (SigmaTU), at both sites is <1, suggesting no likelihood of PAHs toxicity to benthic invertebrates. The study suggests continuous PAH monitoring especially with aquatic species due to their transfer to human via food chain.

  6. A New In Vivo Model System to Assess the Toxicity of Semiconductor Nanocrystals

    Directory of Open Access Journals (Sweden)

    Angela Tino

    2011-01-01

    Full Text Available In the emerging area of nanotechnology, a key issue is related to the potential impacts of the novel nanomaterials on the environment and human health, so that this technology can be used with minimal risk. Specifically designed to combine on a single structure multipurpose tags and properties, smart nanomaterials need a comprehensive characterization of both chemicophysical properties and adequate toxicological evaluation, which is a challenging endeavour; the in vitro toxicity assays that are often employed for nanotoxicity assessments do not accurately predict in vivo response. To overcome these limitations and to evaluate toxicity characteristics of cadmium telluride quantum dots in relation to surface coatings, we have employed the freshwater polyp Hydra vulgaris as a model system. We assessed in vivo acute and sublethal toxicity by scoring for alteration of morphological traits, population growth rates, and influence on the regenerative capabilities providing new investigation clues for nanotoxicology purposes.

  7. A phantom model demonstration of tomotherapy dose painting delivery, including managed respiratory motion without motion management

    Energy Technology Data Exchange (ETDEWEB)

    Kissick, Michael W; Mo Xiaohu; McCall, Keisha C; Mackie, Thomas R [Department of Medical Physics, Wisconsin Institutes for Medical Research, 111 Highland Avenue, University of Wisconsin-Madison, Madison, WI 53705 (United States); Schubert, Leah K [Radiation Oncology Department, University of Nebraska Medical Center, Omaha, NE 68198 (United States); Westerly, David C, E-mail: mwkissick@wisc.ed [Department of Radiation Oncology, University of Colorado Denver, Aurora, CO 80045 (United States)

    2010-05-21

    The aim of the study was to demonstrate a potential alternative scenario for accurate dose-painting (non-homogeneous planned dose) delivery at 1 cm beam width with helical tomotherapy (HT) in the presence of 1 cm, three-dimensional, intra-fraction respiratory motion, but without any active motion management. A model dose-painting experiment was planned and delivered to the average position (proper phase of a 4DCT scan) with three spherical PTV levels to approximate dose painting to compensate for hypothetical hypoxia in a model lung tumor. Realistic but regular motion was produced with the Washington University 4D Motion Phantom. A small spherical Virtual Water(TM) phantom was used to simulate a moving lung tumor inside of the LUNGMAN(TM) anthropomorphic chest phantom to simulate realistic heterogeneity uncertainties. A piece of 4 cm Gafchromic EBT(TM) film was inserted into the 6 cm diameter sphere. TomoTherapy, Inc., DQA(TM) software was used to verify the delivery performed on a TomoTherapy Hi-Art II(TM) device. The dose uncertainty in the purposeful absence of motion management and in the absence of large, low frequency drifts (periods greater than the beam width divided by the couch velocity) or randomness in the breathing displacement yields very favorable results. Instead of interference effects, only small blurring is observed because of the averaging of many breathing cycles and beamlets and the avoidance of interference. Dose painting during respiration with helical tomotherapy is feasible in certain situations without motion management. A simple recommendation is to make respiration as regular as possible without low frequency drifting. The blurring is just small enough to suggest that it may be acceptable to deliver without motion management if the motion is equal to the beam width or smaller (at respiration frequencies) when registered to the average position.

  8. A phantom model demonstration of tomotherapy dose painting delivery, including managed respiratory motion without motion management

    International Nuclear Information System (INIS)

    Kissick, Michael W; Mo Xiaohu; McCall, Keisha C; Mackie, Thomas R; Schubert, Leah K; Westerly, David C

    2010-01-01

    The aim of the study was to demonstrate a potential alternative scenario for accurate dose-painting (non-homogeneous planned dose) delivery at 1 cm beam width with helical tomotherapy (HT) in the presence of 1 cm, three-dimensional, intra-fraction respiratory motion, but without any active motion management. A model dose-painting experiment was planned and delivered to the average position (proper phase of a 4DCT scan) with three spherical PTV levels to approximate dose painting to compensate for hypothetical hypoxia in a model lung tumor. Realistic but regular motion was produced with the Washington University 4D Motion Phantom. A small spherical Virtual Water(TM) phantom was used to simulate a moving lung tumor inside of the LUNGMAN(TM) anthropomorphic chest phantom to simulate realistic heterogeneity uncertainties. A piece of 4 cm Gafchromic EBT(TM) film was inserted into the 6 cm diameter sphere. TomoTherapy, Inc., DQA(TM) software was used to verify the delivery performed on a TomoTherapy Hi-Art II(TM) device. The dose uncertainty in the purposeful absence of motion management and in the absence of large, low frequency drifts (periods greater than the beam width divided by the couch velocity) or randomness in the breathing displacement yields very favorable results. Instead of interference effects, only small blurring is observed because of the averaging of many breathing cycles and beamlets and the avoidance of interference. Dose painting during respiration with helical tomotherapy is feasible in certain situations without motion management. A simple recommendation is to make respiration as regular as possible without low frequency drifting. The blurring is just small enough to suggest that it may be acceptable to deliver without motion management if the motion is equal to the beam width or smaller (at respiration frequencies) when registered to the average position.

  9. Diaphragm Muscle Adaptation to Sustained Hypoxia: Lessons from Animal Models with Relevance to High Altitude and Chronic Respiratory Diseases

    Directory of Open Access Journals (Sweden)

    Philip Lewis

    2016-12-01

    Full Text Available The diaphragm is the primary inspiratory pump muscle of breathing. Notwithstanding its critical role in pulmonary ventilation, the diaphragm like other striated muscles is malleable in response to physiological and pathophysiological stressors, with potential implications for the maintenance of respiratory homeostasis. This review considers hypoxic adaptation of the diaphragm muscle, with a focus on functional, structural, and metabolic remodeling relevant to conditions such as high altitude and chronic respiratory disease. On the basis of emerging data in animal models, we posit that hypoxia is a significant driver of respiratory muscle plasticity, with evidence suggestive of both compensatory and deleterious adaptations in conditions of sustained exposure to low oxygen. Cellular strategies driving diaphragm remodeling during exposure to sustained hypoxia appear to confer hypoxic tolerance at the expense of peak force-generating capacity, a key functional parameter that correlates with patient morbidity and mortality. Changes include, but are not limited to: redox-dependent activation of hypoxia-inducible factor (HIF and MAP kinases; time-dependent carbonylation of key metabolic and functional proteins; decreased mitochondrial respiration; activation of atrophic signaling and increased proteolysis; and, altered functional performance. Diaphragm muscle weakness may be a signature effect of sustained hypoxic exposure. We discuss the putative role of reactive oxygen species as mediators of both advantageous and disadvantageous adaptations of diaphragm muscle to sustained hypoxia, and the role of antioxidants in mitigating adverse effects of chronic hypoxic stress on respiratory muscle function.

  10. [Predicting copper toxicity to Hypophthalmichthys molitrix and Ctenopharyngodon idellus based on biotic ligand model].

    Science.gov (United States)

    Wang, Wan-Bin; Chen, Sha; Wu, Min; Zhao, Jing

    2014-10-01

    A series of 96 h copper acute toxicity experiments were conducted with Ctenopharyngodon idellus and Hypophthalmichthys molitrix under different concentrations of DOC [ρ(DOC) 0.05, 0.5, 1, 2, 4 mg · L(-1)]. Higher DOC resulted in a reduction of toxicity, which was in line with the concepts of the biotic ligand model (BLM). It was concluded that the mean absolute deviation (MAD) of LC50 with Ctenopharyngodon idellus and Hypophthalmichthys molitrix was 591.2, 157.14 μg · L(-1) and 728.18, 91.24 μg x L(-1), respectively, by the prediction of copper BLM developed for Fathead minnow and Rainbow trout. Based on speciation analysis of biotic ligand model, it was shown that LA50 values of Ctenopharyngodon idellus and Hypophthalmichthys molitrix were 10.960 and 3.978 nmol · g(-1), respectively. Then the MAD values became 280.52 and 92.25 μg · L(-1) for Ctenopharyngodon idellus and Hypophthalmichthys molitrix using the normalized LA50. Finally by searching toxicity data in literature, the MAD values on Ctenopharyngodon idellus and Hypophthalmichthys molitrix were 252.37 and 50.26 μg · L(-1), successively. This result verified that the toxicity prediction based on biotic ligand model was practical.

  11. Modeling late rectal toxicities based on a parameterized representation of the 3D dose distribution

    Science.gov (United States)

    Buettner, Florian; Gulliford, Sarah L.; Webb, Steve; Partridge, Mike

    2011-04-01

    Many models exist for predicting toxicities based on dose-volume histograms (DVHs) or dose-surface histograms (DSHs). This approach has several drawbacks as firstly the reduction of the dose distribution to a histogram results in the loss of spatial information and secondly the bins of the histograms are highly correlated with each other. Furthermore, some of the complex nonlinear models proposed in the past lack a direct physical interpretation and the ability to predict probabilities rather than binary outcomes. We propose a parameterized representation of the 3D distribution of the dose to the rectal wall which explicitly includes geometrical information in the form of the eccentricity of the dose distribution as well as its lateral and longitudinal extent. We use a nonlinear kernel-based probabilistic model to predict late rectal toxicity based on the parameterized dose distribution and assessed its predictive power using data from the MRC RT01 trial (ISCTRN 47772397). The endpoints under consideration were rectal bleeding, loose stools, and a global toxicity score. We extract simple rules identifying 3D dose patterns related to a specifically low risk of complication. Normal tissue complication probability (NTCP) models based on parameterized representations of geometrical and volumetric measures resulted in areas under the curve (AUCs) of 0.66, 0.63 and 0.67 for predicting rectal bleeding, loose stools and global toxicity, respectively. In comparison, NTCP models based on standard DVHs performed worse and resulted in AUCs of 0.59 for all three endpoints. In conclusion, we have presented low-dimensional, interpretable and nonlinear NTCP models based on the parameterized representation of the dose to the rectal wall. These models had a higher predictive power than models based on standard DVHs and their low dimensionality allowed for the identification of 3D dose patterns related to a low risk of complication.

  12. Modeling late rectal toxicities based on a parameterized representation of the 3D dose distribution

    Energy Technology Data Exchange (ETDEWEB)

    Buettner, Florian; Gulliford, Sarah L; Webb, Steve; Partridge, Mike, E-mail: florian.buttner@icr.ac.uk [Joint Department of Physics, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT (United Kingdom)

    2011-04-07

    Many models exist for predicting toxicities based on dose-volume histograms (DVHs) or dose-surface histograms (DSHs). This approach has several drawbacks as firstly the reduction of the dose distribution to a histogram results in the loss of spatial information and secondly the bins of the histograms are highly correlated with each other. Furthermore, some of the complex nonlinear models proposed in the past lack a direct physical interpretation and the ability to predict probabilities rather than binary outcomes. We propose a parameterized representation of the 3D distribution of the dose to the rectal wall which explicitly includes geometrical information in the form of the eccentricity of the dose distribution as well as its lateral and longitudinal extent. We use a nonlinear kernel-based probabilistic model to predict late rectal toxicity based on the parameterized dose distribution and assessed its predictive power using data from the MRC RT01 trial (ISCTRN 47772397). The endpoints under consideration were rectal bleeding, loose stools, and a global toxicity score. We extract simple rules identifying 3D dose patterns related to a specifically low risk of complication. Normal tissue complication probability (NTCP) models based on parameterized representations of geometrical and volumetric measures resulted in areas under the curve (AUCs) of 0.66, 0.63 and 0.67 for predicting rectal bleeding, loose stools and global toxicity, respectively. In comparison, NTCP models based on standard DVHs performed worse and resulted in AUCs of 0.59 for all three endpoints. In conclusion, we have presented low-dimensional, interpretable and nonlinear NTCP models based on the parameterized representation of the dose to the rectal wall. These models had a higher predictive power than models based on standard DVHs and their low dimensionality allowed for the identification of 3D dose patterns related to a low risk of complication.

  13. Respiratory Failure

    Science.gov (United States)

    Respiratory failure happens when not enough oxygen passes from your lungs into your blood. Your body's organs, such as ... need oxygen-rich blood to work well. Respiratory failure also can happen if your lungs can't ...

  14. Respiratory system

    Science.gov (United States)

    Bartlett, R. G., Jr.

    1973-01-01

    The general anatomy and function of the human respiratory system is summarized. Breathing movements, control of breathing, lung volumes and capacities, mechanical relations, and factors relevant to respiratory support and equipment design are discussed.

  15. Late Rectal Toxicity on RTOG 94-06: Analysis Using a Mixture Lyman Model

    International Nuclear Information System (INIS)

    Tucker, Susan L.; Dong Lei; Bosch, Walter R.; Michalski, Jeff; Winter, Kathryn; Mohan, Radhe; Purdy, James A.; Kuban, Deborah; Lee, Andrew K.; Cheung, M. Rex; Thames, Howard D.; Cox, James D.

    2010-01-01

    Purpose: To estimate the parameters of the Lyman normal-tissue complication probability model using censored time-to-event data for Grade ≥2 late rectal toxicity among patients treated on Radiation Therapy Oncology Group 94-06, a dose-escalation trial designed to determine the maximum tolerated dose for three-dimensional conformal radiotherapy of prostate cancer. Methods and Materials: The Lyman normal-tissue complication probability model was fitted to data from 1,010 of the 1,084 patients accrued on Radiation Therapy Oncology Group 94-06 using an approach that accounts for censored observations. Separate fits were obtained using dose-volume histograms for whole rectum and dose-wall histograms for rectal wall. Results: With a median follow-up of 7.2 years, the crude incidence of Grade ≥2 late rectal toxicity was 15% (n = 148). The parameters of the Lyman model fitted to dose-volume histograms data, with 95% profile-likelihood confidence intervals, were TD 50 = 79.1 Gy (75.3 Gy, 84.3 Gy), m = 0.146 (0.107, 0.225), and n = 0.077 (0.041, 0.156). The fit based on dose-wall histogram data was not significantly different. Patients with cardiovascular disease had a significantly higher incidence of late rectal toxicity (p = 0.015), corresponding to a dose-modifying factor of 5.3%. No significant association with late rectal toxicity was found for diabetes, hypertension, rectal volume, rectal length, neoadjuvant hormone therapy, or prescribed dose per fraction (1.8 Gy vs. 2 Gy). Conclusions: These results, based on a large cohort of patients from a multi-institutional trial, are expected to be widely representative of the ability of the Lyman model to describe the long-term risk of Grade ≥2 late rectal toxicity after three-dimensional conformal radiotherapy of prostate cancer.

  16. Insights on in vitro models for safety and toxicity assessment of cosmetic ingredients.

    Science.gov (United States)

    Almeida, Andreia; Sarmento, Bruno; Rodrigues, Francisca

    2017-03-15

    According to the current European legislation, the safety assessment of each individual cosmetic ingredient of any formulation is the basis for the safety evaluation of a cosmetic product. Also, animal testing in the European Union is prohibited for cosmetic ingredients and products since 2004 and 2009, respectively. Additionally, the commercialization of any cosmetic products containing ingredients tested on animal models was forbidden in 2009. In consequence of these boundaries, the European Centre for the Validation of Alternative Methods (ECVAM) proposes a list of validated cell-based in vitro models for predicting the safety and toxicity of cosmetic ingredients. These models have been demonstrated as valuable and effective tools to overcome the limitations of animal in vivo studies. Although the use of in vitro cell-based models for the evaluation of absorption and permeability of cosmetic ingredients is widespread, a detailed study on the properties of these platforms and the in vitro-in vivo correlation compared with human data are required. Moreover, additional efforts must be taken to develop in vitro models to predict carcinogenicity, repeat dose toxicity and reproductive toxicity, for which no alternative in vitro methods are currently available. This review paper summarizes and characterizes the most relevant in vitro models validated by ECVAM employed to predict the safety and toxicology of cosmetic ingredients. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. The Continual Reassessment Method for Multiple Toxicity Grades: A Bayesian Model Selection Approach

    Science.gov (United States)

    Yuan, Ying; Zhang, Shemin; Zhang, Wenhong; Li, Chanjuan; Wang, Ling; Xia, Jielai

    2014-01-01

    Grade information has been considered in Yuan et al. (2007) wherein they proposed a Quasi-CRM method to incorporate the grade toxicity information in phase I trials. A potential problem with the Quasi-CRM model is that the choice of skeleton may dramatically vary the performance of the CRM model, which results in similar consequences for the Quasi-CRM model. In this paper, we propose a new model by utilizing bayesian model selection approach – Robust Quasi-CRM model – to tackle the above-mentioned pitfall with the Quasi-CRM model. The Robust Quasi-CRM model literally inherits the BMA-CRM model proposed by Yin and Yuan (2009) to consider a parallel of skeletons for Quasi-CRM. The superior performance of Robust Quasi-CRM model was demonstrated by extensive simulation studies. We conclude that the proposed method can be freely used in real practice. PMID:24875783

  18. Population Pharmacokinetic-Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats.

    Science.gov (United States)

    Kobuchi, Shinji; Ito, Yukako; Sakaeda, Toshiyuki

    2017-08-01

    Myelosuppression is a dose-limiting toxicity of 5-fluorouracil (5-FU). Predicting the inter- and intra-patient variability in pharmacokinetics and toxicities of 5-FU may contribute to the individualized medicine. This study aimed to establish a population pharmacokinetic-pharmacodynamic model that could evaluate the inter- and intra-individual variability in the plasma 5-FU concentration, 5-FU-induced body weight loss and myelosuppression in rats. Plasma 5-FU concentrations, body weight loss, and blood cell counts in rats following the intravenous administration of various doses of 5-FU for 4 days were used to develop the population pharmacokinetic-pharmacodynamic model. The population pharmacokinetic model consisting of a two-compartment model with Michaelis-Menten elimination kinetics successfully characterized the individual and population predictions of the plasma concentration of 5-FU and provided credible parameter estimates. The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively. The population pharmacokinetic-pharmacodynamic model adequately described the individual complete time-course of alterations in body weight loss, erythrocyte, leukocyte, and lymphocyte counts in rats treated with various doses of 5-FU. The inter-individual variability of the drug effects in the pharmacodynamic model for body weight loss was 82.6%, which was relatively high. The results of the present study suggest that not only individual fluctuations in the 5-FU concentration but also the cell sensitivity would affect the onset and degree of 5-FU-induced toxicity. This population pharmacokinetic-pharmacodynamic model could evaluate the inter- and intra-individual variability in drug-induced toxicity and guide the assessments of novel anticancer agents in drug development.

  19. Phrenic and hypoglossal nerve activity during respiratory response to hypoxia in 6-OHDA unilateral model of Parkinson's disease.

    Science.gov (United States)

    Andrzejewski, Kryspin; Budzińska, Krystyna; Kaczyńska, Katarzyna

    2017-07-01

    Parkinson's disease (PD) patients apart from motor dysfunctions exhibit respiratory disturbances. Their mechanism is still unknown and requires investigation. Our research was designed to examine the activity of phrenic (PHR) and hypoglossal (HG) nerves activity during a hypoxic respiratory response in the 6-hydroxydopamine (6-OHDA) model of PD. Male adult Wistar rats were injected unilaterally with 6-OHDA (20μg) or the vehicle into the right medial forebrain bundle (MFB). Two weeks after the surgery the activity of the phrenic and hypoglossal nerve was registered in anesthetized, vagotomized, paralyzed, and mechanically ventilated rats under normoxic and hypoxic conditions. Lesion effectiveness was confirmed by the cylinder test, performed before the MFB injection and 14days after, before the respiratory experiment. 6-OHDA lesioned animals showed a significant increase in normoxic inspiratory time. Expiratory time and total time of the respiratory cycle were prolonged in PD rats after hypoxia. The amplitude of the PHR activity and its minute activity were increased in comparison to the sham group at recovery time and during 30s of hypoxia. The amplitude of the HG activity was increased in response to hypoxia in 6-OHDA lesioned animals. The degeneration of dopaminergic neurons decreased the pre-inspiratory/inspiratory ratio of the hypoglossal burst amplitude during and after hypoxia. Unilateral MFB lesion changed the activity of the phrenic and hypoglossal nerves. The altered pre-inspiratory hypoglossal nerve activity indicates modifications to the central mechanisms controlling the activity of the HG nerve and may explain respiratory disorders seen in PD, i.e. apnea. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Toxicity data for modeling impacts of oil components in an Arctic ecosystem.

    Science.gov (United States)

    Olsen, G H; Klok, C; Hendriks, A J; Geraudie, P; De Hoop, L; De Laender, F; Farmen, E; Grøsvik, B E; Hansen, B H; Hjorth, M; Jansen, C R; Nordtug, T; Ravagnan, E; Viaene, K; Carroll, J

    2013-09-01

    Ecological impact assessment modeling systems are valuable support tools for managing impacts from commercial activities on marine habitats and species. The inclusion of toxic effects modeling in these systems is predicated on the availability and quality of ecotoxicology data. Here we report on a data gathering exercise to obtain toxic effects data on oil compounds for a selection of cold-water marine species of fish and plankton associated with the Barents Sea ecosystem. Effects data were collated from historical and contemporary literature resources for the endpoints mortality, development, growth, bioaccumulation and reproduction. Evaluating the utility and applicability of these data for modeling, we find that data coverage is limited to a sub-set of the required endpoints. There is a need for new experimental studies for zooplankton focused on the endpoints development and bioaccumulation and for larvae and juvenile fish focused on growth and development. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Cynomolgus macaque as an animal model for severe acute respiratory syndrome.

    Directory of Open Access Journals (Sweden)

    James V Lawler

    2006-05-01

    Full Text Available The emergence of severe acute respiratory syndrome (SARS in 2002 and 2003 affected global health and caused major economic disruption. Adequate animal models are required to study the underlying pathogenesis of SARS-associated coronavirus (SARS-CoV infection and to develop effective vaccines and therapeutics. We report the first findings of measurable clinical disease in nonhuman primates (NHPs infected with SARS-CoV.In order to characterize clinically relevant parameters of SARS-CoV infection in NHPs, we infected cynomolgus macaques with SARS-CoV in three groups: Group I was infected in the nares and bronchus, group II in the nares and conjunctiva, and group III intravenously. Nonhuman primates in groups I and II developed mild to moderate symptomatic illness. All NHPs demonstrated evidence of viral replication and developed neutralizing antibodies. Chest radiographs from several animals in groups I and II revealed unifocal or multifocal pneumonia that peaked between days 8 and 10 postinfection. Clinical laboratory tests were not significantly changed. Overall, inoculation by a mucosal route produced more prominent disease than did intravenous inoculation. Half of the group I animals were infected with a recombinant infectious clone SARS-CoV derived from the SARS-CoV Urbani strain. This infectious clone produced disease indistinguishable from wild-type Urbani strain.SARS-CoV infection of cynomolgus macaques did not reproduce the severe illness seen in the majority of adult human cases of SARS; however, our results suggest similarities to the milder syndrome of SARS-CoV infection characteristically seen in young children.

  2. Pharmacophore modeling and in silico toxicity assessment of potential anticancer agents from African medicinal plants.

    Science.gov (United States)

    Ntie-Kang, Fidele; Simoben, Conrad Veranso; Karaman, Berin; Ngwa, Valery Fuh; Judson, Philip Neville; Sippl, Wolfgang; Mbaze, Luc Meva'a

    2016-01-01

    Molecular modeling has been employed in the search for lead compounds of chemotherapy to fight cancer. In this study, pharmacophore models have been generated and validated for use in virtual screening protocols for eight known anticancer drug targets, including tyrosine kinase, protein kinase B β, cyclin-dependent kinase, protein farnesyltransferase, human protein kinase, glycogen synthase kinase, and indoleamine 2,3-dioxygenase 1. Pharmacophore models were validated through receiver operating characteristic and Güner-Henry scoring methods, indicating that several of the models generated could be useful for the identification of potential anticancer agents from natural product databases. The validated pharmacophore models were used as three-dimensional search queries for virtual screening of the newly developed AfroCancer database (~400 compounds from African medicinal plants), along with the Naturally Occurring Plant-based Anticancer Compound-Activity-Target dataset (comprising ~1,500 published naturally occurring plant-based compounds from around the world). Additionally, an in silico assessment of toxicity of the two datasets was carried out by the use of 88 toxicity end points predicted by the Lhasa's expert knowledge-based system (Derek), showing that only an insignificant proportion of the promising anticancer agents would be likely showing high toxicity profiles. A diversity study of the two datasets, carried out using the analysis of principal components from the most important physicochemical properties often used to access drug-likeness of compound datasets, showed that the two datasets do not occupy the same chemical space.

  3. COMPARATIVE COMPUTATIONAL MODELING OF AIRFLOWS AND VAPOR DOSIMETY IN THE RESPIRATORY TRACTS OF RAT, MONKEY, AND HUMAN

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Richard A.; Kabilan, Senthil; Kuprat, Andrew P.; Carson, James P.; Minard, Kevin R.; Jacob, Rick E.; Timchalk, Charles; Glenny, Robb W.; Pipavath, Sudhaker; Cox, Timothy C.; Wallis, Chris; Larson, Richard; Fanucchi, M.; Postlewait, Ed; Einstein, Daniel R.

    2012-07-01

    Coupling computational fluid dynamics (CFD) with physiologically based pharmacokinetic (PBPK) models is 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. Historically, these models were limited to discrete regions of the respiratory system. CFD/PBPK models have now been developed for the rat, monkey, and human that encompass airways from the nose or mouth to the lung. A PBPK model previously developed to describe acrolein uptake in nasal tissues was adapted to the extended airway models as an example application. Model parameters for each anatomic region were obtained from the literature, measured directly, or estimated from published data. Airflow and site-specific acrolein uptake patterns were determined under steadystate inhalation conditions to provide direct comparisons with prior data and nasalonly simulations. Results confirmed that regional uptake was dependent upon airflow rates and acrolein concentrations with nasal extraction efficiencies predicted to be greatest in the rat, followed by the monkey, then the human. For human oral-breathing simulations, acrolein uptake rates in oropharyngeal and laryngeal tissues were comparable to nasal tissues following nasal breathing under the same exposure conditions. For both breathing modes, higher uptake rates were predicted for lower tracheo-bronchial tissues of humans than either the rat or monkey. These extended airway models provide a unique foundation for comparing dosimetry across a significantly more extensive range of conducting airways in the rat, monkey, and human than prior CFD models.

  4. An evaluation of biotic ligand models predicting acute copper toxicity to Daphnia magna in wastewater effluent.

    Science.gov (United States)

    Constantino, Carlos; Scrimshaw, Mark; Comber, Sean; Churchley, John

    2011-04-01

    The toxicity of Cu to Daphnia magna was investigated in a series of 48-h immobilization assays in effluents from four wastewater treatment works. The assay results were compared with median effective concentration (EC50) forecasts produced by the HydroQual biotic ligand model (BLM), the refined D. magna BLM, and a modified BLM that was constructed by integrating the refined D. magna biotic ligand characterization with the Windermere humic aqueous model (WHAM) VI geochemical speciation model, which also accommodated additional effluent characteristics as model inputs. The results demonstrated that all the BLMs were capable of predicting toxicity by within a factor of two, and that the modified BLM produced the most accurate toxicity forecasts. The refined D. magna BLM offered the most robust assessment of toxicity in that it was not reliant on the inclusion of effluent characteristics or optimization of the dissolved organic carbon active fraction to produce forecasts that were accurate by within a factor of two. The results also suggested that the biotic ligand stability constant for Na may be a poor approximation of the mechanisms governing the influence of Na where concentrations exceed the range within which the biotic ligand stability constant value had been determined. These findings support the use of BLMs for the establishment of site-specific water quality standards in waters that contain a substantial amount of wastewater effluent, but reinforces the need for regulators to scrutinize the composition of models, their thermodynamic and biotic ligand parameters, and the limitations of those parameters. Copyright © 2011 SETAC.

  5. A Novel Experimental and Modelling Strategy for Nanoparticle Toxicity Testing Enabling the Use of Small Quantities.

    Science.gov (United States)

    van Pomeren, Marinda; Peijnenburg, Willie J G M; Brun, Nadja R; Vijver, Martina G

    2017-11-06

    Metallic nanoparticles (NPs) differ from other metal forms with respect to their large surface to volume ratio and subsequent inherent reactivity. Each new modification to a nanoparticle alters the surface to volume ratio, fate and subsequently the toxicity of the particle. Newly-engineered NPs are commonly available only in low quantities whereas, in general, rather large amounts are needed for fate characterizations and effect studies. This challenge is especially relevant for those NPs that have low inherent toxicity combined with low bioavailability. Therefore, within our study, we developed new testing strategies that enable working with low quantities of NPs. The experimental testing method was tailor-made for NPs, whereas we also developed translational models based on different dose-metrics allowing to determine dose-response predictions for NPs. Both the experimental method and the predictive models were verified on the basis of experimental effect data collected using zebrafish embryos exposed to metallic NPs in a range of different chemical compositions and shapes. It was found that the variance in the effect data in the dose-response predictions was best explained by the minimal diameter of the NPs, whereas the data confirmed that the predictive model is widely applicable to soluble metallic NPs. The experimental and model approach developed in our study support the development of (eco)toxicity assays tailored to nano-specific features.

  6. Modeling acute respiratory illness during the 2007 San Diego wildland fires using a coupled emissions-transport system and generalized additive modeling.

    Science.gov (United States)

    Thelen, Brian; French, Nancy H F; Koziol, Benjamin W; Billmire, Michael; Owen, Robert Chris; Johnson, Jeffrey; Ginsberg, Michele; Loboda, Tatiana; Wu, Shiliang

    2013-11-05

    A study of the impacts on respiratory health of the 2007 wildland fires in and around San Diego County, California is presented. This study helps to address the impact of fire emissions on human health by modeling the exposure potential of proximate populations to atmospheric particulate matter (PM) from vegetation fires. Currently, there is no standard methodology to model and forecast the potential respiratory health effects of PM plumes from wildland fires, and in part this is due to a lack of methodology for rigorously relating the two. The contribution in this research specifically targets that absence by modeling explicitly the emission, transmission, and distribution of PM following a wildland fire in both space and time. Coupled empirical and deterministic models describing particulate matter (PM) emissions and atmospheric dispersion were linked to spatially explicit syndromic surveillance health data records collected through the San Diego Aberration Detection and Incident Characterization (SDADIC) system using a Generalized Additive Modeling (GAM) statistical approach. Two levels of geographic aggregation were modeled, a county-wide regional level and division of the county into six sub regions. Selected health syndromes within SDADIC from 16 emergency departments within San Diego County relevant for respiratory health were identified for inclusion in the model. The model captured the variability in emergency department visits due to several factors by including nine ancillary variables in addition to wildfire PM concentration. The model coefficients and nonlinear function plots indicate that at peak fire PM concentrations the odds of a person seeking emergency care is increased by approximately 50% compared to non-fire conditions (40% for the regional case, 70% for a geographically specific case). The sub-regional analyses show that demographic variables also influence respiratory health outcomes from smoke. The model developed in this study allows a

  7. Two-stage Bayesian model to evaluate the effect of air pollution on chronic respiratory diseases using drug prescriptions.

    Science.gov (United States)

    Blangiardo, Marta; Finazzi, Francesco; Cameletti, Michela

    2016-08-01

    Exposure to high levels of air pollutant concentration is known to be associated with respiratory problems which can translate into higher morbidity and mortality rates. The link between air pollution and population health has mainly been assessed considering air quality and hospitalisation or mortality data. However, this approach limits the analysis to individuals characterised by severe conditions. In this paper we evaluate the link between air pollution and respiratory diseases using general practice drug prescriptions for chronic respiratory diseases, which allow to draw conclusions based on the general population. We propose a two-stage statistical approach: in the first stage we specify a space-time model to estimate the monthly NO2 concentration integrating several data sources characterised by different spatio-temporal resolution; in the second stage we link the concentration to the β2-agonists prescribed monthly by general practices in England and we model the prescription rates through a small area approach. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. A randomized placebo controlled trial of ibuprofen for respiratory syncytial infection in a bovine model study

    Science.gov (United States)

    Background: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to ...

  9. Models to predict both sensible and latent heat transfer in the respiratory tract of Morada Nova sheep under semiarid tropical environment

    Science.gov (United States)

    Fonseca, Vinícius Carvalho; Saraiva, Edilson Paes; Maia, Alex Sandro Campos; Nascimento, Carolina Cardoso Nagib; da Silva, Josinaldo Araújo; Pereira, Walter Esfraim; Filho, Edgard Cavalcanti Pimenta; Almeida, Maria Elivânia Vieira

    2017-05-01

    The aim of this study was to build a prediction model both sensible and latent heat transfer by respiratory tract for Morada Nova sheep under field conditions in a semiarid tropical environment, using easily measured physiological and environmental parameters. Twelve dry Morada Nova ewes with an average of 3 ± 1.2 years old and average body weight of 32.76 ± 3.72 kg were used in a Latin square design 12 × 12 (12 days of records and 12 schedules). Tidal volume, respiratory rate, expired air temperature, and partial vapor pressure of the expired air were obtained from the respiratory facial mask and using a physiological measurement system. Ewes were evaluated from 0700 to 1900 h in each day under shade. A simple nonlinear model to estimate tidal volume as a function of respiratory rate was developed. Equation to estimate the expired air temperature was built, and the ambient air temperature was the best predictor together with relative humidity and ambient vapor pressure. In naturalized Morada Nova sheep, respiratory convection seems to be a mechanism of heat transfer of minor importance even under mild air temperature. Evaporation from the respiratory system increased together with ambient air temperature. At ambient air temperature, up to 35 °C respiratory evaporation accounted 90 % of the total heat lost by respiratory system, on average. Models presented here allow to estimate the heat flow from the respiratory tract for Morada Nova sheep bred in tropical region, using easily measured physiological and environmental traits as respiratory rate, ambient air temperature, and relative humidity.

  10. From basic physics to mechanisms of toxicity: the ``liquid drop'' approach applied to develop predictive classification models for toxicity of metal oxide nanoparticles

    Science.gov (United States)

    Sizochenko, Natalia; Rasulev, Bakhtiyor; Gajewicz, Agnieszka; Kuz'min, Victor; Puzyn, Tomasz; Leszczynski, Jerzy

    2014-10-01

    Many metal oxide nanoparticles are able to cause persistent stress to live organisms, including humans, when discharged to the environment. To understand the mechanism of metal oxide nanoparticles' toxicity and reduce the number of experiments, the development of predictive toxicity models is important. In this study, performed on a series of nanoparticles, the comparative quantitative-structure activity relationship (nano-QSAR) analyses of their toxicity towards E. coli and HaCaT cells were established. A new approach for representation of nanoparticles' structure is presented. For description of the supramolecular structure of nanoparticles the ``liquid drop'' model was applied. It is expected that a novel, proposed approach could be of general use for predictions related to nanomaterials. In addition, in our study fragmental simplex descriptors and several ligand-metal binding characteristics were calculated. The developed nano-QSAR models were validated and reliably predict the toxicity of all studied metal oxide nanoparticles. Based on the comparative analysis of contributed properties in both models the LDM-based descriptors were revealed to have an almost similar level of contribution to toxicity in both cases, while other parameters (van der Waals interactions, electronegativity and metal-ligand binding characteristics) have unequal contribution levels. In addition, the models developed here suggest different mechanisms of nanotoxicity for these two types of cells.Many metal oxide nanoparticles are able to cause persistent stress to live organisms, including humans, when discharged to the environment. To understand the mechanism of metal oxide nanoparticles' toxicity and reduce the number of experiments, the development of predictive toxicity models is important. In this study, performed on a series of nanoparticles, the comparative quantitative-structure activity relationship (nano-QSAR) analyses of their toxicity towards E. coli and HaCaT cells were

  11. Computational systems biology and dose-response modeling in relation to new directions in toxicity testing.

    Science.gov (United States)

    Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E; Conolly, Rory B

    2010-02-01

    The new paradigm envisioned for toxicity testing in the 21st century advocates shifting from the current animal-based testing process to a combination of in vitro cell-based studies, high-throughput techniques, and in silico modeling. A strategic component of the vision is the adoption of the systems biology approach to acquire, analyze, and interpret toxicity pathway data. As key toxicity pathways are identified and their wiring details elucidated using traditional and high-throughput techniques, there is a pressing need to understand their qualitative and quantitative behaviors in response to perturbation by both physiological signals and exogenous stressors. The complexity of these molecular networks makes the task of understanding cellular responses merely by human intuition challenging, if not impossible. This process can be aided by mathematical modeling and computer simulation of the networks and their dynamic behaviors. A number of theoretical frameworks were developed in the last century for understanding dynamical systems in science and engineering disciplines. These frameworks, which include metabolic control analysis, biochemical systems theory, nonlinear dynamics, and control theory, can greatly facilitate the process of organizing, analyzing, and understanding toxicity pathways. Such analysis will require a comprehensive examination of the dynamic properties of "network motifs"--the basic building blocks of molecular circuits. Network motifs like feedback and feedforward loops appear repeatedly in various molecular circuits across cell types and enable vital cellular functions like homeostasis, all-or-none response, memory, and biological rhythm. These functional motifs and associated qualitative and quantitative properties are the predominant source of nonlinearities observed in cellular dose response data. Complex response behaviors can arise from toxicity pathways built upon combinations of network motifs. While the field of computational cell

  12. A Bayesian SIRS model for the analysis of respiratory syncytial virus in the region of Valencia, Spain.

    Science.gov (United States)

    Corberán-Vallet, Ana; Santonja, Francisco J

    2014-09-01

    We present a Bayesian stochastic susceptible-infected-recovered-susceptible (SIRS) model in discrete time to understand respiratory syncytial virus dynamics in the region of Valencia, Spain. A SIRS model based on ordinary differential equations has also been proposed to describe RSV dynamics in the region of Valencia. However, this continuous-time deterministic model is not suitable when the initial number of infected individuals is small. Stochastic epidemic models based on a probability of disease transmission provide a more natural description of the spread of infectious diseases. In addition, by allowing the transmission rate to vary stochastically over time, the proposed model provides an improved description of RSV dynamics. The Bayesian analysis of the model allows us to calculate both the posterior distribution of the model parameters and the posterior predictive distribution, which facilitates the computation of point forecasts and prediction intervals for future observations. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Evaluation of the toxicity of tirapazamine plus cisplatin in a mouse tumor model

    International Nuclear Information System (INIS)

    Adam, M.; Ottenjann, S.; Kuenzel, G.; Nieder, C.; Molls, M.; Busch, R.; Erhardt, W.

    2006-01-01

    Background and purpose: tirapazamine (TPZ) is an anticancer drug that is selectively activated by the low oxygen environment in solid tumors. Furthermore, TPZ also enhances the tumor cell-killing effect of cisplatin. So far, detailed information on the toxicity of combined treatment is rare. The authors evaluated the toxicity of TPZ in combination with cisplatin in a mouse tumor model. For this purpose, general toxicity was monitored and all inner organs were examined histologically. Material and methods: RIF-1 fibrosarcomas of murine origin growing in the right hindfoot dorsum of C3H mice were used. The animals were treated with 10 x 2 Gy irradiation plus six i.p. injections of 4 mg/kg cisplatin (total dose 24 mg/kg) together with varying doses of TPZ (0-28 mg/kg per injection; total dose 0, 43.2, 86.4, 129.6, 151.2, 172.8 mg/kg). Treatment was applied within 2 weeks (figure 1). Total observation period was up to 35 days. Results: combined treatment with TPZ led to a dose-dependent, significant decrease in motor activity (table 1) and body weight and an increase in mortality (figures 2 and 3, tables 2 and 3). Histological analyses showed areas of necrosis in the heart, liver and kidney and gastric ulcers (table 4). Cisplatin alone produced no severe toxicity. Tumor doubling times were TPZ dose-dependent and comparable with data from the literature (figures 4 and 5, table 3). (orig.)

  14. Toxicity evaluation of biodegradable chitosan nanoparticles using a zebrafish embryo model

    Science.gov (United States)

    Hu, Yu-Lan; Qi, Wang; Han, Feng; Shao, Jian-Zhong; Gao, Jian-Qing

    2011-01-01

    Background Although there are a number of reports regarding the toxicity evaluation of inorganic nanoparticles, knowledge on biodegradable nanomaterials, which have always been considered safe, is still limited. For example, the toxicity of chitosan nanoparticles, one of the most widely used drug/gene delivery vehicles, is largely unknown. In the present study, the zebrafish model was used for a safety evaluation of this nanocarrier. Methods Chitosan nanoparticles with two particle sizes were prepared by ionic cross-linking of chitosan with sodium tripolyphosphate. Chitosan nanoparticles of different concentrations were incubated with zebrafish embryos, and ZnO nanoparticles were used as the positive control. Results Embryo exposure to chitosan nanoparticles and ZnO nanoparticles resulted in a decreased hatching rate and increased mortality, which was concentration-dependent. Chitosan nanoparticles at a size of 200 nm caused malformations, including a bent spine, pericardial edema, and an opaque yolk in zebrafish embryos. Furthermore, embryos exposed to chitosan nanoparticles showed an increased rate of cell death, high expression of reactive oxygen species, as well as overexpression of heat shock protein 70, indicating that chitosan nanoparticles can cause physiological stress in zebrafish. The results also suggest that the toxicity of biodegradable nanocarriers such as chitosan nanoparticles must be addressed, especially considering the in vivo distribution of these nanoscaled particles. Conclusion Our results add new insights into the potential toxicity of nanoparticles produced by biodegradable materials, and may help us to understand better the nanotoxicity of drug delivery carriers. PMID:22267920

  15. Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities.

    Science.gov (United States)

    Tirmenstein, Mark; Horvath, Joseph; Graziano, Michael; Mangipudy, Raja; Dorr, Thomas; Colman, Karyn; Zinker, Bradley; Kirby, Mark; Cheng, Peter T W; Patrone, Laura; Kozlosky, John; Reilly, Timothy P; Wang, Victor; Janovitz, Evan

    2015-08-01

    Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia. © 2015 by The Author(s).

  16. Modeling the evolution of the aerosol cloud of toxicants in the atmosphere

    Directory of Open Access Journals (Sweden)

    Bondarchuk Ivan

    2017-01-01

    Full Text Available Using the methods of mathematical modeling, the formation and evolution of aerosol clouds of toxicants in the atmosphere from the chemical industry enterprises, thermal power engineering and rocket carriers of space vehicles is analyzed. The processes of dynamic interaction of drops between themselves and a two-phase flow, processes of agglomeration, crushing and evaporation of aerosol particles are taken into account. The results of numerical calculations are presented.

  17. The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease.

    Science.gov (United States)

    Spincemaille, Pieter; Pham, Duc-Hung; Chandhok, Gursimran; Verbeek, Jef; Zibert, Andree; Libbrecht, Louis; Schmidt, Hartmut; Esguerra, Camila V; de Witte, Peter A M; Cammue, Bruno P A; Cassiman, David; Thevissen, Karin

    2014-10-15

    Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B(H1069Q), but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. USEtox - The UNEP-SETAC toxicity model: recommended characterisation factors for human toxicity and freshwater ecotoxicity in Life Cycle Impact Assessment

    DEFF Research Database (Denmark)

    Rosenbaum, Ralph K.; Bachmann, Till M; Gold, Lois S.

    2008-01-01

    key fate, exposure and effect issues via comparison of the final characterisation factors and selected intermediate outputs for fate, human exposure and toxic effects for the test set applied to all models. Results. Through this process, we were able to reduce inter-model variation from an initial...... variation between the CFs of each model respectively. The achieved reduction of inter-model variability by up to 11 orders of magnitude is a significant improvement. Conclusions. USEtox provides a parsimonious and transparent tool for human health and ecosystem CF estimates. Based on a referenced database......, it has now been used to calculate CFs for several thousand substances and forms the basis of the recommendations from UNEP-SETAC’s Life Cycle Initiative regarding characterization of toxic impacts in Life Cycle Assessment. Recommendations and Perspectives. We provide both recommended and interim (not...

  19. Generation of fluoroscopic 3D images with a respiratory motion model based on an external surrogate signal.

    Science.gov (United States)

    Hurwitz, Martina; Williams, Christopher L; Mishra, Pankaj; Rottmann, Joerg; Dhou, Salam; Wagar, Matthew; Mannarino, Edward G; Mak, Raymond H; Lewis, John H

    2015-01-21

    Respiratory motion during radiotherapy can cause uncertainties in definition of the target volume and in estimation of the dose delivered to the target and healthy tissue. In this paper, we generate volumetric images of the internal patient anatomy during treatment using only the motion of a surrogate signal. Pre-treatment four-dimensional CT imaging is used to create a patient-specific model correlating internal respiratory motion with the trajectory of an external surrogate placed on the chest. The performance of this model is assessed with digital and physical phantoms reproducing measured irregular patient breathing patterns. Ten patient breathing patterns are incorporated in a digital phantom. For each patient breathing pattern, the model is used to generate images over the course of thirty seconds. The tumor position predicted by the model is compared to ground truth information from the digital phantom. Over the ten patient breathing patterns, the average absolute error in the tumor centroid position predicted by the motion model is 1.4 mm. The corresponding error for one patient breathing pattern implemented in an anthropomorphic physical phantom was 0.6 mm. The global voxel intensity error was used to compare the full image to the ground truth and demonstrates good agreement between predicted and true images. The model also generates accurate predictions for breathing patterns with irregular phases or amplitudes.

  20. Generation of fluoroscopic 3D images with a respiratory motion model based on an external surrogate signal

    International Nuclear Information System (INIS)

    Hurwitz, Martina; Williams, Christopher L; Mishra, Pankaj; Rottmann, Joerg; Dhou, Salam; Wagar, Matthew; Mannarino, Edward G; Mak, Raymond H; Lewis, John H

    2015-01-01

    Respiratory motion during radiotherapy can cause uncertainties in definition of the target volume and in estimation of the dose delivered to the target and healthy tissue. In this paper, we generate volumetric images of the internal patient anatomy during treatment using only the motion of a surrogate signal. Pre-treatment four-dimensional CT imaging is used to create a patient-specific model correlating internal respiratory motion with the trajectory of an external surrogate placed on the chest. The performance of this model is assessed with digital and physical phantoms reproducing measured irregular patient breathing patterns. Ten patient breathing patterns are incorporated in a digital phantom. For each patient breathing pattern, the model is used to generate images over the course of thirty seconds. The tumor position predicted by the model is compared to ground truth information from the digital phantom. Over the ten patient breathing patterns, the average absolute error in the tumor centroid position predicted by the motion model is 1.4 mm. The corresponding error for one patient breathing pattern implemented in an anthropomorphic physical phantom was 0.6 mm. The global voxel intensity error was used to compare the full image to the ground truth and demonstrates good agreement between predicted and true images. The model also generates accurate predictions for breathing patterns with irregular phases or amplitudes. (paper)

  1. Dispersion modeling of accidental releases of toxic gases - Sensitivity study and optimization of the meteorological input

    Science.gov (United States)

    Baumann-Stanzer, K.; Stenzel, S.

    2009-04-01

    Several air dispersion models are available for prediction and simulation of the hazard areas associated with accidental releases of toxic gases. The most model packages (commercial or free of charge) include a chemical database, an intuitive graphical user interface (GUI) and automated graphical output for effective presentation of results. The models are designed especially for analyzing different accidental toxic release scenarios ("worst-case scenarios"), preparing emergency response plans and optimal countermeasures as well as for real-time risk assessment and management. Uncertainties in the meteorological input together with incorrect estimates of the source play a critical role for the model results. The research project RETOMOD (reference scenarios calculations for toxic gas releases - model systems and their utility for the fire brigade) was conducted by the Central Institute for Meteorology and Geodynamics (ZAMG) in cooperation with the Vienna fire brigade, OMV Refining & Marketing GmbH and Synex Ries & Greßlehner GmbH. RETOMOD was funded by the KIRAS safety research program at the Austrian Ministry of Transport, Innovation and Technology (www.kiras.at). The main tasks of this project were 1. Sensitivity study and optimization of the meteorological input for modeling of the hazard areas (human exposure) during the accidental toxic releases. 2. Comparison of several model packages (based on reference scenarios) in order to estimate the utility for the fire brigades. This presentation gives a short introduction to the project and presents the results of task 1 (meteorological input). The results of task 2 are presented by Stenzel and Baumann-Stanzer in this session. For the aim of this project, the observation-based analysis and forecasting system INCA, developed in the Central Institute for Meteorology and Geodynamics (ZAMG) was used. INCA (Integrated Nowcasting through Comprehensive Analysis) data were calculated with 1 km horizontal resolution and

  2. L-carnitine increases survival in a murine model of severe verapamil toxicity.

    Science.gov (United States)

    Perez, Eric; Chu, Jason; Bania, Theodore; Medlej, Kamal

    2011-11-01

    L-carnitine is an essential compound involved in cellular energy production through free fatty acid metabolism. It has been theorized that severe verapamil toxicity "shifts" heart energy production away from free fatty acids and toward other sources, contributing to profound cardiogenic shock. The primary study objective was to determine whether intravenous (IV) L-carnitine affects survival in severe verapamil toxicity. Secondary objectives were to determine the effects on hemodynamic parameters. The authors hypothesized that IV L-carnitine would increase both survival and hemodynamic parameters in severe verapamil toxicity. This was a controlled, blinded animal investigation. Sixteen male rats were anesthetized, ventilated, and instrumented to record mean arterial pressure (MAP) and heart rate. Verapamil toxicity was achieved by a constant infusion of 5 mg/kg/hr. After 5 minutes a bolus of 50 mg/kg of either L-carnitine or normal saline was given. The experiment concluded when either 10% of baseline MAP was achieved or 150 minutes had elapsed. The data were analyzed using Kaplan-Meier analysis, log rank test, and analysis of variance. The median survival for the animals in the L-carnitine group was 140.75 minutes (interquartile range [IQR] = 98.6 to 150 minutes), and for those in the normal saline group it was 49.19 minutes (IQR = 39.02 to 70.97 minutes; p = 0.0001). At 15 minutes the MAP was 20.45 mm Hg greater in the animals in the L-carnitine group than in the animals in the normal saline group (95% confidence interval [CI] = 0.25 to 40.65; p = 0.047). When compared with saline, IV L-carnitine increases survival and MAP in a murine model of severe verapamil toxicity. © 2011 by the Society for Academic Emergency Medicine.

  3. Large-scale assessment of the zebrafish embryo as a possible predictive model in toxicity testing.

    Directory of Open Access Journals (Sweden)

    Shaukat Ali

    Full Text Available BACKGROUND: In the drug discovery pipeline, safety pharmacology is a major issue. The zebrafish has been proposed as a model that can bridge the gap in this field between cell assays (which are cost-effective, but low in data content and rodent assays (which are high in data content, but less cost-efficient. However, zebrafish assays are only likely to be useful if they can be shown to have high predictive power. We examined this issue by assaying 60 water-soluble compounds representing a range of chemical classes and toxicological mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Over 20,000 wild-type zebrafish embryos (including controls were cultured individually in defined buffer in 96-well plates. Embryos were exposed for a 96 hour period starting at 24 hours post fertilization. A logarithmic concentration series was used for range-finding, followed by a narrower geometric series for LC(50 determination. Zebrafish embryo LC(50 (log mmol/L, and published data on rodent LD(50 (log mmol/kg, were found to be strongly correlated (using Kendall's rank correlation tau and Pearson's product-moment correlation. The slope of the regression line for the full set of compounds was 0.73403. However, we found that the slope was strongly influenced by compound class. Thus, while most compounds had a similar toxicity level in both species, some compounds were markedly more toxic in zebrafish than in rodents, or vice versa. CONCLUSIONS: For the substances examined here, in aggregate, the zebrafish embryo model has good predictivity for toxicity in rodents. However, the correlation between zebrafish and rodent toxicity varies considerably between individual compounds and compound class. We discuss the strengths and limitations of the zebrafish model in light of these findings.

  4. Dispersion modeling of accidental releases of toxic gases - Comparison of the models and their utility for the fire brigades.

    Science.gov (United States)

    Stenzel, S.; Baumann-Stanzer, K.

    2009-04-01

    Dispersion modeling of accidental releases of toxic gases - Comparison of the models and their utility for the fire brigades. Sirma Stenzel, Kathrin Baumann-Stanzer In the case of accidental release of hazardous gases in the atmosphere, the emergency responders need a reliable and fast tool to assess the possible consequences and apply the optimal countermeasures. For hazard prediction and simulation of the hazard zones a number of air dispersion models are available. The most model packages (commercial or free of charge) include a chemical database, an intuitive graphical user interface (GUI) and automated graphical output for display the results, they are easy to use and can operate fast and effective during stress situations. The models are designed especially for analyzing different accidental toxic release scenarios ("worst-case scenarios"), preparing emergency response plans and optimal countermeasures as well as for real-time risk assessment and management. There are also possibilities for model direct coupling to automatic meteorological stations, in order to avoid uncertainties in the model output due to insufficient or incorrect meteorological data. Another key problem in coping with accidental toxic release is the relative width spectrum of regulations and values, like IDLH, ERPG, AEGL, MAK etc. and the different criteria for their application. Since the particulate emergency responders and organizations require for their purposes unequal regulations and values, it is quite difficult to predict the individual hazard areas. There are a quite number of research studies and investigations coping with the problem, anyway the end decision is up to the authorities. The research project RETOMOD (reference scenarios calculations for toxic gas releases - model systems and their utility for the fire brigade) was conducted by the Central Institute for Meteorology and Geodynamics (ZAMG) in cooperation with the Vienna fire brigade, OMV Refining & Marketing GmbH and

  5. Modelling of polysomnographic respiratory measurements for artefact detection and signal restoration

    International Nuclear Information System (INIS)

    Rathnayake, S I; Abeyratne, U R; Hukins, C; Duce, B

    2008-01-01

    Polysomnography (PSG), which incorporates measures of sleep with measures of EEG arousal, air flow, respiratory movement and oxygenation, is universally regarded as the reference standard in diagnosing sleep-related respiratory diseases such as obstructive sleep apnoea syndrome. Over 15 channels of physiological signals are measured from a subject undergoing a typical overnight PSG session. The signals often suffer from data losses, interferences and artefacts. In a typical sleep scoring session, artefact-corrupted signal segments are visually detected and removed from further consideration. This is a highly time-consuming process, and subjective judgement is required for the job. During typical sleep scoring sessions, the target is the detection of segments of diagnostic interest, and signal restoration is not utilized for distorted segments. In this paper, we propose a novel framework for artefact detection and signal restoration based on the redundancy among respiratory flow signals. We focus on the air flow (thermistor sensors) and nasal pressure signals which are clinically significant in detecting respiratory disturbances. The method treats the respiratory system and other organs that provide respiratory-related inputs/outputs to it (e.g., cardiovascular, brain) as a possibly nonlinear coupled-dynamical system, and uses the celebrated Takens embedding theorem as the theoretical basis for signal prediction. Nonlinear prediction across time (self-prediction) and signals (cross-prediction) provides us with a mechanism to detect artefacts as unexplained deviations. In addition to detection, the proposed method carries the potential to correct certain classes of artefacts and restore the signal. In this study, we categorize commonly occurring artefacts and distortions in air flow and nasal pressure measurements into several groups and explore the efficacy of the proposed technique in detecting/recovering them. The results we obtained from a database of clinical

  6. Absence of respiratory inflammatory reaction of elemental sulfur using the California Pesticide Illness Database and a mouse model.

    Science.gov (United States)

    Lee, Kiyoung; Smith, Jodi L; Last, Jerold A

    2005-01-01

    Elemental sulfur, a natural substance, is used as a fungicide. Elemental sulfur is the most heavily used agricultural chemical in California. In 2003, annual sulfur usage in California was about 34% of the total weight of pesticide active ingredient used in production agriculture. Even though sulfur is mostly used in dust form, the respiratory health effects of elemental sulfur are not well documented. The purpose of this paper is to address the possible respiratory effect of elemental sulfur using the California Pesticide Illness Database and laboratory experiments with mice. We analyzed the California Pesticide Illness Database between 1991 and 2001. Among 127 reports of definite, probable, and possible illness involving sulfur, 21 cases (16%) were identified as respiratory related. A mouse model was used to examine whether there was an inflammatory or fibrotic response to elemental sulfur. Dust solutions were injected intratracheally into ovalbumin sensitized mice and lung damage was evaluated. Lung inflammatory response was analyzed via total lavage cell counts and differentials, and airway collagen content was analyzed histologically and biochemically. No significant differences from controls were seen in animals exposed to sulfur particles. The findings suggest that acute exposure of elemental sulfur itself may not cause an inflammatory reaction. However, further studies are needed to understand the possible health effects of chronic sulfur exposure and environmental weathering of sulfur dust.

  7. The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease

    Energy Technology Data Exchange (ETDEWEB)

    Spincemaille, Pieter [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium); Pham, Duc-Hung [Laboratory for Molecular Biodiscovery, KU Leuven, Campus Gasthuisberg, Herestraat 49, O and N2, 3000 Leuven (Belgium); Chandhok, Gursimran [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Verbeek, Jef [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Zibert, Andree [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Libbrecht, Louis [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Department of Pathology, University Hospital Ghent, De Pintelaan 185, 9000 Ghent (Belgium); Schmidt, Hartmut [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Esguerra, Camila V.; Witte, Peter A.M. de [Laboratory for Molecular Biodiscovery, KU Leuven, Campus Gasthuisberg, Herestraat 49, O and N2, 3000 Leuven (Belgium); Cammue, Bruno P.A., E-mail: bruno.cammue@biw.kuleuven.be [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium); Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent (Belgium); Cassiman, David [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Thevissen, Karin [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium)

    2014-10-15

    Background: Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods: The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results: OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B{sup H1069Q}, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. Conclusions: OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance: All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. - Highlights: • Wilson disease (WD) is characterized by accumulation of toxic copper (Cu). • OSIP108 increases viability of Cu-treated cellular models applicable to WD. • OSIP108 injections preserve liver morphology of Cu-treated zebrafish larvae. • OSIP108 injections into zebrafish larvae abrogates Cu-induced oxidative stress.

  8. SU-F-J-138: An Extension of PCA-Based Respiratory Deformation Modeling Via Multi-Linear Decomposition

    Energy Technology Data Exchange (ETDEWEB)

    Iliopoulos, AS; Sun, X [Duke University, Durham, North Carolina (United States); Pitsianis, N [Aristotle University of Thessaloniki (Greece); Duke University, Durham, North Carolina (United States); Yin, FF; Ren, L

    2016-06-15

    Purpose: To address and lift the limited degree of freedom (DoF) of globally bilinear motion components such as those based on principal components analysis (PCA), for encoding and modeling volumetric deformation motion. Methods: We provide a systematic approach to obtaining a multi-linear decomposition (MLD) and associated motion model from deformation vector field (DVF) data. We had previously introduced MLD for capturing multi-way relationships between DVF variables, without being restricted by the bilinear component format of PCA-based models. PCA-based modeling is commonly used for encoding patient-specific deformation as per planning 4D-CT images, and aiding on-board motion estimation during radiotherapy. However, the bilinear space-time decomposition inherently limits the DoF of such models by the small number of respiratory phases. While this limit is not reached in model studies using analytical or digital phantoms with low-rank motion, it compromises modeling power in the presence of relative motion, asymmetries and hysteresis, etc, which are often observed in patient data. Specifically, a low-DoF model will spuriously couple incoherent motion components, compromising its adaptability to on-board deformation changes. By the multi-linear format of extracted motion components, MLD-based models can encode higher-DoF deformation structure. Results: We conduct mathematical and experimental comparisons between PCA- and MLD-based models. A set of temporally-sampled analytical trajectories provides a synthetic, high-rank DVF; trajectories correspond to respiratory and cardiac motion factors, including different relative frequencies and spatial variations. Additionally, a digital XCAT phantom is used to simulate a lung lesion deforming incoherently with respect to the body, which adheres to a simple respiratory trend. In both cases, coupling of incoherent motion components due to a low model DoF is clearly demonstrated. Conclusion: Multi-linear decomposition can

  9. A search for an animal model of the Spanish toxic oil syndrome.

    Science.gov (United States)

    Hard, G C

    2002-11-01

    To date, pathology characteristics of toxic oil syndrome (TOS), a disease associated with consumption of a contaminated cooking oil in Spain in 1981, have not been reproduced in an animal model. As vasculitis, eosinophilia, and a rise in circulating IgE levels were features of the acute phase of TOS, leading to an autoimmune outcome, a review of predisposition to these aspects across species was conducted. The intent was to determine predisposed strains or species that potentially might be effective in testing the toxic oils and thus defining the precise identity of the toxic contaminant(s). A number of potential candidates emerge from this review. Among mice, these include the NZB mouse hybrids, the MRL/lpr and SJL/J strains, and a transgenic mouse model of eosinophilia. The Brown Norway may be the most appropriate rat strain, while beagle dogs inbred to be genetically predisposed to immune complex disease and vasculitis are also a candidate species. Of the more exotic species, the mink and ferret have characteristics that might make them suitable candidates for testing oil samples.

  10. Use of physiologically based kinetic modeling-facilitated reverse dosimetry of in vitro toxicity data for prediction of in vivo developmental toxicity of tebuconazole in rats.

    Science.gov (United States)

    Li, Hequn; Zhang, Mengying; Vervoort, Jacques; Rietjens, Ivonne M C M; van Ravenzwaay, Bennard; Louisse, Jochem

    2017-01-15

    Toxicological hazard and risk assessment largely rely on animal testing. For economic and ethical reasons, the development and validation of reliable alternative methods for these animal studies, such as in vitro assays, are urgently needed. In vitro concentration-response curves, however, need to be translated into in vivo dose-response curves for risk assessment purposes. In the present study, we translated in vitro concentration-response data of the antifungal compound tebuconazole, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose-response data for developmental toxicity using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry. Using the predicted in vivo dose-response data BMD(L)10 values for developmental toxicity in rat were calculated and compared with NOAEL values for developmental toxicity data in rats as reported in the literature. The results show that the BMDL10 value from predicted dose-response data are a reasonable approximation of the NOAEL values (ca. 3-fold difference). It is concluded that PBK modeling-facilitated reverse dosimetry of in vitro toxicity data is a promising tool to predict in vivo dose-response curves and may have the potential to define a point of departure for deriving safe exposure limits in risk assessment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Modeling of Respiratory System Dysfunction Among Nuclear Workers: A Preliminary Study

    OpenAIRE

    Belyaeva, Z.D.; Osovets, S.V.; Scott, B.R.; Zhuntova, G.V.; Grigoryeva, E.S.

    2008-01-01

    Numerous studies have reported on cancers among Mayak Production Association (PA) nuclear workers. Other studies have reported on serious deterministic effects of large radiation doses for the same population. This study relates to deterministic effects (respiratory system dysfunction) in Mayak workers after relatively small chronic radiation doses (alpha plus gamma). Because cigarette smoke is a confounding factor, we also account for smoking effects. Here we present a new empirical mathemat...

  12. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.

    Science.gov (United States)

    Shi, Ting; McAllister, David A; O'Brien, Katherine L; Simoes, Eric A F; Madhi, Shabir A; Gessner, Bradford D; Polack, Fernando P; Balsells, Evelyn; Acacio, Sozinho; Aguayo, Claudia; Alassani, Issifou; Ali, Asad; Antonio, Martin; Awasthi, Shally; Awori, Juliet O; Azziz-Baumgartner, Eduardo; Baggett, Henry C; Baillie, Vicky L; Balmaseda, Angel; Barahona, Alfredo; Basnet, Sudha; Bassat, Quique; Basualdo, Wilma; Bigogo, Godfrey; Bont, Louis; Breiman, Robert F; Brooks, W Abdullah; Broor, Shobha; Bruce, Nigel; Bruden, Dana; Buchy, Philippe; Campbell, Stuart; Carosone-Link, Phyllis; Chadha, Mandeep; Chipeta, James; Chou, Monidarin; Clara, Wilfrido; Cohen, Cheryl; de Cuellar, Elizabeth; Dang, Duc-Anh; Dash-Yandag, Budragchaagiin; Deloria-Knoll, Maria; Dherani, Mukesh; Eap, Tekchheng; Ebruke, Bernard E; Echavarria, Marcela; de Freitas Lázaro Emediato, Carla Cecília; Fasce, Rodrigo A; Feikin, Daniel R; Feng, Luzhao; Gentile, Angela; Gordon, Aubree; Goswami, Doli; Goyet, Sophie; Groome, Michelle; Halasa, Natasha; Hirve, Siddhivinayak; Homaira, Nusrat; Howie, Stephen R C; Jara, Jorge; Jroundi, Imane; Kartasasmita, Cissy B; Khuri-Bulos, Najwa; Kotloff, Karen L; Krishnan, Anand; Libster, Romina; Lopez, Olga; Lucero, Marilla G; Lucion, Florencia; Lupisan, Socorro P; Marcone, Debora N; McCracken, John P; Mejia, Mario; Moisi, Jennifer C; Montgomery, Joel M; Moore, David P; Moraleda, Cinta; Moyes, Jocelyn; Munywoki, Patrick; Mutyara, Kuswandewi; Nicol, Mark P; Nokes, D James; Nymadawa, Pagbajabyn; da Costa Oliveira, Maria Tereza; Oshitani, Histoshi; Pandey, Nitin; Paranhos-Baccalà, Gláucia; Phillips, Lia N; Picot, Valentina Sanchez; Rahman, Mustafizur; Rakoto-Andrianarivelo, Mala; Rasmussen, Zeba A; Rath, Barbara A; Robinson, Annick; Romero, Candice; Russomando, Graciela; Salimi, Vahid; Sawatwong, Pongpun; Scheltema, Nienke; Schweiger, Brunhilde; Scott, J Anthony G; Seidenberg, Phil; Shen, Kunling; Singleton, Rosalyn; Sotomayor, Viviana; Strand, Tor A; Sutanto, Agustinus; Sylla, Mariam; Tapia, Milagritos D; Thamthitiwat, Somsak; Thomas, Elizabeth D; Tokarz, Rafal; Turner, Claudia; Venter, Marietjie; Waicharoen, Sunthareeya; Wang, Jianwei; Watthanaworawit, Wanitda; Yoshida, Lay-Myint; Yu, Hongjie; Zar, Heather J; Campbell, Harry; Nair, Harish

    2017-09-02

    We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population. Globally, RSV is a common cause

  13. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Directory of Open Access Journals (Sweden)

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  14. Metal Oxide Nanomaterial QNAR Models: Available Structural Descriptors and Understanding of Toxicity Mechanisms

    Directory of Open Access Journals (Sweden)

    Jiali Ying

    2015-10-01

    Full Text Available Metal oxide nanomaterials are widely used in various areas; however, the divergent published toxicology data makes it difficult to determine whether there is a risk associated with exposure to metal oxide nanomaterials. The application of quantitative structure activity relationship (QSAR modeling in metal oxide nanomaterials toxicity studies can reduce the need for time-consuming and resource-intensive nanotoxicity tests. The nanostructure and inorganic composition of metal oxide nanomaterials makes this approach different from classical QSAR study; this review lists and classifies some structural descriptors, such as size, cation charge, and band gap energy, in recent metal oxide nanomaterials quantitative nanostructure activity relationship (QNAR studies and discusses the mechanism of metal oxide nanomaterials toxicity based on these descriptors and traditional nanotoxicity tests.

  15. Caenorhabditis elegans as a Model for Toxic Effects of Nanoparticles: Lethality, Growth, and Reproduction.

    Science.gov (United States)

    Maurer, Laura L; Ryde, Ian T; Yang, Xinyu; Meyer, Joel N

    2015-11-02

    The nematode Caenorhabditis elegans is extensively utilized in toxicity studies. C. elegans offers a high degree of homology with higher organisms, and its ease of use and relatively inexpensive maintenance have made it an attractive complement to mammalian and ecotoxicological models. C. elegans provides multiple benefits, including the opportunity to perform relatively high-throughput assays on whole organisms, a wide range of genetic tools permitting investigation of mechanisms and genetic sensitivity, and transparent bodies that facilitate toxicokinetic studies. This unit describes protocols for three nanotoxicity assays in C. elegans: lethality, growth, and reproduction. This unit focuses on how to use these well-established assays with nanoparticles, which are being produced in ever-increasing volume and exhibit physicochemical properties that require alteration of standard toxicity assays. These assays permit a broad phenotypic assessment of nanotoxicity in C. elegans, and, when used in combination with genetic tools and other assays, also permit mechanistic insight. Copyright © 2015 John Wiley & Sons, Inc.

  16. A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy

    International Nuclear Information System (INIS)

    Hobbs, Robert F; Song Hong; Sgouros, George; Watchman, Christopher J; Bolch, Wesley E; Aksnes, Anne-Kirsti; Ramdahl, Thomas; Flux, Glenn D

    2012-01-01

    Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the

  17. Development of a biotic ligand model and a regression model predicting acute copper toxicity to the earthworm Aporrectodea caliginosa.

    Science.gov (United States)

    Steenbergen, Nathanaël T T M; Iaccino, Federica; de Winkel, Maaike; Reijnders, Lucas; Peijnenburg, Willie J G M

    2005-08-01

    The purpose of this study was to develop a terrestrial biotic ligand model (BLM) for predicting acute copper toxicity to the earthworm Aporrectodea caliginosa. To overcome the basic problems hampering development of BLMs for terrestrial organisms, an artificial flow-through exposure system was developed consisting of an inert quartz sand matrix and a nutrient solution, of which the composition was univariately modified. A. caliginosa was exposed for 7 days under varying concentrations of copper and the major cations modifying toxicity: H+, Ca2+, Mg2+, and Na+. In addition copper speciation was modulated by means of EDTA or dissolved organic carbon (DOC). An increase in pH or pNa resulted in a linear decrease of 7-days median lethal concentrations. Increasing Ca2+ and Mg2+ activities had inconsistent effects. EDTA addition decreased toxicity when the total copper concentration in the pore water was kept the same. This is attributed to the strong complexation capacity of EDTA and shows that total copper is not the toxic species. DOC was more protective than could be explained by its metal complexing properties. The BLM developed incorporates the effects of H+ and Na+. This BLM was validated with the results of a set of bioassays with artificial pore water in quartz sand and by a set of bioassays in spiked field soils. Prediction error was within a factor of 2, but some predictions were not within the 95% confidence interval. Therefore a more widely applicable regression type model was developed that was able to explain >95% of the (lack of) toxicity observed. To our knowledge this is the first report of the successful development of a terrestrial BLM.

  18. Modelling of accidental released toxic gases for emergency responders in Austria, Kosovo and Bulgaria.

    Science.gov (United States)

    Stenzel, Sirma; Baumann-Stanzer, Kathrin; Gashi, Salih; Thaci, Bashkim; Batchvarova, Ekaterina; Spassova, Tatiana

    2010-05-01

    In the case of accidental release of hazardous gases in the atmosphere, the emergency responders need a reliable and fast tool to assess the possible consequences and apply the optimal countermeasures. A number of models for the prediction and simulation of hazard areas affected by accidental releases of toxic gases are available worldwide. Modelling accidental releases may be required for a variety of reasons: for analyzing different accidental toxic release scenarios ("worst-case scenarios"), for preparing emergency response plans and optimal countermeasures as well as for real-time risk assessment and management (e.g. in the frame of the SEVESO directive). Depending on the demand and the particular purposes, the choice of the appropriate model is up to the authorities. The one year project was funded by the Austrian Science and research liaison Office (ASO, www.aso.zsi.at) as a part of the program: Research Cooperation and Networking between Austria, the public higher education institutions in Kosovo and South Eastern Europe. The project was conducted by the Central Institute for Meteorology and Geodynamics (ZAMG, http://www.zamg.ac.at) in cooperation with the University of Prishtina (Kosovo, www.uni-pr.edu and the National Institute of meteorology and Hydrology (NIHM Bulgaria, www.meteo.bg). One of the main purposes of the project was to provide the both partners with basic knowledge in modelling with accidental release of toxic gases, based on the practical experience of the meteorologists from the ZAMG in the area. This knowledge can be used as scientific response to society driven current or upcoming problems especially in Kosovo. The activities involved know-how transfer on European standards and practice among the project partners, as well as joint efforts to adapt and disseminate the scientific methods and results in Kosovo. Within the project, the partners from Kosovo and Bulgaria were introduced to the atmospheric dispersion model (ALOHA - Areal

  19. The influence of toxicity constraints in models of chemotherapeutic protocol escalation

    KAUST Repository

    Boston, E. A. J.

    2011-04-06

    The prospect of exploiting mathematical and computational models to gain insight into the influence of scheduling on cancer chemotherapeutic effectiveness is increasingly being considered. However, the question of whether such models are robust to the inclusion of additional tumour biology is relatively unexplored. In this paper, we consider a common strategy for improving protocol scheduling that has foundations in mathematical modelling, namely the concept of dose densification, whereby rest phases between drug administrations are reduced. To maintain a manageable scope in our studies, we focus on a single cell cycle phase-specific agent with uncomplicated pharmacokinetics, as motivated by 5-Fluorouracil-based adjuvant treatments of liver micrometastases. In particular, we explore predictions of the effectiveness of dose densification and other escalations of the protocol scheduling when the influence of toxicity constraints, cell cycle phase specificity and the evolution of drug resistance are all represented within the modelling. For our specific focus, we observe that the cell cycle and toxicity should not simply be neglected in modelling studies. Our explorations also reveal the prediction that dose densification is often, but not universally, effective. Furthermore, adjustments in the duration of drug administrations are predicted to be important, especially when dose densification in isolation does not yield improvements in protocol outcomes. © The author 2011. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

  20. Viscoelastic Model for Lung Parenchyma for Multi-Scale Modeling of Respiratory System, Phase II: Dodecahedral Micro-Model

    Energy Technology Data Exchange (ETDEWEB)

    Freed, Alan D.; Einstein, Daniel R.; Carson, James P.; Jacob, Rick E.

    2012-03-01

    In the first year of this contractual effort a hypo-elastic constitutive model was developed and shown to have great potential in modeling the elastic response of parenchyma. This model resides at the macroscopic level of the continuum. In this, the second year of our support, an isotropic dodecahedron is employed as an alveolar model. This is a microscopic model for parenchyma. A hopeful outcome is that the linkage between these two scales of modeling will be a source of insight and inspiration that will aid us in the final year's activity: creating a viscoelastic model for parenchyma.

  1. Predicting toxic effects of copper on aquatic biota in mineralized areas by using the Biotic Ligand Model

    Science.gov (United States)

    Smith, Kathleen S.; Ranville, James F.; Adams, M.; Choate, LaDonna M.; Church, Stan E.; Fey, David L.; Wanty, Richard B.; Crock, James G.

    2006-01-01

    The chemical speciation of metals influences their biological effects. The Biotic Ligand Model (BLM) is a computational approach to predict chemical speciation and acute toxicological effects of metals on aquatic biota. Recently, the U.S. Environmental Protection Agency incorporated the BLM into their regulatory water-quality criteria for copper. Results from three different laboratory copper toxicity tests were compared with BLM predictions for simulated test-waters. This was done to evaluate the ability of the BLM to accurately predict the effects of hardness and concentrations of dissolved organic carbon (DOC) and iron on aquatic toxicity. In addition, we evaluated whether the BLM and the three toxicity tests provide consistent results. Comparison of BLM predictions with two types of Ceriodaphnia dubia toxicity tests shows that there is fairly good agreement between predicted LC50 values computed by the BLM and LC50 values determined from the two toxicity tests. Specifically, the effect of increasing calcium concentration (and hardness) on copper toxicity appears to be minimal. Also, there is fairly good agreement between the BLM and the two toxicity tests for test solutions containing elevated DOC, for which the LC50 is 3-to-5 times greater (less toxic) than the LC50 for the lower-DOC test water. This illustrates the protective effects of DOC on copper toxicity and demonstrates the ability of the BLM to predict these protective effects. In contrast, for test solutions with added iron there is a decrease in LC50 values (increase in toxicity) in results from the two C. dubia toxicity tests, and the agreement between BLM LC50 predictions and results from these toxicity tests is poor. The inability of the BLM to account for competitive iron binding to DOC or DOC fractionation may be a significant shortcoming of the BLM for predicting site- specific water-quality criteria in streams affected by iron-rich acidic drainage in mined and mineralized areas.

  2. Real-time prediction of respiratory motion based on a local dynamic model in an augmented space.

    Science.gov (United States)

    Hong, S-M; Jung, B-H; Ruan, D

    2011-03-21

    Motion-adaptive radiotherapy aims to deliver ablative radiation dose to the tumor target with minimal normal tissue exposure, by accounting for real-time target movement. In practice, prediction is usually necessary to compensate for system latency induced by measurement, communication and control. This work focuses on predicting respiratory motion, which is most dominant for thoracic and abdominal tumors. We develop and investigate the use of a local dynamic model in an augmented space, motivated by the observation that respiratory movement exhibits a locally circular pattern in a plane augmented with a delayed axis. By including the angular velocity as part of the system state, the proposed dynamic model effectively captures the natural evolution of respiratory motion. The first-order extended Kalman filter is used to propagate and update the state estimate. The target location is predicted by evaluating the local dynamic model equations at the required prediction length. This method is complementary to existing work in that (1) the local circular motion model characterizes 'turning', overcoming the limitation of linear motion models; (2) it uses a natural state representation including the local angular velocity and updates the state estimate systematically, offering explicit physical interpretations; (3) it relies on a parametric model and is much less data-satiate than the typical adaptive semiparametric or nonparametric method. We tested the performance of the proposed method with ten RPM traces, using the normalized root mean squared difference between the predicted value and the retrospective observation as the error metric. Its performance was compared with predictors based on the linear model, the interacting multiple linear models and the kernel density estimator for various combinations of prediction lengths and observation rates. The local dynamic model based approach provides the best performance for short to medium prediction lengths under relatively

  3. Assessment of dermal toxicity of nanosilica using cultured keratinocytes, a human skin equivalent model and an invivo model

    International Nuclear Information System (INIS)

    Park, Yoon-Hee; Kim, Ji Na; Jeong, Sang Hoon; Choi, Jae Eun; Lee, Seung-Ho; Choi, Byeong Hyeok; Lee, Jung Pyo; Sohn, Kyung Hee; Park, Kui Lea; Kim, Meyoung-Kon; Son, Sang Wook

    2010-01-01

    Assessments of skin irritation potentials are important aspects of the development of nanotechnology. Nanosilica is currently being widely used for commercial purposes, but little literature is available on its skin toxicity and irritation potential. This study was designed to determine whether nanosilica has the potential to cause acute cutaneous toxicity, using cultured HaCaT keratinocytes (CHK), a human skin equivalent model (HSEM), and invivo model. Nanosilica was characterized by scanning electron microscopy. We evaluated the cytotoxic effects of nanosilica on CHKs and the HSEM. In addition, we also investigated whether two commercially available nanosilicas with different sizes (7 and 10-20 nm) have different effects. To confirm invitro results, we evaluated the irritation potentials of nanosilicas on rabbit skin. Nanosilicas reduced the cell viabilities of CHKs in a dose-dependent manner. However, the HSEM revealed no irritation at 500 μg/ml of nanosilica. Furthermore, this result concurred with Draize skin irritation test findings. The present study data indicate that nanosilica does not cause acute cutaneous irritation. Furthermore, this study shows that the HSEM used provides more useful screening data than the conventional cell culture model on the relative toxicities of NPs.

  4. Uptake, translocation and elimination in sediment-rooted macrophytes: A model-supported analysis of whole sediment toxicity test data

    NARCIS (Netherlands)

    Diepens, N.J.; Arts, G.H.P.; Focks, A.; Koelmans, A.A.

    2014-01-01

    Understanding bioaccumulation in sediment-rooted macrophytes is crucial for the development of sediment toxicity tests using macrophytes. Here we explore bioaccumulation in sediment-rooted macrophytes by tracking and modelling chemical flows of chlorpyrifos, linuron, and six PCBs in

  5. (CCUGn RNA toxicity in a Drosophila model of myotonic dystrophy type 2 (DM2 activates apoptosis

    Directory of Open Access Journals (Sweden)

    Vildan Betul Yenigun

    2017-08-01

    Full Text Available The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1 and type 2 (DM2 are caused by different unstable, noncoding microsatellite repeat expansions – (CTGDM1 in DMPK and (CCTGDM2 in CNBP. Although transcription of mutant repeats into (CUGDM1 or (CCUGDM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUGDM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUGn repeats of variable length (n=16 and 106. Expression of noncoding (CCUG106, but not (CCUG16, in muscle and retinal cells led to the formation of ribonuclear foci and mis-splicing of genes implicated in DM pathology. Mis-splicing could be rescued by co-expression of human MBNL1, but not by CUGBP1 (CELF1 complementation. Flies with (CCUG106 displayed strong disruption of external eye morphology and of the underlying retina. Furthermore, expression of (CCUG106 in developing retinae caused a strong apoptotic response. Inhibition of apoptosis rescued the retinal disruption in (CCUG106 flies. Finally, we tested two chemical compounds that have shown therapeutic potential in DM1 models. Whereas treatment of (CCUG106 flies with pentamidine had no effect, treatment with a PKR inhibitor blocked both the formation of RNA foci and apoptosis in retinae of (CCUG106 flies. Our data indicate that expression of expanded (CCUGDM2 repeats is toxic, causing inappropriate cell death in affected fly eyes. Our Drosophila DM2 model might provide a convenient tool for in vivo drug screening.

  6. Age modulates Fe3O4 nanoparticles liver toxicity: dose-dependent decrease in mitochondrial respiratory chain complexes activities and coupling in middle-aged as compared to young rats.

    Science.gov (United States)

    Baratli, Yosra; Charles, Anne-Laure; Wolff, Valérie; Ben Tahar, Lotfi; Smiri, Leila; Bouitbir, Jamal; Zoll, Joffrey; Sakly, Mohsen; Auger, Cyril; Vogel, Thomas; Abdelmelek, Hafedh; Tebourbi, Olfa; Geny, Bernard

    2014-01-01

    We examined the effects of iron oxide nanoparticles (IONPs) on mitochondrial respiratory chain complexes activities and mitochondrial coupling in young (3 months) and middle-aged (18 months) rat liver, organ largely involved in body iron detoxification. Isolated liver mitochondria were extracted using differential centrifugations. Maximal oxidative capacities (V(max), complexes I, III, and IV activities), V(succ) (complexes II, III, and IV activities), and V tmpd, (complex IV activity), together with mitochondrial coupling (V(max)/V0) were determined in controls conditions and after exposure to 250, 300, and 350 μ g/ml Fe3O4 in young and middle-aged rats. In young liver mitochondria, exposure to IONPs did not alter mitochondrial function. In contrast, IONPs dose-dependently impaired all complexes of the mitochondrial respiratory chain in middle-aged rat liver: V(max) (from 30 ± 1.6 to 17.9 ± 1.5; P V(succ) (from 33.9 ± 1.7 to 24.3 ± 1.0; P V(tmpd) (from 43.0 ± 1.6 to 26.3 ± 2.2 µmol O2/min/g protein; P < 0.001) using Fe3O4 350 µg/ml. Mitochondrial coupling also decreased. Interestingly, 350 μ g/ml Fe3O4 in the form of Fe(3+) solution did not impair liver mitochondrial function in middle-aged rats. Thus, IONPs showed a specific toxicity in middle-aged rats suggesting caution when using it in old age.

  7. Concentration addition and independent action model: Which is better in predicting the toxicity for metal mixtures on zebrafish larvae.

    Science.gov (United States)

    Gao, Yongfei; Feng, Jianfeng; Kang, Lili; Xu, Xin; Zhu, Lin

    2018-01-01

    The joint toxicity of chemical mixtures has emerged as a popular topic, particularly on the additive and potential synergistic actions of environmental mixtures. We investigated the 24h toxicity of Cu-Zn, Cu-Cd, and Cu-Pb and 96h toxicity of Cd-Pb binary mixtures on the survival of zebrafish larvae. Joint toxicity was predicted and compared using the concentration addition (CA) and independent action (IA) models with different assumptions in the toxic action mode in toxicodynamic processes through single and binary metal mixture tests. Results showed that the CA and IA models presented varying predictive abilities for different metal combinations. For the Cu-Cd and Cd-Pb mixtures, the CA model simulated the observed survival rates better than the IA model. By contrast, the IA model simulated the observed survival rates better than the CA model for the Cu-Zn and Cu-Pb mixtures. These findings revealed that the toxic action mode may depend on the combinations and concentrations of tested metal mixtures. Statistical analysis of the antagonistic or synergistic interactions indicated that synergistic interactions were observed for the Cu-Cd and Cu-Pb mixtures, non-interactions were observed for the Cd-Pb mixtures, and slight antagonistic interactions for the Cu-Zn mixtures. These results illustrated that the CA and IA models are consistent in specifying the interaction patterns of binary metal mixtures. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Introducing Toxics

    Directory of Open Access Journals (Sweden)

    David C. Bellinger

    2013-04-01

    Full Text Available With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present their work in as much detail as they wish. Toxics will publish original research papers, conventional reviews, meta-analyses, short communications, theoretical papers, case reports, commentaries and policy perspectives, and book reviews (Book reviews will be solicited and should not be submitted without invitation. Toxins and toxicants concern individuals from a wide range of disciplines, and Toxics is interested in receiving papers that represent the full range of approaches applied to their study, including in vitro studies, studies that use experimental animal or non-animal models, studies of humans or other biological populations, and mathematical modeling. We are excited to get underway and look forward to working with authors in the scientific and medical communities and providing them with a novel venue for sharing their work. [...

  9. Toxicity assessment and modelling of Moringa oleifera seeds in water purification by whole cell bioreporter.

    Science.gov (United States)

    Al-Anizi, Ali Adnan; Hellyer, Maria Theresa; Zhang, Dayi

    2014-06-01

    Moringa oleifera has been used as a coagulation reagent for drinking water purification, especially in developing countries such as Malawi. This research revealed the cytoxicity and genotoxicity of M. oleifera by Acinetobacter bioreporter. The results indicated that significant cytoxicity effects were observed when the powdered M. oleifera seeds concentration is from 1 to 50 mg/L. Through direct contact, ethanolic-water extraction and hexane extraction, the toxic effects of hydrophobic and hydrophilic components in M. oleifera seeds were distinguished. It suggested that the hydrophobic lipids contributed to the dominant cytoxicity, consequently resulting in the dominant genotoxicity in the water-soluble fraction due to limited dissolution when the M. oleifera seeds granule concentration was from 10 to 1000 mg/L. Based on cytoxicity and genotoxicity model, the LC50 and LC90 of M. oleifera seeds were 8.5 mg/L and 300 mg/L respectively and their genotoxicity was equivalent to 8.3 mg mitomycin C per 1.0 g dry M. oleifera seed. The toxicity of M. oleifera has also remarkable synergistic effects, suggesting whole cell bioreporter as an appropriate and complementary tool to chemical analysis for environmental toxicity assessment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Modeling the effects of reformulated gasoline usages on ambient concentrations of ozone and five air toxics

    International Nuclear Information System (INIS)

    Ligocki, M.P.; Schulhof, R.R.; Jackson, R.E.; Jimenez, M.M.; Atkinson, D.

    1993-01-01

    The use of reformulated gasolines to reduce motor-vehicle-related hydrocarbon emissions has been mandated by the 1990 Clean Air Act Amendments for nine severely polluted urban areas. Using a version of the Urban Airshed Model that includes explicit representation of five motor-vehicle-related air toxics, the effects of reformulated gasoline usage on ambient ozone and toxics concentrations were simulated. Simulations were conducted for two urban areas. Baltimore-Washington and Houston, for the year 1995. Additional simulation were conducted for Baltimore-Washington including winter and 1999 scenarios. In the Baltimore-Washington areas, the 1995 Federal reformulated gasoline scenario produce reductions of 1.1 percent in simulated peak ozone and 2.7 percent in the areal extent of simulated ozone exceedances. Simulated ozone reductions were much smaller in Houston. In the reformulated gasoline simulations, secondary formulation of formaldehyde and acetaldehyde was reduced, and decreases in ambient benzene and polycyclic organic matter (POM) concentrations were simulated. Larger reductions in ozone and toxics concentrations were simulated for reformulated gasolines meeting California Phase II standards than for those meeting Federal standards. The effects of reductions in motor-vehicle-related nitrogen oxides (NO x ) emissions, alone and in combination with hydrocarbon reductions, were also examined

  11. Surface ligand dependent toxicity of zinc oxide nanoparticles in HepG2 cell model

    International Nuclear Information System (INIS)

    Bartczak, D; Baradez, M-O; Merson, S; Goenaga-Infante, H; Marshall, D

    2013-01-01

    Physicochemical properties of nanoparticles (NP) strongly affect their influence on cell behaviour, but can be significantly distorted by interactions with the proteins present in biological solutions. In this study we show how different surface functionalities of zinc oxide (ZnO) NP lead to changes in the size distribution and dissolution of the NP in serum containing cell culture media and how this impacts on NP toxicity. NPs capped with weakly bound large proteins undergo substantial transformations due to the exchange of the original surface ligands to the components of the cell culture media. Conversely, NP capped with a tight monolayer of small organic molecules or with covalently conjugated proteins show significantly higher stability. These differences in ligand exchange also affect the toxicity of the NP to the HepG2 liver cell model, with the NP capped with small organic molecules being more toxic than those capped with large proteins. This study highlights the importance of characterising NPs in biological media and the effect the media has during in-vitro analysis.

  12. A new Caenorhabditis elegans model of human huntingtin 513 aggregation and toxicity in body wall muscles.

    Directory of Open Access Journals (Sweden)

    Amy L Lee

    Full Text Available Expanded polyglutamine repeats in different proteins are the known determinants of at least nine progressive neurodegenerative disorders whose symptoms include cognitive and motor impairment that worsen as patients age. One such disorder is Huntington's Disease (HD that is caused by a polyglutamine expansion in the human huntingtin protein (htt. The polyglutamine expansion destabilizes htt leading to protein misfolding, which in turn triggers neurodegeneration and the disruption of energy metabolism in muscle cells. However, the molecular mechanisms that underlie htt proteotoxicity have been somewhat elusive, and the muscle phenotypes have not been well studied. To generate tools to elucidate the basis for muscle dysfunction, we engineered Caenorhabditis elegans to express a disease-associated 513 amino acid fragment of human htt in body wall muscle cells. We show that this htt fragment aggregates in C. elegans in a polyglutamine length-dependent manner and is toxic. Toxicity manifests as motor impairment and a shortened lifespan. Compared to previous models, the data suggest that the protein context in which a polyglutamine tract is embedded alters aggregation propensity and toxicity, likely by affecting interactions with the muscle cell environment.

  13. Toxicity of Nanoparticles on the Reproductive System in Animal Models: A Review

    Directory of Open Access Journals (Sweden)

    Rahim Dad Brohi

    2017-09-01

    Full Text Available In the last two decades, nanotechnologies demonstrated various applications in different fields, including detection, sensing, catalysis, electronics, and biomedical sciences. However, public concerns regarding the well-being of human may hinder the wide utilization of this promising innovation. Although, humans are exposed to airborne nanosized particles from an early age, exposure to such particles has risen dramatically within the last century due to anthropogenic sources of nanoparticles. The wide application of nanomaterials in industry, consumer products, and medicine has raised concerns regarding the potential toxicity of nanoparticles in humans. In this review, the effects of nanomaterials on the reproductive system in animal models are discussed. Females are particularly more vulnerable to nanoparticle toxicity, and toxicity in this population may affect reproductivity and fetal development. Moreover, various types of nanoparticles have negative impacts on male germ cells, fetal development, and the female reproductive system. These impacts are associated with nanoparticle modification, composition, concentration, route of administration, and the species of the animal. Therefore, understanding the impacts of nanoparticles on animal growth and reproduction is essential. Many studies have examined the effects of nanoparticles on primary and secondary target organs, with a concentration on the in vivo and in vitro effects of nanoparticles on the male and female reproductive systems at the clinical, cellular, and molecular levels. This review provides important information regarding organism safety and the potential hazards of nanoparticle use and supports the application of nanotechnologies by minimizing the adverse effects of nanoparticles in vulnerable populations.

  14. Toxicity of Nanoparticles on the Reproductive System in Animal Models: A Review

    Science.gov (United States)

    Brohi, Rahim Dad; Wang, Li; Talpur, Hira Sajjad; Wu, Di; Khan, Farhan Anwar; Bhattarai, Dinesh; Rehman, Zia-Ur; Farmanullah, F.; Huo, Li-Jun

    2017-01-01

    In the last two decades, nanotechnologies demonstrated various applications in different fields, including detection, sensing, catalysis, electronics, and biomedical sciences. However, public concerns regarding the well-being of human may hinder the wide utilization of this promising innovation. Although, humans are exposed to airborne nanosized particles from an early age, exposure to such particles has risen dramatically within the last century due to anthropogenic sources of nanoparticles. The wide application of nanomaterials in industry, consumer products, and medicine has raised concerns regarding the potential toxicity of nanoparticles in humans. In this review, the effects of nanomaterials on the reproductive system in animal models are discussed. Females are particularly more vulnerable to nanoparticle toxicity, and toxicity in this population may affect reproductivity and fetal development. Moreover, various types of nanoparticles have negative impacts on male germ cells, fetal development, and the female reproductive system. These impacts are associated with nanoparticle modification, composition, concentration, route of administration, and the species of the animal. Therefore, understanding the impacts of nanoparticles on animal growth and reproduction is essential. Many studies have examined the effects of nanoparticles on primary and secondary target organs, with a concentration on the in vivo and in vitro effects of nanoparticles on the male and female reproductive systems at the clinical, cellular, and molecular levels. This review provides important information regarding organism safety and the potential hazards of nanoparticle use and supports the application of nanotechnologies by minimizing the adverse effects of nanoparticles in vulnerable populations. PMID:28928662

  15. Surface ligand dependent toxicity of zinc oxide nanoparticles in HepG2 cell model

    Science.gov (United States)

    Bartczak, D.; Baradez, M.-O.; Merson, S.; Goenaga-Infante, H.; Marshall, D.

    2013-04-01

    Physicochemical properties of nanoparticles (NP) strongly affect their influence on cell behaviour, but can be significantly distorted by interactions with the proteins present in biological solutions. In this study we show how different surface functionalities of zinc oxide (ZnO) NP lead to changes in the size distribution and dissolution of the NP in serum containing cell culture media and how this impacts on NP toxicity. NPs capped with weakly bound large proteins undergo substantial transformations due to the exchange of the original surface ligands to the components of the cell culture media. Conversely, NP capped with a tight monolayer of small organic molecules or with covalently conjugated proteins show significantly higher stability. These differences in ligand exchange also affect the toxicity of the NP to the HepG2 liver cell model, with the NP capped with small organic molecules being more toxic than those capped with large proteins. This study highlights the importance of characterising NPs in biological media and the effect the media has during in-vitro analysis.

  16. Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models

    Directory of Open Access Journals (Sweden)

    Tania Jacobo-Estrada

    2017-07-01

    Full Text Available Even decades after the discovery of Cadmium (Cd toxicity, research on this heavy metal is still a hot topic in scientific literature: as we wrote this review, more than 1440 scientific articles had been published and listed by the PubMed.gov website during 2017. Cadmium is one of the most common and harmful heavy metals present in our environment. Since pregnancy is a very particular physiological condition that could impact and modify essential pathways involved in the handling of Cd, the prenatal life is a critical stage for exposure to this non-essential element. To give the reader an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy, we decided to compile some of the most relevant experimental studies performed in experimental models and to summarize the advances in this field such as the Cd distribution and the factors that could alter it (diet, binding-proteins and membrane transporters, the Cd-induced toxicity in dams (preeclampsia, fertility, kidney injury, alteration in essential element homeostasis and bone mineralization, in placenta and in fetus (teratogenicity, central nervous system, liver and kidney.

  17. Deficiency of GABAergic synaptic inhibition in the Kölliker-Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome.

    Science.gov (United States)

    Abdala, Ana Paula; Toward, Marie A; Dutschmann, Mathias; Bissonnette, John M; Paton, Julian F R

    2016-01-01

    Life threatening breathing irregularity and central apnoeas are highly prevalent in children suffering from Rett syndrome. Abnormalities in inhibitory synaptic transmission have been associated with the physiopathology of this syndrome, and may underlie the respiratory disorder. In a mouse model of Rett syndrome, GABAergic terminal projections are markedly reduced in the Kölliker-Fuse nucleus (KF) in the dorsolateral pons, an important centre for control of respiratory rhythm regularity. Administration of a drug that augments endogenous GABA localized to this region of the pons reduced the incidence of apnoea and the respiratory irregularity of Rett female mice. Conversely, the respiratory disorder was recapitulated by blocking GABAergic transmission in the KF area of healthy rats. This study helps us understand the mechanism for generation of respiratory abnormality in Rett syndrome, pinpoints a brain site responsible and provides a clear anatomical target for the development of a translatable drug treatment. Central apnoeas and respiratory irregularity are a common feature in Rett syndrome (RTT), a neurodevelopmental disorder most often caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). We used a MECP2 deficient mouse model of RTT as a strategy to obtain insights into the neurobiology of the disease and into mechanisms essential for respiratory rhythmicity during normal breathing. Previously, we showed that, systemic administration of a GABA reuptake blocker in MECP2 deficient mice markedly reduced the occurrence of central apnoeas. Further, we found that, during central apnoeas, post-inspiratory drive (adductor motor) to the upper airways was enhanced in amplitude and duration in Mecp2 heterozygous female mice. Since the pontine Kölliker-Fuse area (KF) drives post-inspiration, suppresses inspiration, and can reset the respiratory oscillator phase, we hypothesized that synaptic inhibition in this area is essential for respiratory rhythm

  18. A Novel Experimental and Modelling Strategy for Nanoparticle Toxicity Testing Enabling the Use of Small Quantities

    Directory of Open Access Journals (Sweden)

    Marinda van Pomeren

    2017-11-01

    Full Text Available Metallic nanoparticles (NPs differ from other metal forms with respect to their large surface to volume ratio and subsequent inherent reactivity. Each new modification to a nanoparticle alters the surface to volume ratio, fate and subsequently the toxicity of the particle. Newly-engineered NPs are commonly available only in low quantities whereas, in general, rather large amounts are needed for fate characterizations and effect studies. This challenge is especially relevant for those NPs that have low inherent toxicity combined with low bioavailability. Therefore, within our study, we developed new testing strategies that enable working with low quantities of NPs. The experimental testing method was tailor-made for NPs, whereas we also developed translational models based on different dose-metrics allowing to determine dose-response predictions for NPs. Both the experimental method and the predictive models were verified on the basis of experimental effect data collected using zebrafish embryos exposed to metallic NPs in a range of different chemical compositions and shapes. It was found that the variance in the effect data in the dose-response predictions was best explained by the minimal diameter of the NPs, whereas the data confirmed that the predictive model is widely applicable to soluble metallic NPs. The experimental and model approach developed in our study support the development of (ecotoxicity assays tailored to nano-specific features.

  19. Estimating intratidal nonlinearity of respiratory system mechanics: a model study using the enhanced gliding-SLICE method

    International Nuclear Information System (INIS)

    Schumann, Stefan; Burcza, Boris; Guttmann, Josef; Haberthür, Christoph; Lichtwarck-Aschoff, Michael

    2009-01-01

    In the clinical situation and in most research work, the analysis of respiratory system mechanics is limited to the estimation of single-value compliances during static or quasi-static conditions. In contrast, our SLICE method analyses intratidal nonlinearity under the dynamic conditions of mechanical ventilation by calculating compliance and resistance for six conjoined volume portions (slices) of the pressure–volume loop by multiple linear regression analysis. With the gliding-SLICE method we present a new approach to determine continuous intratidal nonlinear compliance. The performance of the gliding-SLICE method was tested both in computer simulations and in a physical model of the lung, both simulating different intratidal compliance profiles. Compared to the original SLICE method, the gliding-SLICE method resulted in smaller errors when calculating the compliance or pressure course (all p 2 O s L −1 to 0.8 ± 0.3 cmH 2 O s L −1 (mathematical model) and from 7.2 ± 3.9 cmH 2 O s L −1 to 0.4 ± 0.2 cmH 2 O s L −1 (physical model) (all p < 0.001). We conclude that the new gliding-SLICE method allows detailed assessment of intratidal nonlinear respiratory system mechanics without discontinuity error

  20. Respiratory system model for quasistatic pulmonary pressure-volume (P-V) curve: inflation-deflation loop analyses.

    Science.gov (United States)

    Amini, R; Narusawa, U

    2008-06-01

    A respiratory system model (RSM) is developed for the deflation process of a quasistatic pressure-volume (P-V) curve, following the model for the inflation process reported earlier. In the RSM of both the inflation and the deflation limb, a respiratory system consists of a large population of basic alveolar elements, each consisting of a piston-spring-cylinder subsystem. A normal distribution of the basic elements is derived from Boltzmann statistical model with the alveolar closing (opening) pressure as the distribution parameter for the deflation (inflation) process. An error minimization by the method of least squares applied to existing P-V loop data from two different data sources confirms that a simultaneous inflation-deflation analysis is required for an accurate determination of RSM parameters. Commonly used terms such as lower inflection point, upper inflection point, and compliance are examined based on the P-V equations, on the distribution function, as well as on the geometric and physical properties of the basic alveolar element.

  1. Toxicity evaluation of biodegradable chitosan nanoparticles using a zebrafish embryo model

    Directory of Open Access Journals (Sweden)

    Hu YL

    2011-12-01

    Full Text Available Yu-Lan Hu1, Wang Qi1, Feng Han2, Jian-Zhong Shao3, Jian-Qing Gao11Institute of Pharmaceutics, College of Pharmaceutical Sciences, 2Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, 3College of Life Sciences, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang University, Hangzhou, Zhejiang, People's Republic of ChinaBackground: Although there are a number of reports regarding the toxicity evaluation of inorganic nanoparticles, knowledge on biodegradable nanomaterials, which have always been considered safe, is still limited. For example, the toxicity of chitosan nanoparticles, one of the most widely used drug/gene delivery vehicles, is largely unknown. In the present study, the zebrafish model was used for a safety evaluation of this nanocarrier.Methods: Chitosan nanoparticles with two particle sizes were prepared by ionic cross-linking of chitosan with sodium tripolyphosphate. Chitosan nanoparticles of different concentrations were incubated with zebrafish embryos, and ZnO nanoparticles were used as the positive control.Results: Embryo exposure to chitosan nanoparticles and ZnO nanoparticles resulted in a decreased hatching rate and increased mortality, which was concentration-dependent. Chitosan nanoparticles at a size of 200 nm caused malformations, including a bent spine, pericardial edema, and an opaque yolk in zebrafish embryos. Furthermore, embryos exposed to chitosan nanoparticles showed an increased rate of cell death, high expression of reactive oxygen species, as well as overexpression of heat shock protein 70, indicating that chitosan nanoparticles can cause physiological stress in zebrafish. The results also suggest that the toxicity of biodegradable nanocarriers such as chitosan nanoparticles must be addressed, especially considering the in vivo distribution of these nanoscaled particles.Conclusion: Our results add new insights into the potential toxicity of nanoparticles produced by

  2. USEtox - The UNEP-SETAC toxicity model: recommended characterisation factors for human toxicity and freshwater ecotoxicity in Life Cycle Impact Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Rosenbaum, Ralph K.; Bachmann, Till M.; Swirsky Gold, Lois; Huijbregts, Mark A.J.; Jolliet, Olivier; Juraske, Ronnie; Koehler, Annette; Larsen, Henrik F.; MacLeod, Matthew; Margni, Manuele; McKone, Thomas E.; Payet, Jerome; Schuhmacher, Marta; van de Meent, Dik; Hauschild, Michael Z.

    2008-02-03

    Background, Aim and Scope. In 2005 a comprehensive comparison of LCIA toxicity characterisation models was initiated by the UNEP-SETAC Life Cycle Initiative, directly involving the model developers of CalTOX, IMPACT 2002, USES-LCA, BETR, EDIP, WATSON, and EcoSense. In this paper we describe this model-comparison process and its results--in particular the scientific consensus model developed by the model developers. The main objectives of this effort were (i) to identify specific sources of differences between the models' results and structure, (ii) to detect the indispensable model components, and (iii) to build a scientific consensus model from them, representing recommended practice. Methods. A chemical test set of 45 organics covering a wide range of property combinations was selected for this purpose. All models used this set. In three workshops, the model comparison participants identified key fate, exposure and effect issues via comparison of the final characterisation factors and selected intermediate outputs for fate, human exposure and toxic effects for the test set applied to all models. Results. Through this process, we were able to reduce inter-model variation from an initial range of up to 13 orders of magnitude down to no more than 2 orders of magnitude for any substance. This led to the development of USEtox, a scientific consensus model that contains only the most influential model elements. These were, for example, process formulations accounting for intermittent rain, defining a closed or open system environment, or nesting an urban box in a continental box. Discussion. The precision of the new characterisation factors (CFs) is within a factor of 100-1000 for human health and 10-100 for freshwater ecotoxicity of all other models compared to 12 orders of magnitude variation between the CFs of each model respectively. The achieved reduction of inter-model variability by up to 11 orders of magnitude is a significant improvement

  3. Variable Ventilation Improved Respiratory System Mechanics and Ameliorated Pulmonary Damage in a Rat Model of Lung Ischemia-Reperfusion.

    Science.gov (United States)

    Soluri-Martins, André; Moraes, Lillian; Santos, Raquel S; Santos, Cintia L; Huhle, Robert; Capelozzi, Vera L; Pelosi, Paolo; Silva, Pedro L; de Abreu, Marcelo Gama; Rocco, Patricia R M

    2017-01-01

    Lung ischemia-reperfusion injury remains a major complication after lung transplantation. Variable ventilation (VV) has been shown to improve respiratory function and reduce pulmonary histological damage compared to protective volume-controlled ventilation (VCV) in different models of lung injury induced by endotoxin, surfactant depletion by saline lavage, and hydrochloric acid. However, no study has compared the biological impact of VV vs. VCV in lung ischemia-reperfusion injury, which has a complex pathophysiology different from that of other experimental models. Thirty-six animals were randomly assigned to one of two groups: (1) ischemia-reperfusion (IR), in which the left pulmonary hilum was completely occluded and released after 30 min; and (2) Sham, in which animals underwent the same surgical manipulation but without hilar clamping. Immediately after surgery, the left (IR-injured) and right (contralateral) lungs from 6 animals per group were removed, and served as non-ventilated group (NV) for molecular biology analysis. IR and Sham groups were further randomized to one of two ventilation strategies: VCV ( n = 6/group) [tidal volume (V T ) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 2 cmH 2 O, fraction of inspired oxygen (FiO 2 ) = 0.4]; or VV, which was applied on a breath-to-breath basis as a sequence of randomly generated V T values ( n = 1200; mean V T = 6 mL/kg), with a 30% coefficient of variation. After 5 min of ventilation and at the end of a 2-h period (Final), respiratory system mechanics and arterial blood gases were measured. At Final, lungs were removed for histological and molecular biology analyses. Respiratory system elastance and alveolar collapse were lower in VCV than VV (mean ± SD, VCV 3.6 ± 1.3 cmH 2 0/ml and 2.0 ± 0.8 cmH 2 0/ml, p = 0.005; median [interquartile range], VCV 20.4% [7.9-33.1] and VV 5.4% [3.1-8.8], p = 0.04, respectively). In left lungs of IR animals, VCV increased the expression of interleukin-6 and

  4. Ocular tropism of respiratory viruses.

    Science.gov (United States)

    Belser, Jessica A; Rota, Paul A; Tumpey, Terrence M

    2013-03-01

    Respiratory viruses (including adenovirus, influenza virus, respiratory syncytial virus, coronavirus, and rhinovirus) cause a broad spectrum of disease in humans, ranging from mild influenza-like symptoms to acute respiratory failure. While species D adenoviruses and subtype H7 influenza viruses are known to possess an ocular tropism, documented human ocular disease has been reported following infection with all principal respiratory viruses. In this review, we describe the anatomical proximity and cellular receptor distribution between ocular and respiratory tissues. All major respiratory viruses and their association with human ocular disease are discussed. Research utilizing in vitro and in vivo models to study the ability of respiratory viruses to use the eye as a portal of entry as well as a primary site of virus replication is highlighted. Identification of shared receptor-binding preferences, host responses, and laboratory modeling protocols among these viruses provides a needed bridge between clinical and laboratory studies of virus tropism.

  5. The AIMAR recommendations for early diagnosis of chronic obstructive respiratory disease based on the WHO/GARD model*

    Science.gov (United States)

    2014-01-01

    the Italian context; the document of the Agency for Regional Healthcare Services (AGE.NA.S) is a more suited compendium for consultation, and the recent joint statement on integrated COPD management of the three major Italian scientific Associations in the respiratory area together with the contribution of a Society of General Medicine deals prevalently with some critical issues (appropriateness of diagnosis, pharmacological treatment, rehabilitation, continuing care); also the document “Care Continuity: Chronic Obstructive Pulmonary Disease (COPD)” of the Global Alliance against chronic Respiratory Diseases (GARD)-Italy does not treat in depth the issue of early diagnosis. The present document – produced by the AIMAR (Interdisciplinary Association for Research in Lung Disease) Task Force for early diagnosis of chronic respiratory disease based on the WHO/GARD model and on available evidence and expertise –after a general examination of the main epidemiologic aspects, proposes to integrate the above-mentioned existing documents. In particular: a) it formally indicates on the basis of the available evidence the modalities and the instruments necessary for carrying out secondary prevention at the primary care level (a pro-active,‘case-finding’approach; assessment of the individual’s level of risk of COPD; use of short questionnaires for an initial screening based on symptoms; use of simple spirometry for the second level of screening); b) it identifies possible ways of including these activities within primary care practice; c) it places early diagnosis within the “systemic”, consequential management of chronic respiratory diseases, which will be briefly described with the aid of schemes taken from the Italian and international reference documents. PMID:25473523

  6. Untargeted metabolomics of neuronal cell culture: A model system for the toxicity testing of insecticide chemical exposure.

    Science.gov (United States)

    Hayton, Sarah; Maker, Garth L; Mullaney, Ian; Trengove, Robert D

    2017-12-01

    Toxicity testing is essential for the protection of human health from exposure to toxic environmental chemicals. As traditional toxicity testing is carried out using animal models, mammalian cell culture models are becoming an increasingly attractive alternative to animal testing. Combining the use of mammalian cell culture models with screening-style molecular profiling technologies, such as metabolomics, can uncover previously unknown biochemical bases of toxicity. We have used a mass spectrometry-based untargeted metabolomics approach to characterize for the first time the changes in the metabolome of the B50 cell line, an immortalised rat neuronal cell line, following acute exposure to two known neurotoxic chemicals that are common environmental contaminants; the pyrethroid insecticide permethrin and the organophosphate insecticide malathion. B50 cells were exposed to either the dosing vehicle (methanol) or an acute dose of either permethrin or malathion for 6 and 24 hours. Intracellular metabolites were profiled by gas chromatography-mass spectrometry. Using principal components analysis, we selected the key metabolites whose abundance was altered by chemical exposure. By considering the major fold changes in abundance (>2.0 or culture metabolomics to detect finer metabolic effects of acute exposure to known toxic chemicals, and validate the need for further development of this process in the application of trace-level dose and chronic toxicity studies, and toxicity testing of unknown chemicals. Copyright © 2017 John Wiley & Sons, Ltd.

  7. Acute toxicities of pharmaceuticals toward green algae. mode of action, biopharmaceutical drug disposition classification system and quantile regression models.

    Science.gov (United States)

    Villain, Jonathan; Minguez, Laetitia; Halm-Lemeille, Marie-Pierre; Durrieu, Gilles; Bureau, Ronan

    2016-02-01

    The acute toxicities of 36 pharmaceuticals towards green algae were estimated from a set of quantile regression models representing the first global quantitative structure-activity relationships. The selection of these pharmaceuticals was based on their predicted environmental concentrations. An agreement between the estimated values and the observed acute toxicity values was found for several families of pharmaceuticals, in particular, for antidepressants. A recent classification (BDDCS) of drugs based on ADME properties (Absorption, Distribution, Metabolism and Excretion) was clearly correlated with the acute ecotoxicities towards algae. Over-estimation of toxicity from our QSAR models was observed for classes 2, 3 and 4 whereas our model results were in agreement for the class 1 pharmaceuticals. Clarithromycin, a class 3 antibiotic characterized by weak metabolism and high solubility, was the most toxic to algae (molecular stability and presence in surface water). Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Knowledge Brokering: An Innovative Model for Supporting Evidence-Informed Practice in Respiratory Care

    Directory of Open Access Journals (Sweden)

    Alison M Hoens

    2013-01-01

    Full Text Available The process of adopting research findings in the clinical setting is challenging, regardless of the area of practice. One strategy to facilitate this process is the use of knowledge brokering. Knowledge brokers (KBs are individuals who work to bridge the gap between researchers and knowledge users. In the health care setting, KBs work closely with clinicians to facilitate enhanced uptake of research findings into clinical practice. They also work with researchers to ensure research findings are translatable and meaningful to clinical practice. The present article discusses a KB’s role in a respiratory care setting. Working closely with both researchers and clinicians, the KB has led teams in the process of conceptualizing, developing, testing, disseminating and evaluating several projects related to respiratory care, including projects related to mobility in critical care settings and acute exacerbations of chronic obstructive pulmonary disease; inspiratory muscle training; and the use of incentive spirometry in postsurgical populations. The KB role has provided an important communication link between researcher and knowledge user that has facilitated evidence-informed practice to improve patient care.

  9. Understanding cellular responses to toxic agents: a model for mechanism-choice in bacterial metal resistance.

    Science.gov (United States)

    Rouch, D A; Lee, B T; Morby, A P

    1995-02-01

    Bacterial resistances to metals are heterogeneous in both their genetic and biochemical bases. Metal resistance may be chromosomally-, plasmid- or transposon-encoded, and one or more genes may be involved: at the biochemical level at least six different mechanisms are responsible for resistance. Various types of resistance mechanisms can occur singly or in combination and for a particular metal different mechanisms of resistance can occur in the same species. To understand better the diverse responses of bacteria to metal ion challenge we have constructed a qualitative model for the selection of metal resistance in bacteria. How a bacterium becomes resistant to a particular metal depends on the number and location of cellular components sensitive to the specific metal ion. Other important selective factors include the nature of the uptake systems for the metal, the role and interactions of the metal in the normal metabolism of the cell and the availability of plasmid (or transposon) encoded resistance mechanisms. The selection model presented is based on the interaction of these factors and allows predictions to be made about the evolution of metal resistance in bacterial populations. It also allows prediction of the genetic basis and of mechanisms of resistance which are in substantial agreement with those in well-documented populations. The interaction of, and selection for resistance to, toxic substances in addition to metals, such as antibiotics and toxic analogues, involve similar principles to those concerning metals. Potentially, models for selection of resistance to any substance can be derived using this approach.

  10. Climate change air toxic co-reduction in the context of macroeconomic modelling.

    Science.gov (United States)

    Crawford-Brown, Douglas; Chen, Pi-Cheng; Shi, Hsiu-Ching; Chao, Chia-Wei

    2013-08-15

    This paper examines the health implications of global PM reduction accompanying greenhouse gas emissions reductions in the 180 national economies of the global macroeconomy. A human health effects module based on empirical data on GHG emissions, PM emissions, background PM concentrations, source apportionment and human health risk coefficients is used to estimate reductions in morbidity and mortality from PM exposures globally as co-reduction of GHG reductions. These results are compared against the "fuzzy bright line" that often underlies regulatory decisions for environmental toxics, and demonstrate that the risk reduction through PM reduction would usually be considered justified in traditional risk-based decisions for environmental toxics. It is shown that this risk reduction can be on the order of more than 4 × 10(-3) excess lifetime mortality risk, with global annual cost savings of slightly more than $10B, when uniform GHG reduction measures across all sectors of the economy form the basis for climate policy ($2.2B if only Annex I nations reduce). Consideration of co-reduction of PM-10 within a climate policy framework harmonized with other environmental policies can therefore be an effective driver of climate policy. An error analysis comparing results of the current model against those of significantly more spatially resolved models at city and national scales indicates errors caused by the low spatial resolution of the global model used here may be on the order of a factor of 2. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Trophic State and Toxic Cyanobacteria Density in Optimization Modeling of Multi-Reservoir Water Resource Systems

    Directory of Open Access Journals (Sweden)

    Andrea Sulis

    2014-04-01

    Full Text Available The definition of a synthetic index for classifying the quality of water bodies is a key aspect in integrated planning and management of water resource systems. In previous works [1,2], a water system optimization modeling approach that requires a single quality index for stored water in reservoirs has been applied to a complex multi-reservoir system. Considering the same modeling field, this paper presents an improved quality index estimated both on the basis of the overall trophic state of the water body and on the basis of the density values of the most potentially toxic Cyanobacteria. The implementation of the index into the optimization model makes it possible to reproduce the conditions limiting water use due to excessive nutrient enrichment in the water body and to the health hazard linked to toxic blooms. The analysis of an extended limnological database (1996–2012 in four reservoirs of the Flumendosa-Campidano system (Sardinia, Italy provides useful insights into the strengths and limitations of the proposed synthetic index.

  12. NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction

    International Nuclear Information System (INIS)

    Wennberg, Berit M.; Baumann, Pia; Gagliardi, Giovanna

    2011-01-01

    Background. In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Material and methods. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/β = 3 Gy was used and the USC parameters used were: α/β = 3 Gy, D 0 = 1.0 Gy, n = 10, α 0.206 Gy-1 and d T = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether 'high doses to small volumes' or 'low doses to large volumes' are most important for lung toxicity. Results and Discussion. NTCP analysis with the LKB-model using parameters m = 0.4, D50 = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D 50 = 20 Gy n = 0.93 with LQ correction and n 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling

  13. Chimeric antigen receptor T cells for the treatment of cancer and the future of preclinical models for predicting their toxicities.

    Science.gov (United States)

    Wegner, Anja

    2017-06-01

    Chimeric antigen receptor T-cell therapy has achieved highly promising results in clinical trials, particularly in B-cell malignancies. However, reports of serious adverse events including a number of patient deaths have raised concerns about safety of this treatment. Presently available preclinical models are not designed for predicting toxicities seen in human patients. Besides choosing the right animal model, careful considerations must be taken in chimeric antigen receptor T-cell design and the amount of T cells infused. The development of more sophisticated in vitro models and humanized mouse models for preclinical modeling and toxicity tests will help us to improve the design of clinical trials in cancer immunotherapy.

  14. Enhancement of Antituberculosis Immunity in a Humanized Model System by a Novel Virus-Vectored Respiratory Mucosal Vaccine.

    Science.gov (United States)

    Yao, Yushi; Lai, Rocky; Afkhami, Sam; Haddadi, Siamak; Zganiacz, Anna; Vahedi, Fatemeh; Ashkar, Ali A; Kaushic, Charu; Jeyanathan, Mangalakumari; Xing, Zhou

    2017-07-01

    The translation of preclinically promising novel tuberculosis vaccines to ultimate human applications has been challenged by the lack of animal models with an immune system equivalent to the human immune system in its genetic diversity and level of susceptibility to tuberculosis. We have developed a humanized mice (Hu-mice) tuberculosis model system to investigate the clinical relevance of a novel virus-vectored (VV) tuberculosis vaccine administered via respiratory mucosal or parenteral route. We find that VV vaccine activates T cells in Hu-mice as it does in human vaccinees. The respiratory mucosal route for delivery of VV vaccine in Hu-mice, but not the parenteral route, significantly reduces the humanlike lung tuberculosis outcomes in a human T-cell-dependent manner. Our results suggest that the Hu-mouse can be used to predict the protective efficacy of novel tuberculosis vaccines/strategies before they proceed to large, expensive human trials. This new vaccine testing system will facilitate the global pace of clinical tuberculosis vaccine development. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  15. Rigorous selection of random forest models for identifying compounds that activate toxicity-related pathways

    Directory of Open Access Journals (Sweden)

    Yoshihiro eUesawa

    2016-02-01

    Full Text Available Random forest (RF is a machine-learning ensemble method with high predictive performance. Majority voting in RF uses the discrimination results in numerous decision trees produced from bootstrapping data. For the same dataset, the bootstrapping process yields different predictive capacities in each generation. As participants in the Toxicology in the 21st Century (Tox21 DATA Challenge 2014, we produced numerous RF models for predicting the structures of compounds that can activate each toxicity-related pathway, and then selected the model with the highest predictive ability. Half of the compounds in the training dataset supplied by the competition organizer were allocated to the validation dataset. The remaining compounds were used in model construction. The charged and uncharged forms of each molecule were calculated using the molecular operating environment (MOE software. Subsequently, the descriptors were computed using MOE, MarvinView, and Dragon. These combined methods yielded over 4,071 descriptors for model construction. Using these descriptors, pattern recognition analyses were performed by RF implemented in JMP Pro (a statistical software package. A hundred to two hundred RF models were generated for each pathway. The predictive performance of each model was tested against the validation dataset, and the best-performing model was selected. In the competition, the latter model selected a best-performing model from the 50% test set that best predicted the structures of compounds that activate the estrogen receptor ligand-binding domain (ER-LBD.

  16. Dependence of subject-specific parameters for a fast helical CT respiratory motion model on breathing rate: an animal study

    Science.gov (United States)

    O'Connell, Dylan; Thomas, David H.; Lamb, James M.; Lewis, John H.; Dou, Tai; Sieren, Jered P.; Saylor, Melissa; Hofmann, Christian; Hoffman, Eric A.; Lee, Percy P.; Low, Daniel A.

    2018-02-01

    To determine if the parameters relating lung tissue displacement to a breathing surrogate signal in a previously published respiratory motion model vary with the rate of breathing during image acquisition. An anesthetized pig was imaged using multiple fast helical scans to sample the breathing cycle with simultaneous surrogate monitoring. Three datasets were collected while the animal was mechanically ventilated with different respiratory rates: 12 bpm (breaths per minute), 17 bpm, and 24 bpm. Three sets of motion model parameters describing the correspondences between surrogate signals and tissue displacements were determined. The model error was calculated individually for each dataset, as well asfor pairs of parameters and surrogate signals from different experiments. The values of one model parameter, a vector field denoted α which related tissue displacement to surrogate amplitude, determined for each experiment were compared. The mean model error of the three datasets was 1.00  ±  0.36 mm with a 95th percentile value of 1.69 mm. The mean error computed from all combinations of parameters and surrogate signals from different datasets was 1.14  ±  0.42 mm with a 95th percentile of 1.95 mm. The mean difference in α over all pairs of experiments was 4.7%  ±  5.4%, and the 95th percentile was 16.8%. The mean angle between pairs of α was 5.0  ±  4.0 degrees, with a 95th percentile of 13.2 mm. The motion model parameters were largely unaffected by changes in the breathing rate during image acquisition. The mean error associated with mismatched sets of parameters and surrogate signals was 0.14 mm greater than the error achieved when using parameters and surrogate signals acquired with the same breathing rate, while maximum respiratory motion was 23.23 mm on average.

  17. Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models.

    Science.gov (United States)

    Plengsuriyakarn, Tullayakorn; Viyanant, Vithoon; Eursitthichai, Veerachai; Picha, Porntipa; Kupradinun, Piengchai; Itharat, Arunporn; Na-Bangchang, Kesara

    2012-03-27

    Chemotherapy of cholangiocarcinoma (CCA), a devastating cancer with increasing worldwide incidence and mortality rates, is largely ineffective. The discovery and development of effective chemotherapeutics is urgently needed. The study aimed at evaluating anticancer activities, toxicity, and pharmacological activities of the curcumin compound (CUR), the crude ethanolic extracts of rhizomes of Zingiber officinale Roscoe (Ginger: ZO) and Atractylodes lancea thung. DC (Khod-Kha-Mao: AL), fruits of Piper chaba Hunt. (De-Plee: PC), and Pra-Sa-Prao-Yhai formulation (a mixture of parts of 18 Thai medicinal plants: PPF) were investigated in animal models. Anti-cholangiocarcinoma (anti-CCA) was assessed using CCA-xenograft nude mouse model. The antihypertensive, analgesic, anti-inflammatory, antipyretic, and anti-ulcer activities and effects on motor coordination were investigated using Rota-rod test, CODA tail-cuff system, writhing and hot plate tests, carrageenan-induced paw edema test, brewer's yeast test, and alcohol-induced gastric ulcer test, respectively. Acute and subacute toxicity tests were performed according to the OECD guideline for testing of chemicals with modification. Promising anticancer activity against CCA in nude mouse xenograft model was shown for the ethanolic extract of AL at all oral dose levels (1000, 3000, and 5000 mg/kg body weight) as well as the extracts of ZO, PPF, and CUR compound at the highest dose level (5000, 4000, and 5000 mg/kg body weight, respectively). PC produced no significant anti-CCA activity. Results from acute and subacute toxicity tests both in mice and rats indicate safety profiles of all the test materials in a broad range of dose levels. No significant toxicity except stomach irritation and general CNS depressant signs were observed. Investigation of pharmacological activities of the test materials revealed promising anti-inflammatory (ZO, PPF, and AL), analgesic (CUR and PPF), antipyretic (CUR and AL), antihypertensive (ZO

  18. Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models

    Directory of Open Access Journals (Sweden)

    Plengsuriyakarn Tullayakorn

    2012-03-01

    Full Text Available Abstract Background Chemotherapy of cholangiocarcinoma (CCA, a devastating cancer with increasing worldwide incidence and mortality rates, is largely ineffective. The discovery and development of effective chemotherapeutics is urgently needed. Methods/Design The study aimed at evaluating anticancer activities, toxicity, and pharmacological activities of the curcumin compound (CUR, the crude ethanolic extracts of rhizomes of Zingiber officinale Roscoe (Ginger: ZO and Atractylodes lancea thung. DC (Khod-Kha-Mao: AL, fruits of Piper chaba Hunt. (De-Plee: PC, and Pra-Sa-Prao-Yhai formulation (a mixture of parts of 18 Thai medicinal plants: PPF were investigated in animal models. Anti-cholangiocarcinoma (anti-CCA was assessed using CCA-xenograft nude mouse model. The antihypertensive, analgesic, anti-inflammatory, antipyretic, and anti-ulcer activities and effects on motor coordination were investigated using Rota-rod test, CODA tail-cuff system, writhing and hot plate tests, carrageenan-induced paw edema test, brewer's yeast test, and alcohol-induced gastric ulcer test, respectively. Acute and subacute toxicity tests were performed according to the OECD guideline for testing of chemicals with modification. Results Promising anticancer activity against CCA in nude mouse xenograft model was shown for the ethanolic extract of AL at all oral dose levels (1000, 3000, and 5000 mg/kg body weight as well as the extracts of ZO, PPF, and CUR compound at the highest dose level (5000, 4000, and 5000 mg/kg body weight, respectively. PC produced no significant anti-CCA activity. Results from acute and subacute toxicity tests both in mice and rats indicate safety profiles of all the test materials in a broad range of dose levels. No significant toxicity except stomach irritation and general CNS depressant signs were observed. Investigation of pharmacological activities of the test materials revealed promising anti-inflammatory (ZO, PPF, and AL, analgesic (CUR and

  19. Human neuronal cell based assay: A new in vitro model for toxicity evaluation of ciguatoxin.

    Science.gov (United States)

    Coccini, Teresa; Caloni, Francesca; De Simone, Uliana

    2017-06-01

    Ciguatoxins (CTXs) are emerging marine neurotoxins representing the main cause of ciguatera fish poisoning, an intoxication syndrome which configures a health emergency and constitutes an evolving issue constantly changing due to new vectors and derivatives of CTXs, as well as their presence in new non-endemic areas. The study applied the neuroblastoma cell model of human origin (SH-SY5Y) to evaluate species-specific mechanistic information on CTX toxicity. Metabolic functionality, cell morphology, cytosolic Ca 2+ i responses, neuronal cell growth and proliferation were assessed after short- (4-24h) and long-term exposure (10days) to P-CTX-3C. In SH-SY5Y, P-CTX-3C displayed a powerful cytotoxicity requiring the presence of both Veratridine and Ouabain. SH-SY5Y were very sensitive to Ouabain: 10 and 0.25nM appeared the optimal concentrations, for short- and long-term toxicity studies, respectively, to be used in co-incubation with Veratridine (25μM), simulating the physiological and pathological endogenous Ouabain levels in humans. P-CTX-3C cytotoxic effect, on human neurons co-incubated with OV (Ouabain+Veratridine) mix, was expressed starting from 100pM after short- and 25pM after long-term exposure. Notably, P-CTX-3C alone at 25nM induced cytotoxicity after 24h and prolonged exposure. This human brain-derived cell line appears a suitable cell-based-model to evaluate cytotoxicity of CTX present in marine food contaminated at low toxic levels and to characterize the toxicological profile of other/new congeners. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Modeling the interaction of light intensity, nutrient concentration and uranium toxicity in Lemna minor

    Energy Technology Data Exchange (ETDEWEB)

    Zimmer, E.; Horemans, N.; Vandenhove, H. [Belgian Nuclear Research Centre SCK-CEN (Belgium); Cedergreen, N. [University of Copenhagen (Denmark); Jager, T. [Vrije Universiteit Amsterdam (Netherlands)

    2014-07-01

    Radioecology aims at assessing the effect of radionuclides and radiation on the environment. Since we cannot test every possible environmental situation in the laboratory, we need modeling approaches to extrapolate the results of toxicity assays to environmentally relevant scenarios. Therefore, it is of crucial importance to understand the effect of relevant environmental factors, such as nutrients, temperature and light on the toxicity of the test. Radionuclides are often found to induce the production of reactive oxygen species (ROS). In plants, an overload of ROS can lead to disturbances of the photosynthetic system. Since the light intensity determines the efficiency of the photo-systems in plants, it can be expected to interact with the effect of radionuclides. The nutrient concentration of the test medium determines the physiological state of the plant, affecting in turn the plant's capability of dealing with stress and hence influences the toxicity of the contaminant. To study the interaction of stressors with environmental conditions, mechanistic effect modeling is promoted widely in ecotoxicology. In principle, the modelling aims at a mechanistic understanding of the different processes causing the stress individually, and integrating them in one framework to study their joint effect and possible interaction. We here present a mechanistic effect model for Lemna minor (common duckweed), which is based on Dynamic Energy Budget (DEB) theory. Models based on DEB have been used widely to study the effects of compounds on animals. Due to its general applicability to all types of organisms, it holds potential to be used for comparison of species and compounds in a broad context. Energy uptake from the environment is modeled explicitly, and metabolic rates are set to depend on temperature in DEB models. Therefore, they can be used to extrapolate effects to a wide range of environmentally relevant scenarios. Until now, the DEB research in ecotoxicology has

  1. THE EFFECTS OF CHEMICAL CHARACTERISTICS OF EXPOSURE WATER ON COPPER TOXICITY TO LARVAL FATHEAD MINNOWS: HOW WELL DO BIOAVAILABILITY MODELS FIT?

    Science.gov (United States)

    Current models for the acute toxicity of cationic metals to fish focus on the binding of free metal ions to the gill surface. This binding, and the consequent metal toxicity, can be reduced by metal-complexing ligands...

  2. 5D respiratory motion model based image reconstruction algorithm for 4D cone-beam computed tomography

    Science.gov (United States)

    Liu, Jiulong; Zhang, Xue; Zhang, Xiaoqun; Zhao, Hongkai; Gao, Yu; Thomas, David; Low, Daniel A.; Gao, Hao

    2015-11-01

    4D cone-beam computed tomography (4DCBCT) reconstructs a temporal sequence of CBCT images for the purpose of motion management or 4D treatment in radiotherapy. However the image reconstruction often involves the binning of projection data to each temporal phase, and therefore suffers from deteriorated image quality due to inaccurate or uneven binning in phase, e.g., under the non-periodic breathing. A 5D model has been developed as an accurate model of (periodic and non-periodic) respiratory motion. That is, given the measurements of breathing amplitude and its time derivative, the 5D model parametrizes the respiratory motion by three time-independent variables, i.e., one reference image and two vector fields. In this work we aim to develop a new 4DCBCT reconstruction method based on 5D model. Instead of reconstructing a temporal sequence of images after the projection binning, the new method reconstructs time-independent reference image and vector fields with no requirement of binning. The image reconstruction is formulated as a optimization problem with total-variation regularization on both reference image and vector fields, and the problem is solved by the proximal alternating minimization algorithm, during which the split Bregman method is used to reconstruct the reference image, and the Chambolle's duality-based algorithm is used to reconstruct the vector fields. The convergence analysis of the proposed algorithm is provided for this nonconvex problem. Validated by the simulation studies, the new method has significantly improved image reconstruction accuracy due to no binning and reduced number of unknowns via the use of the 5D model.

  3. Respiratory alkalosis

    Science.gov (United States)

    ... a condition marked by a low level of carbon dioxide in the blood due to breathing excessively. ... aimed at the condition that causes respiratory alkalosis. Breathing ... dioxide -- sometimes helps reduce symptoms when anxiety is the ...

  4. Application of Biotic Ligand Model in Predicting Copper Acute Toxicity to Carp (Cyprinidae).

    Science.gov (United States)

    Wang, Wanbin; Liang, Qibin; Zhao, Jing; Chen, Rui

    2017-01-01

    Three representative species of Cyprinidae fishes (Aristichthys nobilis, Ctenopharyngodon idellus, and Cyprinus carpio), which are abundant in Chinese surface waters, were studied to determine their sensitivity to copper (Cu) in acute exposures. We first performed acute toxicity tests to determine the Cu LC 50 value for each species in water with varying characteristics. The biotic ligand model (BLM) was then calibrated using the toxicity data for these species together with binding properties specific to Cu. The BLM calibration involved the calculation of the level of Cu accumulation in the gills that resulted in 50% lethality (i.e., LA 50 ). The LA 50 values for A. nobilis, C. idellus and C. carpio were 5.16, 11.60 and 9.00 nmol g -1 . The model calibrated to these data was improved by adjusting the Cu-proton exchange constant (pK CuHA-A ) and dissolved organic carbon (DOC) to values of 1.84 and 4.67E-3 mol g -1 , respectively. The calibrated Cu-BLM was validated for these three common fish species by comparing predicted and observed LC 50 values, which were in agreement to within a factor of 2. The results of this study provide an important contribution to ecological risk assessment and establishment of water quality criteria for Cu in China.

  5. Insulin versus Lipid Emulsion in a Rabbit Model of Severe Propranolol Toxicity: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Martyn Harvey

    2011-01-01

    Full Text Available Background and objective. Beta-blocker overdose may result in intractable cardiovascular collapse despite conventional antidotal treatments. High dose insulin/glucose (ING, and more recently intravenous lipid emulsion (ILE, have been proposed as potentially beneficial therapies in beta blocker intoxication. We compare efficacy of the novel antidotes ING, with ILE, in a rabbit model of combined enteric/intravenous propranolol toxicity. Methods. Sedated, mechanically ventilated and invasively monitored New Zealand White rabbits underwent mini-laparotomy and enterostomy formation with 40 mg/kg propranolol instilled into the proximal small bowel. At 30 minutes propranolol infusion was commenced at 4 mg/kg/hr and continued to a target mean arterial pressure (MAP of 50% baseline MAP. Animals were resuscitated with insulin at 3 U/kg plus 0.5 g/kg glucose (ING group, or 10 mL/kg 20% Intralipid (ILE group. Results. Rate pressure product (RPP; RPP = heart rate × mean arterial pressure was greatest in the ING group at 60 minutes (P<.05. A trend toward greater heart rate was observed in the ING group (P=.06. No difference was observed in survival between groups (4/5 ING versus 2/5 ILE; P=.524. Conclusions. High dose insulin resulted in greater rate pressure product compared with lipid emulsion in this rabbit model of severe enteric/intravenous propranolol toxicity.

  6. The galactose-induced decrease in phosphate levels leads to toxicity in yeast models of galactosemia.

    Science.gov (United States)

    Machado, Caio M; De-Souza, Evandro A; De-Queiroz, Ana Luiza F V; Pimentel, Felipe S A; Silva, Guilherme F S; Gomes, Fabio M; Montero-Lomelí, Mónica; Masuda, Claudio A

    2017-06-01

    Classic galactosemia is an inborn error of metabolism caused by deleterious mutations in the GALT gene. A number of evidences indicate that the galactose-1-phosphate accumulation observed in patient cells is a cause of toxicity in this disease. Nevertheless, the consequent molecular events caused by the galactose-1-phosphate accumulation remain elusive. Here we show that intracellular inorganic phosphate levels decreased when yeast models of classic galactosemia were exposed to galactose. The decrease in phosphate levels is probably due to the trapping of phosphate in the accumulated galactose-1-phosphate since the deletion of the galactokinase encoding gene GAL1 suppressed this phenotype. Galactose-induced phosphate depletion caused an increase in glycogen content, an expected result since glycogen breakdown by the enzyme glycogen phosphorylase is dependent on inorganic phosphate. Accordingly, an increase in intracellular phosphate levels suppressed the galactose effect on glycogen content and conferred galactose tolerance to yeast models of galactosemia. These results support the hypothesis that the galactose-induced decrease in phosphate levels leads to toxicity in galactosemia and opens new possibilities for the development of better treatments for this disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. QSAR models for Daphnia magna toxicity prediction of benzoxazinone allelochemicals and their transformation products.

    Science.gov (United States)

    Lo Piparo, Elena; Fratev, Filip; Lemke, Frank; Mazzatorta, Paolo; Smiesko, Martin; Fritz, Jona Ines; Benfenati, Emilio

    2006-02-22

    The overall objective of this study is the ecotoxicological characterization of the benzoxazinone 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), the benzoxazolinones benzoxazolin-2-one (BOA) and 6-methoxybenzoxazolin-2-one (MBOA), and their transformation products: phenoxazinones 2-acetylamino-7-methoxy-3H-phenoxazin-3-one (AAMPO), 2-acetylamino-3H-phenoxazin-3-one (AAPO), 2-amino-7-methoxy-3H-phenoxazin-3-one (AMPO), and 2-amino-3H-phenoxazin-3-one (APO); aminophenol 2-aminophenol AP); acetamide N-(2-hydroxyphenyl)acetamide (HPAA); and malonamic acid amide N-(2-hydroxyphenyl)malonamic acid (HPMA). A comparison between empirical results and theoretical ones using rules-based prediction of toxicity was done, and it can be concluded that only the degradation metabolites exhibited significant ecotoxic effect. Using synthetic pesticides knowledge, several QSAR models were trained with various approaches and descriptors. The models generated exhibited good internal predictive ability (R(cv)2 > 0.6) and were used to predict the toxicity of the natural compounds studied.

  8. Impact of Cardiopulmonary Bypass on Respiratory Mucociliary Function in an Experimental Porcine Model.

    Directory of Open Access Journals (Sweden)

    Rodrigo Sánchez-Véliz

    Full Text Available The impact of cardiac surgery using cardiopulmonary bypass (CPB on the respiratory mucociliary function is unknown. This study evaluated the effects of CPB and interruption of mechanical ventilation on the respiratory mucociliary system.Twenty-two pigs were randomly assigned to the control (n = 10 or CPB group (n = 12. After the induction of anesthesia, a tracheostomy was performed, and tracheal tissue samples were excised (T0 from both groups. All animals underwent thoracotomy. In the CPB group, an aorto-bicaval CPB was installed and maintained for 90 minutes. During the CPB, mechanical ventilation was interrupted, and the tracheal tube was disconnected. A second tracheal tissue sample was obtained 180 minutes after the tracheostomy (T180. Mucus samples were collected from the trachea using a bronchoscope at T0, T90 and T180. Ciliary beat frequency (CBF and in situ mucociliary transport (MCT were studied in ex vivo tracheal epithelium. Mucus viscosity (MV was assessed using a cone-plate viscometer. Qualitative tracheal histological analysis was performed at T180 tissue samples.CBF decreased in the CPB group (13.1 ± 1.9 Hz vs. 11.1 ± 2.1 Hz, p < 0.05 but not in the control group (13.1 ± 1 Hz vs. 13 ± 2.9 Hz. At T90, viscosity was increased in the CPB group compared to the control (p < 0.05. No significant differences were observed in in situ MCT. Tracheal histology in the CPB group showed areas of ciliated epithelium loss, submucosal edema and infiltration of inflammatory cells.CPB acutely contributed to alterations in tracheal mucocilliary function.

  9. Pharmacological Effects of Lactuca serriola L. in Experimental Model of Gastrointestinal, Respiratory, and Vascular Ailments

    Directory of Open Access Journals (Sweden)

    Khalid Hussain Janbaz

    2013-01-01

    Full Text Available Lactuca serriola L. has traditionally been used in folkloric medicine to manage respiratory, gastrointestinal, and multiple other ailments. The present study was undertaken to explore the effect of methanol extract of L. serriola on isolated rabbit tissue preparations, that is, jejunum, trachea, and aorta in an attempt to validate its folkloric use in traditional medicine for gastrointestinal, respiratory, and vascular ailments. The application of the methanol extract to isolated rabbit jejunum preparations exhibited concentration-dependent spasmogenic effect (0.03 to 3.0 mg/mL, but interestingly further increase in concentration (5.0 mg/mL resulted in complete spasmolytic effect. The pretreatment of the tissue preparations with atropine (0.1 μM caused the suppression of the contractile response. Moreover, the same extract also caused relaxation of K+-(80 mM induced spastic contractions of isolated rabbit jejunum preparations (5.0 mg/mL and shifted the Ca++ dose response curves towards right at concentration range of 0.3–1.0 mg/mL. Similarly, the extract application to isolated rabbit tracheal preparations relaxed the carbachol-(1 μM induced (0.3–1.0 mg/mL as well as K+-(80 mM induced contractions (3.0 mg/mL. Furthermore, it relaxed the phenylephrine (1 μM-induced contractions in isolated rabbit aorta preparations (3.0 mg/mL and K+ (80 mM-induced contractions (1.0 mg/mL. These effects were found comparable to that of dicyclomine, as an antagonist of muscarinic receptors as well as a possible Ca++ channel blocker. The previously mentioned findings may partially justify the folkloric use of Lactuca serriola in the management of conditions pertaining to spasm of intestine, bronchioles, and vasculature.

  10. Airway remodeling in a mouse asthma model assessed by in-vivo respiratory-gated micro-computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Lederlin, Mathieu; Montaudon, Michel [Universite Bordeaux 2, Laboratoire de Physiologie Cellulaire Respiratoire, Bordeaux (France); Institut National de la Sante et de la Recherche Medicale (INSERM), U885, Bordeaux (France); CHU Bordeaux, Unite d' Imagerie Thoracique, Pessac (France); Ozier, Annaig; Begueret, Hugues; Ousova, Olga; Marthan, Roger; Berger, Patrick [Universite Bordeaux 2, Laboratoire de Physiologie Cellulaire Respiratoire, Bordeaux (France); Institut National de la Sante et de la Recherche Medicale (INSERM), U885, Bordeaux (France); Laurent, Francois [Universite Bordeaux 2, Laboratoire de Physiologie Cellulaire Respiratoire, Bordeaux (France); Institut National de la Sante et de la Recherche Medicale (INSERM), U885, Bordeaux (France); CHU Bordeaux, Unite d' Imagerie Thoracique, Pessac (France); CHU de Bordeaux, Hopital du Haut-Leveque, Hopital Cardiologique, Unite d' Imagerie Thoracique et Cardiovasculaire, Pessac (France)

    2010-01-15

    The aim of our study was to evaluate the feasibility of non-invasive respiratory-gated micro-computed tomography (micro-CT) for assessment of airway remodelling in a mouse asthma model. Six female BALB/c mice were challenged intranasally with ovalbumin. A control group of six mice received saline inhalation. All mice underwent plethysmographic study and micro-CT. For each mouse, peribronchial attenuation values of 12 bronchi were measured, from which a peribronchial density index (PBDI) was computed. Mice were then sacrificed and lungs examined histologically. Final analysis involved 10 out of 12 mice. Agreement of measurements across observers and over time was very good (intraclass correlation coefficients: 0.94-0.98). There was a significant difference in PBDI between asthmatic and control mice (-210 vs. -338.9 HU, P=0.008). PBDI values were correlated to bronchial muscle area (r=0.72, P=0.018). This study shows that respiratory-gated micro-CT may allow non-invasive monitoring of bronchial remodelling in asthmatic mice and evaluation of innovative treatment effects. (orig.)

  11. Respiratory effects of trichloroethylene.

    Science.gov (United States)

    Dumas, Orianne; Despreaux, Thomas; Perros, Frédéric; Lau, Edmund; Andujar, Pascal; Humbert, Marc; Montani, David; Descatha, Alexis

    2018-01-01

    Trichloroethylene (TCE) is a chlorinated solvent that has been used widely around the world in the twentieth century for metal degreasing and dry cleaning. Although TCE displays general toxicity and is classified as a human carcinogen, the association between TCE exposure and respiratory disorders are conflicting. In this review we aimed to systematically evaluate the current evidence for the respiratory effects of TCE exposure and the implications for the practicing clinician. There is limited evidence of an increased risk of lung cancer associated with TCE exposure based on animal and human data. However, the effect of other chlorinated solvents and mixed solvent exposure should be further investigated. Limited data are available to support an association between TCE exposure and respiratory tract disorders such as asthma, chronic bronchitis, or rhinitis. The most consistent data is the association of TCE with autoimmune and vascular diseases such as systemic sclerosis and pulmonary veno-occlusive disease. Although recent data are reassuring regarding the absence of an increased lung cancer risk with TCE exposure, clinicians should be aware of other potential respiratory effects of TCE. In particular, occupational exposure to TCE has been linked to less common conditions such as systemic sclerosis and pulmonary veno-occlusive disease. Copyright © 2017. Published by Elsevier Ltd.

  12. Application of in silico modelling to estimate toxicity of migrating substances from food packaging.

    Science.gov (United States)

    Price, Nicholas; Chaudhry, Qasim

    2014-09-01

    This study derived toxicity estimates for a set of 136 chemical migrants from food packaging materials using in silico (computational) modelling and read across approaches. Where available, the predicted results for mutagenicity and carcinogenicity were compared with published experimental data. As the packaging compounds are subject to safety assessment, the migrating substances were more likely to be negative for both the endpoints. A set of structural analogues with positive experimental data for carcinogenicity and/or mutagenicity was therefore used as a positive comparator. The results showed that a weight of evidence assembled from different in silico models and read-across from already-tested structurally similar compounds can provide a rapid and reliable means for rapid screening of new yet-untested intentional or unintentional chemical compounds that may migrate to packaged foodstuffs. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  13. Genetic and chemical modifiers of a CUG toxicity model in Drosophila.

    Directory of Open Access Journals (Sweden)

    Amparo Garcia-Lopez

    2008-02-01

    Full Text Available Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL proteins contributing to myotonic dystrophy 1 (DM1. To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and further supported by the co-localization of Muscleblind and CUG repeat RNA in ribonuclear foci. Targeted expression of CUG repeats to the developing eye and brain mushroom bodies was toxic leading to rough eyes and semilethality, respectively. These phenotypes were utilized to identify genetic and chemical modifiers of the CUG-induced toxicity. 15 genetic modifiers of the rough eye phenotype were isolated. These genes identify putative cellular processes unknown to be altered by CUG repeat RNA, and they include mRNA export factor Aly, apoptosis inhibitor Thread, chromatin remodelling factor Nurf-38, and extracellular matrix structural component Viking. Ten chemical compounds suppressed the semilethal phenotype. These compounds significantly improved viability of CUG expressing flies and included non-steroidal anti-inflammatory agents (ketoprofen, muscarinic, cholinergic and histamine receptor inhibitors (orphenadrine, and drugs that can affect sodium and calcium metabolism such as clenbuterol and spironolactone. These findings provide new insights into the DM1 phenotype, and suggest novel candidates for DM1 treatments.

  14. Evaluation of toxic effects of several carboxylic acids on bacterial growth by toxicodynamic modelling

    Directory of Open Access Journals (Sweden)

    Vázquez José

    2011-11-01

    Full Text Available Abstract Background Effects of organic acids on microbial fermentation are commonly tested in investigations about metabolic behaviour of bacteria. However, they typically provide only descriptive information without modelling the influence of acid concentrations on bacterial kinetics. Results We developed and applied a mathematical model (secondary model to capture the toxicological effects of those chemicals on kinetic parameters that define the growth of bacteria in batch cultures. Thus, dose-response kinetics were performed with different bacteria (Leuconostoc mesenteroides, Carnobacterium pisicola, Escherichia coli, Bacillus subtilis and Listonella anguillarum exposed at increasing concentrations of individual carboxylic acids (formic, acetic, propionic, butyric and lactic. In all bioassays the acids affected the maximum bacterial load (Xm and the maximum growth rate (vm but only in specific cases the lag phase (λ was modified. Significance of the parameters was always high and in all fermentations the toxicodynamic equation was statistically consistent and had good predictability. The differences between D and L-lactic acid effects were significant for the growth of E. coli, L. mesenteroides and C. piscicola. In addition, a global parameter (EC50,τ was used to compare toxic effects and provided a realistic characterization of antimicrobial agents using a single value. Conclusions The effect of several organic acids on the growth of different bacteria was accurately studied and perfectly characterized by a bivariate equation which combines the basis of dose-response theory with microbial growth kinetics (secondary model. The toxicity of carboxylic acids was lower with the increase of the molecular weight of these chemicals.

  15. Models for the field-based toxicity of copper and zinc salts to wheat in 11 Australian soils and comparison to laboratory-based models

    International Nuclear Information System (INIS)

    Warne, Michael St.J.; Heemsbergen, Diane; McLaughlin, Mike; Bell, Mike; Broos, Kris; Whatmuff, Mark; Barry, Glenn; Nash, David; Pritchard, Deb; Penney, Nancy

    2008-01-01

    Laboratory-based relationships that model the phytotoxicity of metals using soil properties have been developed. This paper presents the first field-based phytotoxicity relationships. Wheat (Triticum aestivum L.) was grown at 11 Australian field sites at which soil was spiked with copper (Cu) and zinc (Zn) salts. Toxicity was measured as inhibition of plant growth at 8 weeks and grain yield at harvest. The added Cu and Zn EC10 values for both endpoints ranged from approximately 3 to 4760 mg/kg. There were no relationships between field-based 8-week biomass and grain yield toxicity values for either metal. Cu toxicity was best modelled using pH and organic carbon content while Zn toxicity was best modelled using pH and the cation exchange capacity. The best relationships estimated toxicity within a factor of two of measured values. Laboratory-based phytotoxicity relationships could not accurately predict field-based phytotoxicity responses. - Field-based toxicity of Cu and Zn to wheat can be modelled using soil properties. Laboratory-based models should not be used to estimate toxicity in the field

  16. Development of Species Sensitivity Distributions for Wildlife Using Interspecies Toxicity Correlation Models

    Science.gov (United States)

    Species sensitivity distributions (SSD) are cumulative distributions of chemical toxicity of multiple species and have had limited application in wildlife risk assessment because of relatively small datasets of wildlife toxicity values. Interspecies correlation estimation (ICE) m...

  17. Virtual Embryo: Cell-Agent Based Modeling of Developmental Processes and Toxicities (CSS BOSC)

    Science.gov (United States)

    Spatial regulation of cellular dynamics is fundamental to morphological development. As such, chemical disruption of spatial dynamics is a determinant of developmental toxicity. Incorporating spatial dynamics into AOPs for developmental toxicity is desired but constrained by the ...

  18. Innovative characteristics of the new dosimetric model for the human respiratory tract studied by the ICRP appointed Task Group of Committee 2

    CERN Document Server

    Melandri, C; Tarroni, G

    1991-01-01

    In 1984, the ICRP appointed a Task Group of Committee 2 to review and revise, as necessary, the current lung dosimetric model. On the basis of the knowledge acquired during the past 20 years, the Task Group's approach has been to review, in depth, the morphology and physiology of the human respiratory tract, inspirability of aerosols and regional deposition of inhaled particles as functions of aerosol size and breathing parameters, clearance of deposited materials, nature and specific sites of damage to the respiratory system caused by inhaled radioactive substances. In the proposed model, clearance from the three regions of the respiratory tract (extrathoracic ET, fast-clearing thoracic T sub f and slow-clearing thoracic T sub s , comprising lymph nodes) is described in terms of competition between the mechanical processes moving particles, which do not depend on the substances, and those of absorption into the blood, determined solely by the material. A Task Group report will also include models for calcula...

  19. Daphnia and fish toxicity of (benzo)triazoles: validated QSAR models, and interspecies quantitative activity-activity modelling.

    Science.gov (United States)

    Cassani, Stefano; Kovarich, Simona; Papa, Ester; Roy, Partha Pratim; van der Wal, Leon; Gramatica, Paola

    2013-08-15

    Due to their chemical properties synthetic triazoles and benzo-triazoles ((B)TAZs) are mainly distributed to the water compartments in the environment, and because of their wide use the potential effects on aquatic organisms are cause of concern. Non testing approaches like those based on quantitative structure-activity relationships (QSARs) are valuable tools to maximize the information contained in existing experimental data and predict missing information while minimizing animal testing. In the present study, externally validated QSAR models for the prediction of acute (B)TAZs toxicity in Daphnia magna and Oncorhynchus mykiss have been developed according to the principles for the validation of QSARs and their acceptability for regulatory purposes, proposed by the Organization for Economic Co-operation and Development (OECD). These models are based on theoretical molecular descriptors, and are statistically robust, externally predictive and characterized by a verifiable structural applicability domain. They have been applied to predict acute toxicity for over 300 (B)TAZs without experimental data, many of which are in the pre-registration list of the REACH regulation. Additionally, a model based on quantitative activity-activity relationships (QAAR) has been developed, which allows for interspecies extrapolation from daphnids to fish. The importance of QSAR/QAAR, especially when dealing with specific chemical classes like (B)TAZs, for screening and prioritization of pollutants under REACH, has been highlighted. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Comparison of artificial neural network (ANN) and partial least squares (PLS) regression models for predicting respiratory ventilation: an exploratory study.

    Science.gov (United States)

    Lin, Ming-I Brandon; Groves, William A; Freivalds, Andris; Lee, Eun Gyung; Harper, Martin

    2012-05-01

    The objective of this study was to assess the potential for using artificial neural networks (ANN) to predict inspired minute ventilation (V(I)) during exercise activities. Six physiological/kinematic measurements obtained from a portable ambulatory monitoring system, along with individual's anthropometric and demographic characteristics, were employed as input variables to develop and optimize the ANN configuration with respect to reference values simultaneously measured using a pneumotachograph (PT). The generalization ability of the resulting two-hidden-layer ANN model was compared with a linear predictive model developed through partial least squares (PLS) regression, as well as other V(I) predictive models proposed in the literature. Using an independent dataset recorded from nine 80-min step tests, the results showed that the ANN-estimated V(I) was highly correlated (R(2) = 0.88) with V(I) measured by the PT, with a mean difference of approximately 0.9%. In contrast, the PLS and other regression-based models resulted in larger average errors ranging from 7 to 34%. In addition, the ANN model yielded estimates of cumulative total volume that were on average within 1% of reference PT measurements. Compared with established statistical methods, the proposed ANN model demonstrates the potential to provide improved prediction of respiratory ventilation in workplace applications for which the use of traditional laboratory-based instruments is not feasible. Further research should be conducted to investigate the performance of ANNs for different types of physical activity in larger and more varied worker populations.

  1. Application of the physiological and morphological parameters of the brazilian population sample to the mathematical model of the human respiratory tract

    International Nuclear Information System (INIS)

    Reis, Arlene Alves dos

    2005-01-01

    The Human Respiratory Tract Model proposed by the ICRP Publication 66 accounts for the morphology and physiology of the respiratory tract. The characteristics of air drawn into the lungs and exhaled are greatly influenced by the morphology of the respiratory tract, which causes numerous changes in pressure, flow rate, direction and humidity as air moves into and out of the lungs. Concerning the respiratory physiological parameters the breathing characteristics influence the volume, the inhalation rate of air and the portion that enters through the nose and the mouth. These characteristics are important to determine the fractional deposition. The model uses morphological and physiological parameters from the Caucasian man to establish deposition fractions in the respiratory tract regions. It is known that the morphology and physiology are influenced by environmental, occupational and economic conditions. The ICRP recommends, for a reliable evaluation of the regional deposition, the use of parameters from a local population when information is available. The main purpose of this study is to verify the influence in using the morphology and physiology parameters representative of a sample of the Brazilian population on the deposition model of the ICRP Publication 66. The morphological and physiological data were obtained from the literature. The software EXCEL for Windows (version 2000) was used in order to implement the deposition model and also to allow the changes in parameters of interest. Initially, the implemented model was checked using the parameters defined by the ICRP and the results of the fraction deposition in the respiratory tract compartments were compared. Finally, morphological and physiological parameters from Brazilian adult male were applied and the fractional deposition calculated. The results suggest a significant variation in fractional deposition when Brazilian parameters are applied in the model. (author)

  2. The Toxic Effects of Pathogenic Ataxin-3 Variants in a Yeast Cellular Model

    Science.gov (United States)

    Bonanomi, Marcella; Visentin, Cristina; Invernizzi, Gaetano; Tortora, Paolo; Regonesi, Maria Elena

    2015-01-01

    Ataxin-3 (AT3) is a deubiquitinating enzyme that triggers an inherited neurodegenerative disorder, spinocerebellar ataxia type 3, when its polyglutamine (polyQ) stretch close to the C-terminus exceeds a critical length. AT3 variants carrying the expanded polyQ are prone to associate with each other into amyloid toxic aggregates, which are responsible for neuronal death with ensuing neurodegeneration. We employed Saccharomyces cerevisiae as a eukaryotic cellular model to better clarify the mechanism by which AT3 triggers the disease. We expressed three variants: one normal (Q26), one expanded (Q85) and one truncated for a region lying from the beginning of its polyQ stretch to the end of the protein (291Δ). We found that the expression of the expanded form caused reduction in viability, accumulation of reactive oxygen species, imbalance of the antioxidant defense system and loss in cell membrane integrity, leading to necrotic death. The truncated variant also exerted a qualitatively similar, albeit milder, effect on cell growth and cytotoxicity, which points to the involvement of also non-polyQ regions in cytotoxicity. Guanidine hydrochloride, a well-known inhibitor of the chaperone Hsp104, almost completely restored wild-type survival rate of both 291Δ- and Q85-expressing strains. This suggests that AT3 aggregation and toxicity is mediated by prion forms of yeast proteins, as this chaperone plays a key role in their propagation. PMID:26052945

  3. The Toxic Effects of Pathogenic Ataxin-3 Variants in a Yeast Cellular Model.

    Directory of Open Access Journals (Sweden)

    Marcella Bonanomi

    Full Text Available Ataxin-3 (AT3 is a deubiquitinating enzyme that triggers an inherited neurodegenerative disorder, spinocerebellar ataxia type 3, when its polyglutamine (polyQ stretch close to the C-terminus exceeds a critical length. AT3 variants carrying the expanded polyQ are prone to associate with each other into amyloid toxic aggregates, which are responsible for neuronal death with ensuing neurodegeneration. We employed Saccharomyces cerevisiae as a eukaryotic cellular model to better clarify the mechanism by which AT3 triggers the disease. We expressed three variants: one normal (Q26, one expanded (Q85 and one truncated for a region lying from the beginning of its polyQ stretch to the end of the protein (291Δ. We found that the expression of the expanded form caused reduction in viability, accumulation of reactive oxygen species, imbalance of the antioxidant defense system and loss in cell membrane integrity, leading to necrotic death. The truncated variant also exerted a qualitatively similar, albeit milder, effect on cell growth and cytotoxicity, which points to the involvement of also non-polyQ regions in cytotoxicity. Guanidine hydrochloride, a well-known inhibitor of the chaperone Hsp104, almost completely restored wild-type survival rate of both 291Δ- and Q85-expressing strains. This suggests that AT3 aggregation and toxicity is mediated by prion forms of yeast proteins, as this chaperone plays a key role in their propagation.

  4. Drosophila melanogaster as a model system of aluminum toxicity and aging.

    Science.gov (United States)

    Kijak, Ewelina; Rosato, Ezio; Knapczyk, Katarzyna; Pyza, Elżbieta

    2014-04-01

    The aim of this study was to investigate the toxic effects of aluminum (Al) on the model organism-Drosophila melanogaster. The study is especially concerned with the effects of aluminum on the fruit fly's development, life span, and circadian rhythm in rest and activity. Flies were exposed to aluminum in concentrations from 40 to 280 mg/kg in rearing media or the flies were raised on control medium. Moreover, the life span of insects exposed to aluminum containing 40, 120, or 240 mg/kg of Al in the medium, only during their larval development, during the whole life cycle and only in their adult life was tested. To check if aluminum and aging cause changes in D. melanogaster behavior, the locomotor activity of flies at different ages was recorded. Results showed that aluminum is toxic in concentrations above 160 mg/kg in the rearing medium. Depending on Al concentration and time of exposure, the life span of the flies was shortened. At intermediate concentrations (120 mg/kg), however, Al had a stimulating effect on males increasing their life span and level of locomotor activity. At higher concentration the aluminum exposure increased or decreased the level of locomotor activity of D. melanogaster depending on age of flies. In addition, in the oldest insects reared on aluminum supplemented media and in mid-aged flies reared on the highest concentration of Al the daily rhythm of activity was disrupted. © 2013 Institute of Zoology, Chinese Academy of Sciences.

  5. Efficacious rat model displays non-toxic effect with Korean beechwood creosote: a possible antibiotic substitute.

    Science.gov (United States)

    Quynh, Anh Nguyen Thai; Sharma, Neelesh; Cho, Kwang Keun; Yeo, Tae Jong; Kim, Ki Beom; Jeong, Chul Yon; Min, Tae Sun; Young, Kim Jae; Kim, Jin Nam; Jeong, Dong-Kee

    2014-05-04

    Wood creosote, an herbal anti-diarrheal and a mixture of major volatile compounds, was tested for its non-toxicological effects, using a rat model, with the objective to use the creosote as an antibiotic substitute. A total of 30 Sprague-Dawley rats were studied to form five groups with 6 rats each. Korea beechwood creosote was supplemented into three test groups with 0.03 g/kg, 0.07 g/kg and 0.1 g/kg body weight/day without antibiotic support, along with a positive control of Apramycin sulphate (at 0.5% of the daily feed) and a negative control. Korean beechwood creosote supplementation showed no negative effect on the body weight gain in comparison to the negative and the positive control groups and the feed conversion ratio was also comparable with that of the control groups. The clinical pathology parameters studied were also under the umbrella of normal range, including liver specific enzymes, blood glucose, total protein, blood urea nitrogen (BUN), which indicated no toxic effect of creosote at the given doses. The non-hepatotoxic effect was also confirmed using hepatic damage specific molecular markers like Tim-p1, Tim-p2 and Tgf-β1. The results suggested that Korean beechwood may be used as antibiotic substitute in weanling pigs feed without any toxic effect on the body. Although the antimicrobial properties of creosote were not absolutely similar to those of apramycin sulphate, they were comparable.

  6. Standardizing acute toxicity data for use in ecotoxicology models: influence of test type, life stage, and concentration reporting.

    Science.gov (United States)

    Raimondo, Sandy; Vivian, Deborah N; Barron, Mace G

    2009-10-01

    Ecotoxicological models generally have large data requirements and are frequently based on existing information from diverse sources. Standardizing data for toxicological models may be necessary to reduce extraneous variation and to ensure models reflect intrinsic relationships. However, the extent to which data standardization is necessary remains unclear, particularly when data transformations are used in model development. An extensive acute toxicity database was compiled for aquatic species to comprehensively assess the variation associated with acute toxicity test type (e.g., flow-through, static), reporting concentrations as nominal or measured, and organism life stage. Three approaches were used to assess the influence of these factors on log-transformed acute toxicity: toxicity ratios, log-linear models of factor groups, and comparison of interspecies correlation estimation (ICE) models developed using either standardized test types or reported concentration type. In general, median ratios were generally less than 2.0, the slopes of log-linear models were approximately one for well-represented comparisons, and ICE models developed using data from standardized test types or reported concentrations did not differ substantially. These results indicate that standardizing test data by acute test type, reported concentration type, or life stage may not be critical for developing ecotoxicological models using large datasets of log-transformed values.

  7. Modeling Huntington disease in Drosophila: Insights into axonal transport defects and modifiers of toxicity.

    Science.gov (United States)

    Krench, Megan; Littleton, J Troy

    2013-01-01

    Huntington disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the huntingtin (Htt) gene. Despite years of research, there is no treatment that extends life for patients with the disorder. Similarly, little is known about which cellular pathways that are altered by pathogenic Huntingtin (Htt) protein expression are correlated with neuronal loss. As part of a longstanding effort to gain insights into HD pathology, we have been studying the protein in the context of the fruitfly Drosophila melanogaster. We generated transgenic HD models in Drosophila by engineering flies that carry a 12-exon fragment of the human Htt gene with or without the toxic trinucleotide repeat expansion. We also created variants with a monomeric red fluorescent protein (mRFP) tag fused to Htt that allows in vivo imaging of Htt protein localization and aggregation. While wild-type Htt remains diffuse throughout the cytoplasm of cells, pathogenic Htt forms insoluble aggregates that accumulate in neuronal soma and axons. Aggregates can physically block transport of numerous organelles along the axon. We have also observed that aggregates are formed quickly, within just a few hours of mutant Htt expression. To explore mechanisms of neurodegeneration in our HD model, we performed in vivo and in vitro screens to search for modifiers of viability and pathogenic Htt aggregation. Our results identified several novel candidates for HD therapeutics that can now be tested in mammalian models of HD. Furthermore, these experiments have highlighted the complex relationship between aggregates and toxicity that exists in HD.

  8. Modeling marrow damage from response data: Morphallaxis from radiation biology to benzene toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Jones, T.D.; Morris, M.D.; Hasan, J.S.

    1995-12-01

    Consensus principles from radiation biology were used to describe a generic set of nonlinear, first-order differential equations for modeling of toxicity-induced compensatory cell kinetics in terms of sublethal injury, repair, direct killing, killing of cells with unrepaired sublethal injury, and repopulation. This cellular model was linked to a probit model of hematopoietic mortality that describes death from infection and/or hemorrhage between {approximately} 5 and 30 days. Mortality data from 27 experiments with 851 doseresponse groups, in which doses were protracted by rate and/or fractionation, were used to simultaneously estimate all rate constants by maximum-likelihood methods. Data used represented 18,940 test animals distributed according to: (mice, 12,827); (rats, 2,925); (sheep, 1,676); (swine, 829); (dogs, 479); and (burros, 204). Although a long-term, repopulating hematopoietic stem cell is ancestral to all lineages needed to restore normal homeostasis, the dose-response data from the protracted irradiations indicate clearly that the particular lineage that is ``critical`` to hematopoietic recovery does not resemble stem-like cells with regard to radiosensitivity and repopulation rates. Instead, the weakest link in the chain of hematopoiesis was found to have an intrinsic radioresistance equal to or greater than stromal cells and to repopulate at the same rates. Model validation has been achieved by predicting the LD{sub 50} and/or fractional group mortality in 38 protracted-dose experiments (rats and mice) that were not used in the fitting of model coefficients.

  9. Modeling marrow damage from response data: Morphallaxis from radiation biology to benzene toxicity

    International Nuclear Information System (INIS)

    Jones, T.D.; Morris, M.D.; Hasan, J.S.

    1995-01-01

    Consensus principles from radiation biology were used to describe a generic set of nonlinear, first-order differential equations for modeling of toxicity-induced compensatory cell kinetics in terms of sublethal injury, repair, direct killing, killing of cells with unrepaired sublethal injury, and repopulation. This cellular model was linked to a probit model of hematopoietic mortality that describes death from infection and/or hemorrhage between ∼ 5 and 30 days. Mortality data from 27 experiments with 851 doseresponse groups, in which doses were protracted by rate and/or fractionation, were used to simultaneously estimate all rate constants by maximum-likelihood methods. Data used represented 18,940 test animals distributed according to: (mice, 12,827); (rats, 2,925); (sheep, 1,676); (swine, 829); (dogs, 479); and (burros, 204). Although a long-term, repopulating hematopoietic stem cell is ancestral to all lineages needed to restore normal homeostasis, the dose-response data from the protracted irradiations indicate clearly that the particular lineage that is ''critical'' to hematopoietic recovery does not resemble stem-like cells with regard to radiosensitivity and repopulation rates. Instead, the weakest link in the chain of hematopoiesis was found to have an intrinsic radioresistance equal to or greater than stromal cells and to repopulate at the same rates. Model validation has been achieved by predicting the LD 50 and/or fractional group mortality in 38 protracted-dose experiments (rats and mice) that were not used in the fitting of model coefficients

  10. Accumulation dynamics and acute toxicity of silver nanoparticles to Daphnia magna and Lumbriculus variegatus: implications for metal modeling approaches.

    Science.gov (United States)

    Khan, Farhan R; Paul, Kai B; Dybowska, Agnieszka D; Valsami-Jones, Eugenia; Lead, Jamie R; Stone, Vicki; Fernandes, Teresa F

    2015-04-07

    Frameworks commonly used in trace metal ecotoxicology (e.g., biotic ligand model (BLM) and tissue residue approach (TRA)) are based on the established link between uptake, accumulation and toxicity, but similar relationships remain unverified for metal-containing nanoparticles (NPs). The present study aimed to (i) characterize the bioaccumulation dynamics of PVP-, PEG-, and citrate-AgNPs, in comparison to dissolved Ag, in Daphnia magna and Lumbriculus variegatus; and (ii) investigate whether parameters of bioavailability and accumulation predict acute toxicity. In both species, uptake rate constants for AgNPs were ∼ 2-10 times less than for dissolved Ag and showed significant rank order concordance with acute toxicity. Ag elimination by L. variegatus fitted a 1-compartment loss model, whereas elimination in D. magna was biphasic. The latter showed consistency with studies that reported daphnids ingesting NPs, whereas L. variegatus biodynamic parameters indicated that uptake and efflux were primarily determined by the bioavailability of dissolved Ag released by the AgNPs. Thus, principles of BLM and TRA frameworks are confounded by the feeding behavior of D. magna where the ingestion of AgNPs perturbs the relationship between tissue concentrations and acute toxicity, but such approaches are applicable when accumulation and acute toxicity are linked to dissolved concentrations. The uptake rate constant, as a parameter of bioavailability inclusive of all available pathways, could be a successful predictor of acute toxicity.

  11. Quantitative structure-activity relationship modeling of the toxicity of organothiophosphate pesticides to Daphnia magna and Cyprinus carpio

    NARCIS (Netherlands)

    Zvinavashe, E.; Du, T.; Griff, T.; Berg, van den J.H.J.; Soffers, A.E.M.F.; Vervoort, J.J.M.; Murk, A.J.; Rietjens, I.

    2009-01-01

    Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (QSAR) models are expected to help reduce the number of animals used for experimental testing. The objective of this study was to develop QSAR models to describe the acute toxicity of organothiophosphate

  12. Arteriovenous extracorporeal lung assist allows for maximization of oscillatory frequencies: a large-animal model of respiratory distress

    Directory of Open Access Journals (Sweden)

    Kranke Peter

    2008-11-01

    Full Text Available Abstract Background Although the minimization of the applied tidal volume (VT during high-frequency oscillatory ventilation (HFOV reduces the risk of alveolar shear stress, it can also result in insufficient CO2-elimination with severe respiratory acidosis. We hypothesized that in a model of acute respiratory distress (ARDS the application of high oscillatory frequencies requires the combination of HFOV with arteriovenous extracorporeal lung assist (av-ECLA in order to maintain or reestablish normocapnia. Methods After induction of ARDS in eight female pigs (56.5 ± 4.4 kg, a recruitment manoeuvre was performed and intratracheal mean airway pressure (mPaw was adjusted 3 cmH2O above the lower inflection point (Plow of the pressure-volume curve. All animals were ventilated with oscillatory frequencies ranging from 3–15 Hz. The pressure amplitude was fixed at 60 cmH2O. At each frequency gas exchange and hemodynamic measurements were obtained with a clamped and de-clamped av-ECLA. Whenever the av-ECLA was de-clamped, the oxygen sweep gas flow through the membrane lung was adjusted aiming at normocapnia. Results Lung recruitment and adjustment of the mPaw above Plow resulted in a significant improvement of oxygenation (p Conclusion In this animal model of ARDS, maximization of oscillatory frequencies with subsequent minimization of VT leads to hypercapnia that can only be reversed by adding av-ECLA. When combined with a recruitment strategy, these high frequencies do not impair oxygenation

  13. Arteriovenous Extracorporeal Lung Assist Allows For Maximization Of Oscillatory Frequencies: A Large-animal Model Of Respiratory Distress.

    Science.gov (United States)

    Muellenbach, Ralf M; Kuestermann, Julian; Kredel, Markus; Johannes, Amélie; Wolfsteiner, Ulrike; Schuster, Frank; Wunder, Christian; Kranke, Peter; Roewer, Norbert; Brederlau, Jörg

    2008-11-14

    Although the minimization of the applied tidal volume (VT) during high-frequency oscillatory ventilation (HFOV) reduces the risk of alveolar shear stress, it can also result in insufficient CO₂-elimination with severe respiratory acidosis. We hypothesized that in a model of acute respiratory distress (ARDS) the application of high oscillatory frequencies requires the combination of HFOV with arteriovenous extracorporeal lung assist (av-ECLA) in order to maintain or reestablish normocapnia. After induction of ARDS in eight female pigs (56.5 ± 4.4 kg), a recruitment manoeuvre was performed and intratracheal mean airway pressure (mPaw) was adjusted 3 cmH₂O above the lower inflection point (Plow) of the pressure-volume curve. All animals were ventilated with oscillatory frequencies ranging from 3-15 Hz. The pressure amplitude was fixed at 60 cmH₂O. At each frequency gas exchange and hemodynamic measurements were obtained with a clamped and de-clamped av-ECLA. Whenever the av-ECLA was de-clamped, the oxygen sweep gas flow through the membrane lung was adjusted aiming at normocapnia. Lung recruitment and adjustment of the mPaw above Plow resulted in a significant improvement of oxygenation (p < 0.05). Compared to lung injury, oxygenation remained significantly improved with rising frequencies (p < 0.05). Normocapnia during HFOV was only maintained with the addition of av-ECLA during frequencies of 9 Hz and above. In this animal model of ARDS, maximization of oscillatory frequencies with subsequent minimization of VT leads to hypercapnia that can only be reversed by adding av-ECLA. When combined with a recruitment strategy, these high frequencies do not impair oxygenation.

  14. Predicting acute contact toxicity of pesticides in honeybees (Apis mellifera) through a k-nearest neighbor model.

    Science.gov (United States)

    Como, F; Carnesecchi, E; Volani, S; Dorne, J L; Richardson, J; Bassan, A; Pavan, M; Benfenati, E

    2017-01-01

    Ecological risk assessment of plant protection products (PPPs) requires an understanding of both the toxicity and the extent of exposure to assess risks for a range of taxa of ecological importance including target and non-target species. Non-target species such as honey bees (Apis mellifera), solitary bees and bumble bees are of utmost importance because of their vital ecological services as pollinators of wild plants and crops. To improve risk assessment of PPPs in bee species, computational models predicting the acute and chronic toxicity of a range of PPPs and contaminants can play a major role in providing structural and physico-chemical properties for the prioritisation of compounds of concern and future risk assessments. Over the last three decades, scientific advisory bodies and the research community have developed toxicological databases and quantitative structure-activity relationship (QSAR) models that are proving invaluable to predict toxicity using historical data and reduce animal testing. This paper describes the development and validation of a k-Nearest Neighbor (k-NN) model using in-house software for the prediction of acute contact toxicity of pesticides on honey bees. Acute contact toxicity data were collected from different sources for 256 pesticides, which were divided into training and test sets. The k-NN models were validated with good prediction, with an accuracy of 70% for all compounds and of 65% for highly toxic compounds, suggesting that they might reliably predict the toxicity of structurally diverse pesticides and could be used to screen and prioritise new pesticides. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Toxicity studies of six types of carbon nanoparticles in a chicken-embryo model

    DEFF Research Database (Denmark)

    Kurantowicz, Natalia; Sawosz, Ewa; Halik, Gabriela

    2017-01-01

    In the present study, the toxicity of six different types of carbon nanoparticles (CNPs) was investigated using a chicken-embryo model. Fertilized chicken eggs were divided into the following treatment groups: placebo, diamond NPs, graphite NPs, pristine graphene, small graphene oxide, large...... and the weight of the body and organs measured. The relative ratio of embryo survival decreased after treatment all treatments except diamond NPs. There was no correlation between the rate of survival and the ζ-potential or the surface charge of the CNPs in solution. Body and organ weight, red blood......-cell morphology, blood serum biochemical parameters, and oxidative damage in the liver did not differ among the groups. These results indicate that CNPs can remain in blood circulation without any major side effects, suggesting their potential applicability as vehicles for drug delivery or active compounds per se...

  16. Pretreatment with intravenous lipid emulsion reduces mortality from cocaine toxicity in a rat model.

    Science.gov (United States)

    Carreiro, Stephanie; Blum, Jared; Hack, Jason B

    2014-07-01

    We compare the effects of intravenous lipid emulsion and normal saline solution pretreatment on mortality and hemodynamic changes in a rat model of cocaine toxicity. We hypothesize that intravenous lipid emulsion will decrease mortality and hemodynamic changes caused by cocaine administration compared with saline solution. Twenty male Sprague-Dawley rats were sedated and randomized to receive intravenous lipid emulsion or normal saline solution, followed by a 10 mg/kg bolus of intravenous cocaine. Continuous monitoring included intra-arterial blood pressure, pulse rate and ECG tracing. Endpoints included a sustained undetectable mean arterial pressure (MAP) or return to baseline MAP for 5 minutes. The log-rank test was used to compare mortality. A mixed-effect repeated-measures ANOVA was used to estimate the effects of group (intravenous lipid emulsion versus saline solution), time, and survival on change in MAP, pulse rate, or pulse pressure. In the normal saline solution group, 7 of 10 animals died compared with 2 of 10 in the intravenous lipid emulsion group. The survival rate of 80% (95% confidence interval 55% to 100%) for the intravenous lipid emulsion rats and 30% (95% confidence interval 0.2% to 58%) for the normal saline solution group was statistically significant (P=.045). Intravenous lipid emulsion pretreatment decreased cocaine-induced cardiovascular collapse and blunted hypotensive effects compared with normal saline solution in this rat model of acute lethal cocaine intoxication. Intravenous lipid emulsion should be investigated further as a potential adjunct in the treatment of severe cocaine toxicity. Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

  17. Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination.

    Science.gov (United States)

    Tarbali, Sepideh; Khezri, Shiva

    2016-01-01

    Multiple sclerosis (MS) is a demyelinating disease. The prevalence of MS is highest where environmental supplies of vitamin D are low. Cognitive deficits have been observed in patients with MS. Oxidative damage may contribute to the formation of MS lesions. Considering the involvement of hippocampus in MS, an attempt is made in this study to investigate the effects of vitamin D3 on behavioral process and the oxidative status in the dorsal hippocampus (CA1 area) following the induction of experimental demyelination in rats. Animals were divided into six groups. animals received no surgery and treatment; saline group: animals received normal saline; sham group: animals received 150 μl sesame oil IP; vitamin D3 group: animals received 5 μg/kg vitamin D3 IP; lysophosphatidyl choline (LPC) group (toxic demyelination's model): animals received LPC by stereotaxic intra-hippocampal injection of 2 μl LPC in CA1 area; Vitamin D3- treated group: animals were treated with vitamin D3 at doses of 5 μg/kg IP for 7 and 21 days post lesion. The spatial memory, biochemical parameters including catalase (CAT) activities and lipid peroxidation levels were investigated. Animals in LPC group had more deficits in spatial memory than the control group in radial arm maze. Vitamin D3 significantly improved spatial memory compared to LPC group. Also, results indicated that vitamin D3 caused a decrease in lipid peroxidation levels and an increase in CAT activities. Current findings suggest that vitamin D3 may have a protective effect on cognitive deficits and oxidative stress in toxic demyelination's model.

  18. QSAR models for predicting the toxicity of piperidine derivatives against Aedes aegypti.

    Science.gov (United States)

    Doucet, J P; Papa, E; Doucet-Panaye, A; Devillers, J

    2017-06-01

    QSAR models are proposed for predicting the toxicity of 33 piperidine derivatives against Aedes aegypti. From 2D topological descriptors, calculated with the PaDEL software, ordinary least squares multilinear regression (OLS-MLR) treatment from the QSARINS software and machine learning and related approaches including linear and radial support vector machine (SVM), projection pursuit regression (PPR), radial basis function neural network (RBFNN), general regression neural network (GRNN) and k-nearest neighbours (k-NN), led to four-variable models. Their robustness and predictive ability were evaluated through both internal and external validation. Determination coefficients (r 2 ) greater than 0.85 on the training sets and 0.8 on the test sets were obtained with OLS-MLR and linear SVM. They slightly outperform PPR, radial SVM and RBFNN, whereas GRNN and k-NN showed lower performance. The easy availability of the involved structural descriptors and the simplicity of the MLR model make the corresponding model attractive at an exploratory level for proposing, from this limited dataset, guidelines in the design of new potentially active molecules.

  19. Misoprostol Inhibits Equine Neutrophil Adhesion, Migration, and Respiratory Burst in an In Vitro Model of Inflammation

    Directory of Open Access Journals (Sweden)

    Emily Medlin Martin

    2017-09-01

    Full Text Available In many equine inflammatory disease states, neutrophil activities, such as adhesion, migration, and reactive oxygen species (ROS production become dysregulated. Dysregulated neutrophil activation causes tissue damage in horses with asthma, colitis, laminitis, and gastric glandular disease. Non-steroidal anti-inflammatory drugs do not adequately inhibit neutrophil inflammatory functions and can lead to dangerous adverse effects. Therefore, novel therapies that target mechanisms of neutrophil-mediated tissue damage are needed. One potential neutrophil-targeting therapeutic is the PGE1 analog, misoprostol. Misoprostol is a gastroprotectant that induces intracellular formation of the secondary messenger molecule cyclic AMP (cAMP, which has been shown to have anti-inflammatory effects on neutrophils. Misoprostol is currently used in horses to treat NSAID-induced gastrointestinal injury; however, its effects on equine neutrophils have not been determined. We hypothesized that treatment of equine neutrophils with misoprostol would inhibit equine neutrophil adhesion, migration, and ROS production, in vitro. We tested this hypothesis using isolated equine peripheral blood neutrophils collected from 12 healthy adult teaching/research horses of mixed breed and gender. The effect of misoprostol treatment on adhesion, migration, and respiratory burst of equine neutrophils was evaluated via fluorescence-based adhesion and chemotaxis assays, and luminol-enhanced chemiluminescence, respectively. Neutrophils were pretreated with varying concentrations of misoprostol, vehicle, or appropriate functional inhibitory controls prior to stimulation with LTB4, CXCL8, PAF, lipopolysaccharide (LPS or immune complex (IC. This study revealed that misoprostol pretreatment significantly inhibited LTB4-induced adhesion, LTB4-, CXCL8-, and PAF-induced chemotaxis, and LPS-, IC-, and PMA-induced ROS production in a concentration-dependent manner. This data indicate that

  20. A UWB Radar Signal Processing Platform for Real-Time Human Respiratory Feature Extraction Based on Four-Segment Linear Waveform Model.

    Science.gov (United States)

    Hsieh, Chi-Hsuan; Chiu, Yu-Fang; Shen, Yi-Hsiang; Chu, Ta-Shun; Huang, Yuan-Hao

    2016-02-01

    This paper presents an ultra-wideband (UWB) impulse-radio radar signal processing platform used to analyze human respiratory features. Conventional radar systems used in human detection only analyze human respiration rates or the response of a target. However, additional respiratory signal information is available that has not been explored using radar detection. The authors previously proposed a modified raised cosine waveform (MRCW) respiration model and an iterative correlation search algorithm that could acquire additional respiratory features such as the inspiration and expiration speeds, respiration intensity, and respiration holding ratio. To realize real-time respiratory feature extraction by using the proposed UWB signal processing platform, this paper proposes a new four-segment linear waveform (FSLW) respiration model. This model offers a superior fit to the measured respiration signal compared with the MRCW model and decreases the computational complexity of feature extraction. In addition, an early-terminated iterative correlation search algorithm is presented, substantially decreasing the computational complexity and yielding negligible performance degradation. These extracted features can be considered the compressed signals used to decrease the amount of data storage required for use in long-term medical monitoring systems and can also be used in clinical diagnosis. The proposed respiratory feature extraction algorithm was designed and implemented using the proposed UWB radar signal processing platform including a radar front-end chip and an FPGA chip. The proposed radar system can detect human respiration rates at 0.1 to 1 Hz and facilitates the real-time analysis of the respiratory features of each respiration period.

  1. Predictive Modeling of Chemical Hazard by Integrating Numerical Descriptors of Chemical Structures and Short-term Toxicity Assay Data

    Science.gov (United States)

    Rusyn, Ivan; Sedykh, Alexander; Guyton, Kathryn Z.; Tropsha, Alexander

    2012-01-01

    Quantitative structure-activity relationship (QSAR) models are widely used for in silico prediction of in vivo toxicity of drug candidates or environmental chemicals, adding value to candidate selection in drug development or in a search for less hazardous and more sustainable alternatives for chemicals in commerce. The development of traditional QSAR models is enabled by numerical descriptors representing the inherent chemical properties that can be easily defined for any number of molecules; however, traditional QSAR models often have limited predictive power due to the lack of data and complexity of in vivo endpoints. Although it has been indeed difficult to obtain experimentally derived toxicity data on a large number of chemicals in the past, the results of quantitative in vitro screening of thousands of environmental chemicals in hundreds of experimental systems are now available and continue to accumulate. In addition, publicly accessible toxicogenomics data collected on hundreds of chemicals provide another dimension of molecular information that is potentially useful for predictive toxicity modeling. These new characteristics of molecular bioactivity arising from short-term biological assays, i.e., in vitro screening and/or in vivo toxicogenomics data can now be exploited in combination with chemical structural information to generate hybrid QSAR–like quantitative models to predict human toxicity and carcinogenicity. Using several case studies, we illustrate the benefits of a hybrid modeling approach, namely improvements in the accuracy of models, enhanced interpretation of the most predictive features, and expanded applicability domain for wider chemical space coverage. PMID:22387746

  2. Interaction patterns and toxicities of binary and ternary pesticide mixtures to Daphnia magna estimated by an accelerated failure time model.

    Science.gov (United States)

    Qiu, Xuchun; Tanoue, Wataru; Kawaguchi, Atsushi; Yanagawa, Takashi; Seki, Masanori; Shimasaki, Yohei; Honjo, Tsuneo; Oshima, Yuji

    2017-12-31

    Organisms in natural environments are often exposed to a broad variety of chemicals, and the multi-chemical mixtures exposure may produce significant toxic effects, even though the individual chemicals are present at concentrations below their no-observed-effect concentrations. This study represents the first attempt that uses the accelerated failure time (AFT) model to quantify the interaction and toxicity of multi-chemical mixtures in environmental toxicology. We firstly conducted the acute immobilization tests with Daphnia magna exposed to mixtures of diazinon (DZN), fenitrothion (MEP); and thiobencarb (TB) in single, binary, and ternary formulations, and then fitted the results to the AFT model. The 48-h EC 50 (concentration required to immobilize 50% of the daphnids at 48h) values for each pesticide obtained from the AFT model are within a factor of 2 of the corresponding values calculated from the single pesticide exposure tests, indicating the methodology is able to provide credible toxicity values. The AFT model revealed either significant synergistic (DZN and MEP; DZN and TB) or antagonistic (MEP and TB) interactions in binary mixtures, while the interaction pattern of ternary mixture depended on both the concentration levels and concentration ratios of pesticides. With a factor of 2, the AFT model accurately estimated the toxicities for 78% of binary mixture formulations that exhibited significant synergistic effects, and the toxicities for all the ternary formulations. Our results showed that the AFT model can provide a simple and efficient way to quantify the interactions between pesticides and to assess the toxicity of their mixtures. This ability may greatly facilitate the ecotoxicological risk assessment of exposure to multi-chemical mixtures. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Modelling the Impact of Fractionation on Late Urinary Toxicity After Postprostatectomy Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Fiorino, Claudio, E-mail: fiorino.claudio@hsr.it [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Cozzarini, Cesare [Department of Radiotherapy, San Raffaele Scientific Institute, Milan (Italy); Rancati, Tiziana [Prostate Cancer Program, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan (Italy); Briganti, Alberto [Department of Urology, San Raffaele Scientific Institute, Milan (Italy); Cattaneo, Giovanni Mauro; Mangili, Paola [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Di Muzio, Nadia Gisella [Department of Radiotherapy, San Raffaele Scientific Institute, Milan (Italy); Calandrino, Riccardo [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy)

    2014-12-01

    Purpose: To fit urinary toxicity data of patients treated with postprostatectomy radiation therapy with the linear quadratic (LQ) model with/without introducing a time factor. Methods and Materials: Between 1993 and 2010, 1176 patients were treated with conventional fractionation (1.8 Gy per fraction, median 70.2 Gy, n=929) or hypofractionation (2.35-2.90 Gy per fraction, n=247). Data referred to 2004-2010 (when all schemes were in use, n=563; conventional fractionation: 316; hypofractionation: 247) were fitted as a logit function of biological equivalent dose (BED), according to the LQ model with/without including a time factor γ (fixing α/β = 5 Gy). The 3-year risks of severe urethral stenosis, incontinence, and hematuria were considered as endpoints. Best-fit parameters were derived, and the resulting BEDs were taken in multivariable backward logistic models, including relevant clinical variables, considering the whole population. Results: The 3-year incidences of severe stenosis, incontinence, and hematuria were, respectively, 6.6%, 4.8%, and 3.3% in the group treated in 2004-2010. The best-fitted α/β values were 0.81 Gy and 0.74 Gy for incontinence and hematuria, respectively, with the classic LQ formula. When fixing α/β = 5 Gy, best-fit values for γ were, respectively, 0.66 Gy/d and 0.85 Gy/d. Sensitivity analyses showed reasonable values for γ (0.6-1.0 Gy/d), with comparable goodness of fit for α/β values between 3.5 and 6.5 Gy. Likelihood ratio tests showed that the fits with/without including γ were equivalent. The resulting multivariable backward logistic models in the whole population included BED, pT4, and use of antihypertensives (area under the curve [AUC] = 0.72) for incontinence and BED, pT4, and year of surgery (AUC = 0.80) for hematuria. Stenosis data could not be fitted: a 4-variable model including only clinical factors (acute urinary toxicity, pT4, year of surgery, and use of antihypertensives) was suggested (AUC

  4. Intraindividual comparison of image quality using retrospective and prospective respiratory gating for the acquisition of thin sliced four dimensional multidetector CT of the thorax in a porcine model.

    Science.gov (United States)

    Behzadi, Cyrus; Groth, Michael; Henes, Frank Oliver; Schwarz, Dorothee; Deibele, André; Begemann, Philipp G C; Adam, Gerhard; Regier, Marc

    2015-01-01

    To intraindividually compare image quality and anatomical depiction of the lung and mediastinum using retrospective and prospective respiratory gating techniques for the acquisition of 4D-multidetector computed tomography (MDCT) of the chest in a porcine model. Twelve trachealy intubated domestic pigs underwent 64-row MDCT of the thorax. For retrospective and prospective gating the automated respiratory frequency was adjusted to 10, 14, 18, and 22 respiratory cycles per minute. Further, free breathing MDCT scans of the lung were performed at the same respiratory settings. A breathhold scan was acquired which served as the reference standard. Three reviewers independently analyzed the MDCT data applying a 4-point-grading scale regarding the degree of artifacts observed and anatomical depiction (1, excellent, no artifacts; 4, nondiagnostic due to severe artifacts). For statistical analysis the Wilcoxon matched pairs and Chi-square test were used. Breathhold imaging allowed for the highest image quality (mean value: trachea, 1.00; bronchi, 1.10; lung parenchyma, 1.08; diaphragm, 1.00; pericardium, 1.80). Retrospective gating proved to be of superior image quality compared to prospective gating for all respiratory frequencies. With the respiratory frequency set to 14/min retrospective gating even enabled an identical image quality score as at breathhold. Performing image acquisition during continuous breathing lead to a severe decrease in image quality. High image quality can be acquired using respiratory gating techniques for 4D-MDCT of the thorax. Retrospective is superior to prospective gating and can be of an equivalent image quality as standard breathhold imaging, but at the cost of a significantly higher radiation dose.

  5. Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity.

    Science.gov (United States)

    Calap-Quintana, Pablo; González-Fernández, Javier; Sebastiá-Ortega, Noelia; Llorens, José Vicente; Moltó, María Dolores

    2017-07-06

    Iron, copper and zinc are transition metals essential for life because they are required in a multitude of biological processes. Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. Interestingly, the main components of metal homeostatic pathways are conserved, with many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster . Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. Flies have many advantages in the laboratory, such as a short life cycle, easy handling and inexpensive maintenance. Furthermore, they can be raised in a large number. In addition, flies are greatly appreciated because they offer a considerable number of genetic tools to address some of the unresolved questions concerning disease pathology, which in turn could contribute to our understanding of the metal metabolism and homeostasis. This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided.

  6. Comparing rankings of selected TRI organic chemicals for two environments using a level III fugacity model and toxicity

    International Nuclear Information System (INIS)

    Edwards, F.G.; Egemen, E.; Nirmalakhandan, N.

    1998-01-01

    The Toxics Release Inventory, TRI (USEPA, 1995) is a comprehensive listing of chemicals, mass released, source of releases, and other related information for chemicals which are released into the environment in the US. These chemicals are then ranked according to the mass released as a indication of their environmental impact. Industries have been encouraged to adopt production methods to decrease the release of chemicals which are ranked highly in the TRI. Clearly, this ranking of the chemicals based upon the mass released fails to take into account very important environmental aspects. The first and most obvious aspect is the wide range of toxicity's of the chemicals released. Numerous researchers have proposed systems to rank chemicals according to their toxicity. The second aspect, which a mass released based ranking does not take into account, is the fate and transport of each chemical within the environment. Cohen and Ryan (1985) and Mackay and Paterson (1991) have proposed models to evaluate the fate and transport of chemicals released into the environment. Some authors have incorporated the mass released and toxicity with some fate and transport aspects to rank the impact of released chemicals. But, due to the complexities of modeling the environment, the lack of published data on properties of chemicals, and the lack of information on the speciation of chemicals in complex systems, modeling the fate and transport of toxic chemicals in the environment remains difficult. To provide an indication of the need to rank chemicals according to their environmental impact instead of the mass released, the authors have utilized a subset of 45 organic chemicals from the TRI, modeled the fate and transport of the chemicals using a Level III fugacity model, and compared those equilibrium concentrations with toxicity data to yield a hazard value for each chemical

  7. Toxic volatile organic compounds in environmental tobacco smoke: Emission factors for modeling exposures of California populations

    Energy Technology Data Exchange (ETDEWEB)

    Daisey, J.M.; Mahanama, K.R.R.; Hodgson, A.T. [Lawrence Berkeley Lab., CA (United States)

    1994-10-01

    The primary objective of this study was to measure emission factors for selected toxic air contaminants in environmental tobacco smoke (ETS) using a room-sized environmental chamber. The emissions of 23 volatile organic compounds (VOCs), including, 1,3-butadiene, three aldehydes and two vapor-phase N-nitrosamines were determined for six commercial brands of cigarettes and reference cigarette 1R4F. The commercial brands were selected to represent 62.5% of the cigarettes smoked in California. For each brand, three cigarettes were machine smoked in the chamber. The experiments were conducted over four hours to investigate the effects of aging. Emission factors of the target compounds were also determined for sidestream smoke (SS). For almost all target compounds, the ETS emission factors were significantly higher than the corresponding SS values probably due to less favorable combustion conditions and wall losses in the SS apparatus. Where valid comparisons could be made, the ETS emission factors were generally in good agreement with the literature. Therefore, the ETS emission factors, rather than the SS values, are recommended for use in models to estimate population exposures from this source. The variabilities in the emission factors ({mu}g/cigarette) of the selected toxic air contaminants among brands, expressed as coefficients of variation, were 16 to 29%. Therefore, emissions among brands were Generally similar. Differences among brands were related to the smoked lengths of the cigarettes and the masses of consumed tobacco. Mentholation and whether a cigarette was classified as light or regular did not significantly affect emissions. Aging was determined not to be a significant factor for the target compounds. There were, however, deposition losses of the less volatile compounds to chamber surfaces.

  8. Toxicity studies of six types of carbon nanoparticles in a chicken-embryo model

    Directory of Open Access Journals (Sweden)

    Kurantowicz N

    2017-04-01

    Full Text Available Natalia Kurantowicz,1 Ewa Sawosz,1 Gabriela Halik,1 Barbara Strojny,1 Anna Hotowy,1 Marta Grodzik,1 Radosław Piast,2 Wanvimol Pasanphan,3 André Chwalibog4 1Department of Animal Nutrition and Biotechnology, Warsaw University of Life Sciences, 2Faculty of Chemistry, Warsaw University, Warsaw, Poland; 3Department of Materials Science, Faculty of Science, Kasetsart University, Bangkok, Thailand; 4Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark Abstract: In the present study, the toxicity of six different types of carbon nanoparticles (CNPs was investigated using a chicken-embryo model. Fertilized chicken eggs were divided into the following treatment groups: placebo, diamond NPs, graphite NPs, pristine graphene, small graphene oxide, large graphene oxide, and reduced graphene oxide. Experimental solutions at a concentration of 500 µg/mL were administrated into the egg albumin. Gross pathology and the rate of survival were examined after 5, 10, 15, and 20 days of incubation. After 20 days of incubation, blood samples were collected and the weight of the body and organs measured. The relative ratio of embryo survival decreased after treatment all treatments except diamond NPs. There was no correlation between the rate of survival and the ζ-potential or the surface charge of the CNPs in solution. Body and organ weight, red blood-cell morphology, blood serum biochemical parameters, and oxidative damage in the liver did not differ among the groups. These results indicate that CNPs can remain in blood circulation without any major side effects, suggesting their potential applicability as vehicles for drug delivery or active compounds per se. However, there is a need for further investigation of their properties, which vary depending on production methods and surface functionalization. Keywords: nanoparticles, diamond, graphite, graphene, toxicity, red blood cells, oxidative stress, surface charge

  9. Intramuscular Cobinamide Sulfite in a Rabbit Model of Sub-Lethal Cyanide Toxicity

    Science.gov (United States)

    Brenner, Matthew; Kim, Jae G.; Mahon, Sari B.; Lee, Jangwoen; Kreuter, Kelly A.; Blackledge, William; Mukai, David; Patterson, Steve; Mohammad, Othman; Sharma, Vijay S.; Boss, Gerry R.

    2009-01-01

    Objective To determine the ability of an intramuscular cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity. Background Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B12) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigated the use of intramuscular cobinamide sulfite to reverse cyanide toxicity induced physiologic changes in a sublethal cyanide exposure animal model. Methods New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous wave near infrared spectroscopy monitoring of tissue oxy- and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with cobinamide sulfite (n=6) or inactive vehicle (controls, n=5). Results Intramuscular administration led to rapid mobilization of cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system was in a mean of 1032 minutes in the control group and 9 minutes in the cobinamide group with a difference of 1023 minutes (95% confidence interval [CI] 116, 1874 minutes). In muscle tissue, recovery times were 76 and 24 minutes with a difference of 52 minutes (95% CI 7, 98min). Red blood cell cyanide levels returned towards normal significantly faster in cobinamide sulfite-treated animals than in control animals. Conclusions Intramuscular

  10. Efficacious rat model displays non-toxic effect with Korean beechwood creosote: a possible antibiotic substitute

    Science.gov (United States)

    Quynh, Anh Nguyen Thai; Sharma, Neelesh; Cho, Kwang Keun; Yeo, Tae Jong; Kim, Ki Beom; Jeong, Chul Yon; Min, Tae Sun; Young, Kim Jae; Kim, Jin Nam; Jeong, Dong-Kee

    2014-01-01

    Wood creosote, an herbal anti-diarrheal and a mixture of major volatile compounds, was tested for its non-toxicological effects, using a rat model, with the objective to use the creosote as an antibiotic substitute. A total of 30 Sprague-Dawley rats were studied to form five groups with 6 rats each. Korea beechwood creosote was supplemented into three test groups with 0.03 g/kg, 0.07 g/kg and 0.1 g/kg body weight/day without antibiotic support, along with a positive control of Apramycin sulphate (at 0.5% of the daily feed) and a negative control. Korean beechwood creosote supplementation showed no negative effect on the body weight gain in comparison to the negative and the positive control groups and the feed conversion ratio was also comparable with that of the control groups. The clinical pathology parameters studied were also under the umbrella of normal range, including liver specific enzymes, blood glucose, total protein, blood urea nitrogen (BUN), which indicated no toxic effect of creosote at the given doses. The non-hepatotoxic effect was also confirmed using hepatic damage specific molecular markers like Tim-p1, Tim-p2 and Tgf-β1. The results suggested that Korean beechwood may be used as antibiotic substitute in weanling pigs feed without any toxic effect on the body. Although the antimicrobial properties of creosote were not absolutely similar to those of apramycin sulphate, they were comparable. PMID:26019530

  11. An experimental infection model for reproduction of calf pneumonia with bovine respiratory syncytial virus (BRSV) based on one combined exposure of calves

    DEFF Research Database (Denmark)

    Tjørnehøj, Kirsten; Uttenthal, Åse; Viuff, B.

    2003-01-01

    Bovine respiratory syncytial virus (BRSV) has been recognised as an important pathogen in calf pneumonia for 30 years, but surprisingly few effective infection models for studies of the immune response and the pathogenesis in the natural host have been established. We present a reproducible...

  12. Analysis of impulse oscillometric measures of lung function and respiratory system model parameters in small airway-impaired and healthy children over a 2-year period

    Directory of Open Access Journals (Sweden)

    Nava Pat

    2011-03-01

    Full Text Available Abstract Background Is Impulse Oscillometry System (IOS a valuable tool to measure respiratory system function in Children? Asthma (A is the most prevalent chronic respiratory disease in children. Therefore, early and accurate assessment of respiratory function is of tremendous clinical interest in diagnosis, monitoring and treatment of respiratory conditions in this subpopulation. IOS has been successfully used to measure lung function in children with a high degree of sensitivity and specificity to small airway impairments (SAI and asthma. IOS measures of airway function and equivalent electrical circuit models of the human respiratory system have been developed to quantify the severity of these conditions. Previously, we have evaluated several known respiratory models based on the Mead's model and more parsimonious versions based on fitting IOS data known as extended RIC (eRIC and augmented RIC (aRIC models have emerged, which offer advantages over earlier models. Methods IOS data from twenty-six children were collected and compared during pre-bronchodilation (pre-B and post- bronchodilation (post-B conditions over a period of 2 years. Results and Discussion Are the IOS and model parameters capable of differentiating between healthy children and children with respiratory system distress? Children were classified into two main categories: Healthy (H and Small Airway-Impaired (SAI. The IOS measures and respiratory model parameters analyzed differed consistently between H and SAI children. SAI children showed smaller trend of "growth" and larger trend of bronchodilator responses than H children. The two model parameters: peripheral compliance (Cp and peripheral resistance (Rp tracked IOS indices of small airway function well. Cp was a more sensitive index than Rp. Both eRIC and aRIC Cps and the IOS Reactance Area, AX, (also known as the "Goldman Triangle" showed good correlations. Conclusions What are the most useful IOS and model parameters? In

  13. Diverse and Tissue Specific Mitochondrial Respiratory Response in A Mouse Model of Sepsis-Induced Multiple Organ Failure

    DEFF Research Database (Denmark)

    Karlsson, Michael; Hara, Naomi; Morata, Saori

    2016-01-01

    -production was detected.Liver homogenate from the septic mice displayed a significant increase of the respiratory control ratio at 6 hours. In the 24-hour group, the rate of maximal oxidative phosphorylation, as well as LEAK respiration, was significantly increased compared to controls and the resultant respiratory...

  14. Implementing change in respiratory care.

    Science.gov (United States)

    Stoller, James K

    2010-06-01

    Though people are generally averse to change, change and innovation are critically important in respiratory care to maintain scientific and clinical progress. This paper reviews the issue of change in respiratory care. I summarize several available models of organizational and personal change (ie, those of Kotter and of Silversin and Kornacki, and the Intentional Change Theory of Boyatzis), review the characteristics of change-avid respiratory therapy departments, offer an example of a change effort in respiratory care (implementation of respiratory care protocols) and then analyze this change effort as it took place at one institution, the Cleveland Clinic, using these models. Finally, I present the results of an analysis of change-avid respiratory therapy departments and offer some suggestions regarding change management for the profession and for individual respiratory care clinicians. Common features of theories of organizational change include developing a sense of urgency, overcoming resistance, developing a guiding coalition, and involving key stakeholders early. With the understanding that change efforts may seem unduly "clean" and orderly in retrospect, the models help explain the sustainable success of efforts to implement the Respiratory Therapy Consult Service at the Cleveland Clinic. By implication, these models offer value in planning change efforts prospectively. Further analysis of features of change-avid respiratory therapy departments indicates 11 highly desired features, of which four that especially characterize change-avid departments include: having an up-to-date leadership team; employee involvement in change; celebrating wins; and an overall sense of progressiveness in the department. This analysis suggests that understanding and embracing change is important. To anchor change in our profession, greater attention should be given to developing a pipeline of respiratory care clinicians who, by virtue of their advanced training, have the skills

  15. A Combined Tissue Kinetics and Dosimetric Model of Respiratory Tissue Exposed to Radiation

    Energy Technology Data Exchange (ETDEWEB)

    John R. Ford

    2005-11-01

    Existing dosimetric models of the radiation response of tissues are essentially static. Consideration of changes in the cell populations over time has not been addressed realistically. For a single acute dose this is not a concern, but for modeling chronic exposures or fractionated acute exposures, the natural turnover and progression of cells could have a significant impact on a variety of endpoints. This proposal addresses the shortcomings of current methods by combining current dose-based calculation techniques with information on the cell turnover for a model tissue. The proposed model will examine effects at the single-cell level for an exposure of a section of human bronchiole. The cell model will be combined with Monte Carlo calculations of doses to cells and cell nuclei due to varying dose-rates of different radiation qualities. Predictions from the model of effects on survival, apoptosis rates, and changes in the number of cycling and differentiating cells will be tested experimentally. The availability of dynamic dosimetric models of tissues at the single-cell level will be useful for analysis of low-level radiation exposures and in the development of new radiotherapy protocols.

  16. Adult respiratory distress syndrome

    International Nuclear Information System (INIS)

    Murphy, C.H.; Colvin, R.S.

    1987-01-01

    Due to improved emergency resuscitation procedures, and with advancing medical technology in the field of critical care, an increasing number of patients survive the acute phase of shock and catastrophic trauma. Patients who previously died of massive sepsis, hypovolemic or hypotensive shock, multiple fractures, aspiration, toxic inhalation, and massive embolism are now surviving long enough to develop previously unsuspected and unrecognized secondary effects. With increasing frequency, clinicians are recognizing the clinical and radiographic manifestations of pathologic changes in the lungs occurring secondary to various types of massive insult. This paper gives a list of diseases that have been shown to precipitate or predispose to diffuse lung damage. Various terms have been used to describe the lung damage and respiratory failure secondary to these conditions. The term adult respiratory distress syndrome (ARDS) is applied to several cases of sudden respiratory failure in patients with previously healthy lungs following various types of trauma or shock. Numerous investigations and experiments have studied the pathologic changes in ARDS, and, while there is still no clear indication of why it develops, there is now some correlation of the sequential pathologic developments with the clinical and radiographic changes

  17. Comparative hazard analysis and toxicological modeling of diverse nanomaterials using the embryonic zebrafish (EZ) metric of toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Harper, Bryan [Oregon State University (United States); Thomas, Dennis; Chikkagoudar, Satish; Baker, Nathan [Pacific Northwest National Laboratory (United States); Tang, Kaizhi [Intelligent Automation, Inc. (United States); Heredia-Langner, Alejandro [Pacific Northwest National Laboratory (United States); Lins, Roberto [CPqAM, Oswaldo Cruz Foundation, FIOCRUZ-PE (Brazil); Harper, Stacey, E-mail: stacey.harper@oregonstate.edu [Oregon State University (United States)

    2015-06-15

    The integration of rapid assays, large datasets, informatics, and modeling can overcome current barriers in understanding nanomaterial structure–toxicity relationships by providing a weight-of-the-evidence mechanism to generate hazard rankings for nanomaterials. Here, we present the use of a rapid, low-cost assay to perform screening-level toxicity evaluations of nanomaterials in vivo. Calculated EZ Metric scores, a combined measure of morbidity and mortality in developing embryonic zebrafish, were established at realistic exposure levels and used to develop a hazard ranking of diverse nanomaterial toxicity. Hazard ranking and clustering analysis of 68 diverse nanomaterials revealed distinct patterns of toxicity related to both the core composition and outermost surface chemistry of nanomaterials. The resulting clusters guided the development of a surface chemistry-based model of gold nanoparticle toxicity. Our findings suggest that risk assessments based on the size and core composition of nanomaterials alone may be wholly inappropriate, especially when considering complex engineered nanomaterials. Research should continue to focus on methodologies for determining nanomaterial hazard based on multiple sub-lethal responses following realistic, low-dose exposures, thus increasing the availability of quantitative measures of nanomaterial hazard to support the development of nanoparticle structure–activity relationships.

  18. Toxicity Estimation Software Tool (TEST)

    Science.gov (United States)

    The Toxicity Estimation Software Tool (TEST) was developed to allow users to easily estimate the toxicity of chemicals using Quantitative Structure Activity Relationships (QSARs) methodologies. QSARs are mathematical models used to predict measures of toxicity from the physical c...

  19. Mitigating Errors in External Respiratory Surrogate-Based Models of Tumor Position

    International Nuclear Information System (INIS)

    Malinowski, Kathleen T.; McAvoy, Thomas J.; George, Rohini; Dieterich, Sonja; D'Souza, Warren D.

    2012-01-01

    Purpose: To investigate the effect of tumor site, measurement precision, tumor–surrogate correlation, training data selection, model design, and interpatient and interfraction variations on the accuracy of external marker-based models of tumor position. Methods and Materials: Cyberknife Synchrony system log files comprising synchronously acquired positions of external markers and the tumor from 167 treatment fractions were analyzed. The accuracy of Synchrony, ordinary-least-squares regression, and partial-least-squares regression models for predicting the tumor position from the external markers was evaluated. The quantity and timing of the data used to build the predictive model were varied. The effects of tumor–surrogate correlation and the precision in both the tumor and the external surrogate position measurements were explored by adding noise to the data. Results: The tumor position prediction errors increased during the duration of a fraction. Increasing the training data quantities did not always lead to more accurate models. Adding uncorrelated noise to the external marker-based inputs degraded the tumor–surrogate correlation models by 16% for partial-least-squares and 57% for ordinary-least-squares. External marker and tumor position measurement errors led to tumor position prediction changes 0.3–3.6 times the magnitude of the measurement errors, varying widely with model algorithm. The tumor position prediction errors were significantly associated with the patient index but not with the fraction index or tumor site. Partial-least-squares was as accurate as Synchrony and more accurate than ordinary-least-squares. Conclusions: The accuracy of surrogate-based inferential models of tumor position was affected by all the investigated factors, except for the tumor site and fraction index.

  20. Nonresonant Double Hopf Bifurcation in Toxic Phytoplankton-Zooplankton Model with Delay

    Science.gov (United States)

    Yuan, Rui; Jiang, Weihua; Wang, Yong

    This paper investigates a toxic phytoplankton-zooplankton model with Michaelis-Menten type phytoplankton harvesting. The model has rich dynamical behaviors. It undergoes transcritical, saddle-node, fold, Hopf, fold-Hopf and double Hopf bifurcation, when the parameters change and go through some of the critical values, the dynamical properties of the system will change also, such as the stability, equilibrium points and the periodic orbit. We first study the stability of the equilibria, and analyze the critical conditions for the above bifurcations at each equilibrium. In addition, the stability and direction of local Hopf bifurcations, and the completion bifurcation set by calculating the universal unfoldings near the double Hopf bifurcation point are given by the normal form theory and center manifold theorem. We obtained that the stable coexistent equilibrium point and stable periodic orbit alternate regularly when the digestion time delay is within some finite value. That is, we derived the pattern for the occurrence, and disappearance of a stable periodic orbit. Furthermore, we calculated the approximation expression of the critical bifurcation curve using the digestion time delay and the harvesting rate as parameters, and determined a large range in terms of the harvesting rate for the phytoplankton and zooplankton to coexist in a long term.

  1. Respiratory Home Health Care

    Science.gov (United States)

    ... Healthy Living > Living With Lung Disease > Respiratory Home Health Care Font: Aerosol Delivery Oxygen Resources Immunizations Pollution Nutrition ... Disease Articles written by Respiratory Experts Respiratory Home Health Care Respiratory care at home can contribute to improved ...

  2. A clinical diagnostic model for predicting influenza among young adult military personnel with febrile respiratory illness in Singapore.

    Directory of Open Access Journals (Sweden)

    Vernon J Lee

    Full Text Available INTRODUCTION: Influenza infections present with wide-ranging clinical features. We aim to compare the differences in presentation between influenza and non-influenza cases among those with febrile respiratory illness (FRI to determine predictors of influenza infection. METHODS: Personnel with FRI (defined as fever ≥ 37.5 °C, with cough or sore throat were recruited from the sentinel surveillance system in the Singapore military. Nasal washes were collected, and tested using the Resplex II and additional PCR assays for etiological determination. Interviewer-administered questionnaires collected information on patient demographics and clinical features. Univariate comparison of the various parameters was conducted, with statistically significant parameters entered into a multivariate logistic regression model. The final multivariate model for influenza versus non-influenza cases was used to build a predictive probability clinical diagnostic model. RESULTS: 821 out of 2858 subjects recruited from 11 May 2009 to 25 Jun 2010 had influenza, of which 434 (52.9% had 2009 influenza A (H1N1, 58 (7.1% seasonal influenza A (H3N2 and 269 (32.8% influenza B. Influenza-positive cases were significantly more likely to present with running nose, chills and rigors, ocular symptoms and higher temperature, and less likely with sore throat, photophobia, injected pharynx, and nausea/vomiting. Our clinical diagnostic model had a sensitivity of 65% (95% CI: 58%, 72%, specificity of 69% (95% CI: 62%, 75%, and overall accuracy of 68% (95% CI: 64%, 71%, performing significantly better than conventional influenza-like illness (ILI criteria. CONCLUSIONS: Use of a clinical diagnostic model may help predict influenza better than the conventional ILI definition among young adults with FRI.

  3. Innovative characteristics of the new dosimetric model for the human respiratory tract studied by the ICRP appointed Task Group of Committee 2

    International Nuclear Information System (INIS)

    Melandri, C.; Battisti, P.; Tarroni, G.

    1991-02-01

    In 1984, the ICRP appointed a Task Group of Committee 2 to review and revise, as necessary, the current lung dosimetric model. On the basis of the knowledge acquired during the past 20 years, the Task Group's approach has been to review, in depth, the morphology and physiology of the human respiratory tract, inspirability of aerosols and regional deposition of inhaled particles as functions of aerosol size and breathing parameters, clearance of deposited materials, nature and specific sites of damage to the respiratory system caused by inhaled radioactive substances. In the proposed model, clearance from the three regions of the respiratory tract (extrathoracic ET, fast-clearing thoracic T f and slow-clearing thoracic T s , comprising lymph nodes) is described in terms of competition between the mechanical processes moving particles, which do not depend on the substances, and those of absorption into the blood, determined solely by the material. A Task Group report will also include models for calculating radiation doses to tissues of the respiratory system following inhalation of α, β and γ emitting particulate and gaseous radionuclides. (author)

  4. Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach.

    Science.gov (United States)

    Wunnapuk, Klintean; Mohammed, Fahim; Gawarammana, Indika; Liu, Xin; Verbeeck, Roger K; Buckley, Nicholas A; Roberts, Michael S; Musuamba, Flora T

    2014-10-01

    Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h(-1) , 2.4 l kg(-1) and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l(-1) caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function. The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development. © 2014 The British Pharmacological Society.

  5. Precision-cut intestinal slices as an in vitro model to predict NSAID induced intestinal toxicity

    NARCIS (Netherlands)

    Niu, Xiaoyu; van der Bijl, Henk; Groothuis, Geny; de Graaf, Inge

    2013-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with high prevalence of gastro-intestinal side-effects. In vivo studies suggest that uncoupling of oxidative phosphorylation is an important cause of the toxicity and that the toxicity is aggravated by enterohepatic circulation.

  6. Interspecies Correlation Estimation (ICE) models predict supplemental toxicity data for SSDs

    Science.gov (United States)

    Species sensitivity distributions (SSD) require a large number of toxicity values for a diversity of taxa to define a hazard level protective of multiple species. For most chemicals, measured toxicity data are limited to a few standard test species that are unlikely to adequately...

  7. A probit- log- skew-normal mixture model for repeated measures data with excess zeros, with application to a cohort study of paediatric respiratory symptoms

    Directory of Open Access Journals (Sweden)

    Johnston Neil W

    2010-06-01

    Full Text Available Abstract Background A zero-inflated continuous outcome is characterized by occurrence of "excess" zeros that more than a single distribution can explain, with the positive observations forming a skewed distribution. Mixture models are employed for regression analysis of zero-inflated data. Moreover, for repeated measures zero-inflated data the clustering structure should also be modeled for an adequate analysis. Methods Diary of Asthma and Viral Infections Study (DAVIS was a one year (2004 cohort study conducted at McMaster University to monitor viral infection and respiratory symptoms in children aged 5-11 years with and without asthma. Respiratory symptoms were recorded daily using either an Internet or paper-based diary. Changes in symptoms were assessed by study staff and led to collection of nasal fluid specimens for virological testing. The study objectives included investigating the response of respiratory symptoms to respiratory viral infection in children with and without asthma over a one year period. Due to sparse data daily respiratory symptom scores were aggregated into weekly average scores. More than 70% of the weekly average scores were zero, with the positive scores forming a skewed distribution. We propose a random effects probit/log-skew-normal mixture model to analyze the DAVIS data. The model parameters were estimated using a maximum marginal likelihood approach. A simulation study was conducted to assess the performance of the proposed mixture model if the underlying distribution of the positive response is different from log-skew normal. Results Viral infection status was highly significant in both probit and log-skew normal model components respectively. The probability of being symptom free was much lower for the week a child was viral positive relative to the week she/he was viral negative. The severity of the symptoms was also greater for the week a child was viral positive. The probability of being symptom free was

  8. Ventilatory assistance and respiratory muscle activity. 2: Simulation with an adaptive active ("aa" or "a-squared") model lung.

    Science.gov (United States)

    Mecklenburgh, J S; Mapleson, W W

    1998-04-01

    The aim of this study was to develop a lung model which adapted its active simulation of spontaneous breathing to the ventilatory assistance it received--an "aa" or "a-squared" lung model. The active element required was the waveform of negative pressure (pmus), which is equivalent to respiratory muscle activity. This had been determined previously in 12 healthy volunteers and comprised a contraction phase, relaxation phase and expiratory pause. Ventilatory assistance had shortened the contraction and relaxation phases without changing their shape, and lengthened the pause phase to compensate. In this study, the contraction and relaxation phases could be adequately represented by two quadratic equations, in addition to a third to provide a smooth transition. Therefore, the adaptive element required was the prediction of the duration of the contraction phase. The best predictive variables were flow at the end of contraction or peak mouth pressure. Determination of either of these allowed adjustment of the "standard" waveform to the level of assistance produced by an "average" ventilator, in a manner that matched the mean response of 12 healthy conscious subjects.

  9. Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships (MCBIOS)

    Science.gov (United States)

    Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships Jie Liu1,2, Richard Judson1, Matthew T. Martin1, Huixiao Hong3, Imran Shah1 1National Center for Computational Toxicology (NCCT), US EPA, RTP, NC...

  10. Development and Application of In Vitro Models for Screening Drugs and Environmental Chemicals that Predict Toxicity in Animals and Humans

    Science.gov (United States)

    Development and Application of In Vitro Models for Screening Drugs and Environmental Chemicals that Predict Toxicity in Animals and Humans (Presented by James McKim, Ph.D., DABT, Founder and Chief Science Officer, CeeTox) (5/25/2012)

  11. Investigating copper toxicity in the tropical fish cardinal tetra (Paracheirodon axelrodi) in natural Amazonian waters: Measurements, modeling, and reality.

    Science.gov (United States)

    Crémazy, Anne; Wood, Chris M; Smith, D Scott; Ferreira, Márcio S; Johannsson, Ora E; Giacomin, Marina; Val, Adalberto L

    2016-11-01

    Copper at high concentrations is an ionoregulatory toxicant in fish and its toxicity is known to be strongly modulated by the water chemistry. The toxicity of Cu to the tropical fish cardinal tetra (Paracheirodon axelrodi) was investigated in waters from two major rivers of the Amazon watershed: the Rio Negro (filtered Acute 96-h mortality, Cu bioaccumulation and net flux rates of Na + , Cl - , K + and total ammonia were determined in P. axelrodi exposed in each water. Copper speciation in each water was determined by two thermodynamic models and by potentiometry, and its toxicity was predicted based on the biotic ligand model (BLM) framework. Our results indicate that high Na + loss is the main mode of toxic action of Cu in P. axelrodi, in accordance with general theory. Cardinal tetra showed a particularly high ability to tolerate Cu and to maintain Na + balance, similar to the ability of this and other endemic Rio Negro species to tolerate low pH and ion-poor conditions. Cu toxicity was lower in Rio Negro than in the other two waters tested, and the free [Cu 2+ ] at the LC50, as determined by any of the three speciation methods tested, was approximately 10-fold higher. This variation could not be captured by a realistic set of BLM parameters. At least in part, this observation may be due to gill physiological alterations induced by the abundant dissolved organic matter of the Rio Negro. The implication of this observation is that, for metals risk assessment in tropical waters, similar to the Rio Negro, care must be used in applying BLM models developed using temperate DOC and temperate species. Copyright © 2016. Published by Elsevier B.V.

  12. Prediction of acute toxicity of cadmium and lead to zebrafish larvae by using a refined toxicokinetic-toxicodynamic model

    International Nuclear Information System (INIS)

    Gao, Yongfei; Feng, Jianfeng; Zhu, Lin

    2015-01-01

    Highlights: • We developed a BLM-aided TK-TD model that considers the effects of H + . • The time-course metal concentration in larvae was well described by the TK model. • The time-course survival of zebrafish larvae was well simulated by the TD model. - Abstract: The biotic ligand model (BLM) and the toxicokinetic-toxicodynamic (TK-TD) model are essential in predicting the acute toxicity of metals in various species and exposure conditions; however, these models are usually separately utilized. In this study, a mechanistic TK-TD model was developed to predict the acute toxicity of 10 −6 M Cd and 10 −6 M Pb to zebrafish (Danio rerio) larvae. The novel approach links the BLM with relevant TK processes to simulate the bioaccumulation processes of Cd or Pb as a function of the maximum uptake rate of each metal, the affinity constants, and the concentrations of free metal ions and H + in test solutions. Results showed that the refined TK-TD model can accurately predict the accumulation and acute toxicity of Cd and Pb to zebrafish larvae at pH 5.5, 6.5, and 7.0.

  13. Prediction of acute toxicity of cadmium and lead to zebrafish larvae by using a refined toxicokinetic-toxicodynamic model

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Yongfei; Feng, Jianfeng, E-mail: fengjf@nankai.edu.cn; Zhu, Lin, E-mail: zhulin@nankai.edu.cn

    2015-12-15

    Highlights: • We developed a BLM-aided TK-TD model that considers the effects of H{sup +}. • The time-course metal concentration in larvae was well described by the TK model. • The time-course survival of zebrafish larvae was well simulated by the TD model. - Abstract: The biotic ligand model (BLM) and the toxicokinetic-toxicodynamic (TK-TD) model are essential in predicting the acute toxicity of metals in various species and exposure conditions; however, these models are usually separately utilized. In this study, a mechanistic TK-TD model was developed to predict the acute toxicity of 10{sup −6} M Cd and 10{sup −6} M Pb to zebrafish (Danio rerio) larvae. The novel approach links the BLM with relevant TK processes to simulate the bioaccumulation processes of Cd or Pb as a function of the maximum uptake rate of each metal, the affinity constants, and the concentrations of free metal ions and H{sup +} in test solutions. Results showed that the refined TK-TD model can accurately predict the accumulation and acute toxicity of Cd and Pb to zebrafish larvae at pH 5.5, 6.5, and 7.0.

  14. A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors

    Energy Technology Data Exchange (ETDEWEB)

    Carriger, John F. [U.S. Environmental Protection Agency, Office of Research and Development, Gulf Ecology Division, Gulf Breeze, FL, 32561 (United States); Martin, Todd M. [U.S. Environmental Protection Agency, Office of Research and Development, Sustainable Technology Division, Cincinnati, OH, 45220 (United States); Barron, Mace G., E-mail: barron.mace@epa.gov [U.S. Environmental Protection Agency, Office of Research and Development, Gulf Ecology Division, Gulf Breeze, FL, 32561 (United States)

    2016-11-15

    Highlights: • A Bayesian network was developed to classify chemical mode of action (MoA). • The network was based on the aquatic toxicity MoA for over 1000 chemicals. • A Markov blanket algorithm selected a subset of theoretical molecular descriptors. • Sensitivity analyses found influential descriptors for classifying the MoAs. • Overall precision of the Bayesian MoA classification model was 80%. - Abstract: The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity, but development of predictive MoA classification models in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity MoA using a recently published dataset containing over one thousand chemicals with MoA assignments for aquatic animal toxicity. Two dimensional theoretical chemical descriptors were generated for each chemical using the Toxicity Estimation Software Tool. The model was developed through augmented Markov blanket discovery from the dataset of 1098 chemicals with the MoA broad classifications as a target node. From cross validation, the overall precision for the model was 80.2%. The best precision was for the AChEI MoA (93.5%) where 257 chemicals out of 275 were correctly classified. Model precision was poorest for the reactivity MoA (48.5%) where 48 out of 99 reactive chemicals were correctly classified. Narcosis represented the largest class within the MoA dataset and had a precision and reliability of 80.0%, reflecting the global precision across all of the MoAs. False negatives for narcosis most often fell into electron transport inhibition, neurotoxicity or reactivity MoAs. False negatives for all other MoAs were most often narcosis. A probabilistic sensitivity analysis was undertaken for each MoA to examine the sensitivity to individual and multiple descriptor findings. The results show that the Markov blanket of a structurally complex dataset can simplify analysis and interpretation by

  15. Assessing the impacts of total liquid ventilation on left ventricular diastolic function in a model of neonatal respiratory distress syndrome.

    Directory of Open Access Journals (Sweden)

    Michaël Sage

    Full Text Available Filling the lung with dense liquid perfluorocarbons during total liquid ventilation (TLV might compress the myocardium, a plausible explanation for the instability occasionally reported with this technique. Our objective is to assess the impacts of TLV on the cardiovascular system, particularly left ventricular diastolic function, in an ovine model of neonatal respiratory distress syndrome.Eight newborns lambs, 3.0 ± 0.4 days (3.2 ± 0.3kg were used in this crossover experimental study. Animals were intubated, anesthetized and paralyzed. Catheters were inserted in the femoral and pulmonary arteries. A high-fidelity pressure catheter was inserted into the left ventricle. Surfactant deficiency was induced by repeated lung lavages with normal saline. TLV was then conducted for 2 hours using a liquid ventilator prototype. Thoracic echocardiography and cardiac output assessment by thermodilution were performed before and during TLV.Left ventricular end diastolic pressure (LVEDP (9.3 ± 2.1 vs. 9.2 ± 2.4mmHg, p = 0.89 and dimension (1.90 ± 0.09 vs. 1.86 ± 0.12cm, p = 0.72, negative dP/dt (-2589 ± 691 vs. -3115 ± 866mmHg/s, p = 0.50 and cardiac output (436 ± 28 vs. 481 ± 59ml/kg/min, p = 0.26 were not affected by TLV initiation. Left ventricular relaxation time constant (tau slightly increased from 21.5 ± 3.3 to 24.9 ± 3.7ms (p = 0.03. Mean arterial systemic (48 ± 6 vs. 53 ± 7mmHg, p = 0.38 and pulmonary pressures (31.3 ± 2.5 vs. 30.4 ± 2.3mmHg, p = 0.61 were stable. As expected, the inspiratory phase of liquid cycling exhibited a small but significant effect on most variables (i.e. central venous pressure +2.6 ± 0.5mmHg, p = 0.001; LVEDP +1.18 ± 0.12mmHg, p<0.001.TLV was well tolerated in our neonatal lamb model of severe respiratory distress syndrome and had limited impact on left ventricle diastolic function when compared to conventional mechanical ventilation.

  16. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism

    Science.gov (United States)

    Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Mukai, David; Patterson, Steven E.; Boss, Gerry R.; Tromberg, Bruce J.; Brenner, Matthew

    2012-10-01

    Noninvasive near infrared spectroscopy measurements were performed to monitor cyanide (CN) poisoning and recovery in the brain region and in foreleg muscle simultaneously, and the effects of a novel CN antidote, sulfanegen sodium, on tissue hemoglobin oxygenation changes were compared using a sub-lethal rabbit model. The results demonstrated that the brain region is more susceptible to CN poisoning and slower in endogenous CN detoxification following exposure than peripheral muscles. However, sulfanegen sodium rapidly reversed CN toxicity, with brain region effects reversing more quickly than muscle. In vivo monitoring of multiple organs may provide important clinical information regarding the extent of CN toxicity and subsequent recovery, and facilitate antidote drug development.

  17. Effects of zinc and "health belief model" education on upper respiratory infections in hajj travelers: a randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Mahmoudian S.A

    2007-09-01

    Full Text Available Background: The common cold is the most prevalent sickness and an important cause of absence from job. Furthermore, it often disturbs travel, including the practice of hajj, causing the use of many inappropriate drugs by these travelers. The health belief model is a psychological model that attempts to explain and predict health behaviors. The purpose of this study was to determine the effects of zinc and health belief model based educational intervention on the behavior of hajj travelers with regard to viral upper respiratory tract infections (URTI.Methods: This double-blinded randomized controlled trial was performed among hajj travelers in 2005. Preventive measures were randomly allocated to four groups: 1- education + zinc sulfate. 2- education + placebo. 3- zinc sulfate only 4- placebo only. Data regarding incidence and duration of URTIs, background disorders, vaccination and health behaviors for cold were gathered by questionnaire by physicians and finally analyzed by SPSS 11.5 software using chi-square, t-test and independent samples t-test.Results: A total of 646 travelers were studied. The incidence of common cold in groups receiving zinc were significantly less than that for those receiving the placebo. (P=0.05. However, incidence was statistically the same for those who received education versus those who did not. Use of handkerchief was the most prevalent behavior and use of mask was the least prevalent behavior. Mean duration of symptoms was less in those receiving zinc and education (3.7 days comparing to those who received placebo and education (5.6 days.  Conclusions: This study showed that zinc consumption can decrease the incidence and duration of the common cold. Health belief model based education could promote some preventive behaviors although most people do not take advantage of them. We recommend the use of zinc by those attending hajj.

  18. Modelling the toxicity of a large set of metal and metal oxide nanoparticles using the OCHEM platform.

    Science.gov (United States)

    Kovalishyn, Vasyl; Abramenko, Natalia; Kopernyk, Iryna; Charochkina, Larysa; Metelytsia, Larysa; Tetko, Igor V; Peijnenburg, Willie; Kustov, Leonid

    2018-02-01

    Inorganic nanomaterials have become one of the new areas of modern knowledge and technology and have already found an increasing number of applications. However, some nanoparticles show toxicity to living organisms, and can potentially have a negative influence on environmental ecosystems. While toxicity can be determined experimentally, such studies are time consuming and costly. Computational toxicology can provide an alternative approach and there is a need to develop methods to reliably assess Quantitative Structure-Property Relationships for nanomaterials (nano-QSPRs). Importantly, development of such models requires careful collection and curation of data. This article overviews freely available nano-QSPR models, which were developed using the Online Chemical Modeling Environment (OCHEM). Multiple data on toxicity of nanoparticles to different living organisms were collected from the literature and uploaded in the OCHEM database. The main characteristics of nanoparticles such as chemical composition of nanoparticles, average particle size, shape, surface charge and information about the biological test species were used as descriptors for developing QSPR models. QSPR methodologies used Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks. The predictive ability of the models was tested through cross-validation, giving cross-validated coefficients q 2  = 0.58-0.80 for regression models and balanced accuracies of 65-88% for classification models. These results matched the predictions for the test sets used to develop the models. The proposed nano-QSPR models and uploaded data are freely available online at http://ochem.eu/article/103451 and can be used for estimation of toxicity of new and emerging nanoparticles at the early stages of nanomaterial development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Evaluation of CADASTER QSAR models for the aquatic toxicity of (benzo)triazoles and prioritisation by consensus prediction.

    Science.gov (United States)

    Cassani, Stefano; Kovarich, Simona; Papa, Ester; Roy, Partha Pratim; Rahmberg, Magnus; Nilsson, Sara; Sahlin, Ullrika; Jeliazkova, Nina; Kochev, Nikolay; Pukalov, Ognyan; Tetko, Igor; Brandmaier, Stefan; Durjava, Mojca Kos; Kolar, Boris; Peijnenburg, Willie; Gramatica, Paola

    2013-03-01

    QSAR regression models of the toxicity of triazoles and benzotriazoles ([B]TAZs) to an alga (Pseudokirchneriella subcapitata), Daphnia magna and a fish (Onchorhynchus mykiss), were developed by five partners in the FP7-EU Project, CADASTER. The models were developed by different methods - Ordinary Least Squares (OLS), Partial Least Squares (PLS), Bayesian regularised regression and Associative Neural Network (ASNN) - by using various molecular descriptors (DRAGON, PaDEL-Descriptor and QSPR-THESAURUS web). In addition, different procedures were used for variable selection, validation and applicability domain inspection. The predictions of the models developed, as well as those obtained in a consensus approach by averaging the data predicted from each model, were compared with the results of experimental tests that were performed by two CADASTER partners. The individual and consensus models were able to correctly predict the toxicity classes of the chemicals tested in the CADASTER project, confirming the utility of the QSAR approach. The models were also used for the prediction of aquatic toxicity of over 300 (B)TAZs, many of which are included in the REACH pre-registration list, and were without experimental data. This highlights the importance of QSAR models for the screening and prioritisation of untested chemicals, in order to reduce and focus experimental testing. 2013 FRAME.

  20. WE-D-303-02: Applications of Volumetric Images Generated with a Respiratory Motion Model Based On An External Surrogate Signal

    International Nuclear Information System (INIS)

    Hurwitz, M; Williams, C; Dhou, S; Lewis, J; Mishra, P

    2015-01-01

    Purpose: Respiratory motion can vary significantly over the course of simulation and treatment. Our goal is to use volumetric images generated with a respiratory motion model to improve the definition of the internal target volume (ITV) and the estimate of delivered dose. Methods: Ten irregular patient breathing patterns spanning 35 seconds each were incorporated into a digital phantom. Ten images over the first five seconds of breathing were used to emulate a 4DCT scan, build the ITV, and generate a patient-specific respiratory motion model which correlated the measured trajectories of markers placed on the patients’ chests with the motion of the internal anatomy. This model was used to generate volumetric images over the subsequent thirty seconds of breathing. The increase in the ITV taking into account the full 35 seconds of breathing was assessed with ground-truth and model-generated images. For one patient, a treatment plan based on the initial ITV was created and the delivered dose was estimated using images from the first five seconds as well as ground-truth and model-generated images from the next 30 seconds. Results: The increase in the ITV ranged from 0.2 cc to 6.9 cc for the ten patients based on ground-truth information. The model predicted this increase in the ITV with an average error of 0.8 cc. The delivered dose to the tumor (D95) changed significantly from 57 Gy to 41 Gy when estimated using 5 seconds and 30 seconds, respectively. The model captured this effect, giving an estimated D95 of 44 Gy. Conclusion: A respiratory motion model generating volumetric images of the internal patient anatomy could be useful in estimating the increase in the ITV due to irregular breathing during simulation and in assessing delivered dose during treatment. This project was supported, in part, through a Master Research Agreement with Varian Medical Systems, Inc. and Radiological Society of North America Research Scholar Grant #RSCH1206

  1. Triclosan (TCS) and triclocarban (TCC) induce systemic toxic effects in a model organism the nematode Caenorhabditis elegans.

    Science.gov (United States)

    Lenz, Katrina A; Pattison, Claire; Ma, Hongbo

    2017-12-01

    The broad application of triclosan (TCS) and triclocarban (TCC) as antimicrobials in household and personal care products has led to the concerns regarding their human health risk and environmental impact. Although many studies have examined the toxicological effects of these compounds to a wide range of aquatic organisms from algae to fish, their potential toxicity to an important model organism the nematode Caenorhabditis elegans has never been systematically investigated. Here we assessed the toxicological effects of TCS and TCC in C. elegans using endpoints from organismal to molecular levels, including lethality, reproduction, lifespan, hatching, germline toxicity, and oxidative stress. L4 stage or young adult worms were exposed to TCS or TCC and examined using above-mentioned endpoints. Both TCS and TCC showed acute toxicity to C. elegans, with 24-h LC50s of 3.65 (95% CI: 3.15, 4.3) mg/L and 0.91 (95% CI: 0.47, 1.53) mg/L, respectively. TCS at 0.1-2 mg/L and TCC at 0.01-0.5 mg/L, respectively, induced concentration dependent reduction in the worm's reproduction, lifespan, and delay in hatching. Using a DAF-16:GFP transgenic strain, we found both compounds induced oxidative stress in the worm, indicated by the relocalization of DAF-16:GFP from cytoplasm to the nucleus upon exposure. Germline toxicity of the two compounds was also demonstrated using a xol-1:GFP transgenic strain. These findings suggest that TCS and TCC induce systemic toxic effects in C. elegans. Further studies are needed to elucidate the potential mechanisms of toxicity of these antimicrobials in the model organism, especially their potential endocrine disruption effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Application of the biotic ligand model to explain potassium interaction with thallium uptake and toxicity to plankton.

    Science.gov (United States)

    Hassler, Christel S; Chafin, Ryan D; Klinger, Mary Beth; Twiss, Michael R

    2007-06-01

    Competitive interaction between TI(I) and K was successfully predicted by the biotic ligand model (BLM) for the microalga Chlorella sp. (Chlorophyta; University of Toronto Culture Collection strain 522) during 96-h toxicity tests. Because of a greater affinity of T1(I) (log K = 7.3-7.4) as compared to K (log K = 5.3-6.3) for biologically sensitive sites, an excess of 40- to 160-fold of K is required to suppress T1(I) toxic effects on Chlorella sp., regardless of [T1(I)] in solution. Similar excess of K is required to suppress T1(I) toxicity to Synechococcus leopoliensis (Cyanobacteria; University of Texas Culture Collection strain 625) and Brachionus calyciflorus (Rotifera; strain AB-RIF). The mechanism for the mitigating effect of K on T1(I) toxicity was investigated by measuring 204T1(I) cellular uptake flux and efflux in Chlorella sp. Potassium shows a competitive effect on T1(I) uptake fluxes that could be modeled using the BLM-derived stability constants and a Michaelis-Menten relationship. A strong T1 efflux dependent only on the cellular T1 concentration was measured. Although T1 efflux does not explain the effect of K on T1(I) toxicity and uptake, it is responsible for a high turnover of the cellular T1 pool (intracellular half-life = 12-13.5 min). No effect of Na+, Mg2+, or Ca2+ was observed on T1+ uptake, whereas the absence of trace metals (Cu, Co, Mo, Mn, Fe, and Zn) significantly increased T1 uptake and decreased the mitigating effect of K+. The importance of K+ in determining the aquatic toxicity of T1+ underscores the use of ambient K+ concentration in the establishment of T1 water-quality guidelines and the need to consider K in predicting biogeochemical fates of T1 in the aquatic environment.

  3. Human Adipose Tissue Derived Stem Cells Promote Liver Regeneration in a Rat Model of Toxic Injury

    Directory of Open Access Journals (Sweden)

    Eva Koellensperger

    2013-01-01

    Full Text Available In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20. Injection of cell culture medium performed in group 2 (n = 20 served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017, total protein (P < 0.031, glutamic oxaloacetic transaminase (P < 0.001, and lactate dehydrogenase (P < 0.04 levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.

  4. Studies on the Development of Potential Biomarkers for Rapid Assessment of Copper Toxicity to Freshwater Fish using Esomus danricus as Model

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    Y. Anjaneyulu

    2005-04-01

    Full Text Available Living in an environment that has been altered considerably by anthropogenic activities, fish are often exposed to a multitude of stressors including heavy metals. Copper ions are quite toxic to fish when concentrations are increased in environmental exposures often resulting in physiological, histological, biochemical and enzymatic alterations in fish, which have a great potential to serve as biomarkers. Esomus danricus was chosen as model in the present study and the metabolic rate, gill morphology, total glycogen, total protein, superoxide dismutase and catalase were critically evaluated. The 96h LC50 value was found to be 5.5mg/L (Cu as 1.402mg/L. Fish groups were separately exposed to lethal (5.5mg/L and sub lethal concentrations (0.55 mg/L of copper sulphate over a period of 96h to examine the subtle effects caused at various functional levels. Controls were also maintained simultaneously. Significant decrease in the metabolic rate (p<0.001 of the fish was observed in both the concentrations studied. Studies employing Automated Video Tracking System revealed gross changes in the architecture of gill morphology like loss, fusion, clubbing of secondary gill lamellae, and detachment of gill rakers following softening of gill shaft in fish under lethal exposures indicating reduced respiratory surface area. Biochemical profiles like total glycogen and total protein in gills and muscle of fish exposed to 5.5 mg/L showed appreciable decrease (p<0.05 to 0.001 from control. Significant inhibition of superoxide dismutase (60.83%, catalase (71.57% from control was observed in fish exposed to 5.5 mg/L at the end of 96h exposure only. Interestingly, in fish exposed to 0.55 mg/L enzyme activity is not affected except for catalase. Toxic responses evaluated at various functional levels are more pronounced in fish exposed to 5.5mg/L and these can serve as potential biomarkers for rapid assessment of acute copper toxicity in environmental biomonitoring.

  5. Multi-scale modeling of an upper respiratory airway: Effect of mucosal adhesion on Eustachian tube function in young children.

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    Malik, Jennifer; Ghadiali, Samir N

    2018-01-27

    The Eustachian tube is a collapsible upper respiratory airway that is periodically opened to maintain a healthy middle ear. Young children, function in young children. Multi-scale finite element models were used to simulate the muscle-assisted opening of the Eustachian tube in healthy adults and young children. Airflow during opening was quantified as a function of adhesion strength, muscle forces and tissue mechanics. Although Eustachian tube function was sensitive to increased mucosal adhesion in both adults and children, young children developed Eustachian tube dysfunction at significantly lower values of mucosal adhesion. Specifically, the critical adhesion value was 2 orders of magnitude lower in young children as compared to healthy adults. Although increased adhesion did not alter the sensitivity of Eustachian tube function to tensor and levator veli palatini muscles forces, increased adhesion in young children did reduced the sensitivity of Eustachian tube function to changes in cartilage and mucosal tissue stiffness. These results indicate that increased mucosal adhesion can significantly alter the biomechanical mechanisms of Eustachian tube function in young children and that clinical assessment of adhesion levels may be important in therapy selection. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Targeting the Mitochondrial Respiratory Chain of Cryptococcus through Antifungal Chemosensitization: A Model for Control of Non-Fermentative Pathogens

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    Kathleen L. Chan

    2013-07-01

    Full Text Available Enhanced control of species of Cryptococcus, non-fermentative yeast pathogens, was achieved by chemosensitization through co-application of certain compounds with a conventional antimicrobial drug. The species of Cryptococcus tested showed higher sensitivity to mitochondrial respiratory chain (MRC inhibition compared to species of Candida. This higher sensitivity results from the inability of Cryptococcus to generate cellular energy through fermentation. To heighten disruption of cellular MRC, octyl gallate (OG or 2,3-dihydroxybenzaldehyde (2,3-DHBA, phenolic compounds inhibiting mitochondrial functions, were selected as chemosensitizers to pyraclostrobin (PCS; an inhibitor of complex III of MRC. The cryptococci were more susceptible to the chemosensitization (i.e., PCS + OG or 2,3-DHBA than the Candida with all Cryptococcus strains tested being sensitive to this chemosensitization. Alternatively, only few of the Candida strains showed sensitivity. OG possessed higher chemosensitizing potency than 2,3-DHBA, where the concentration of OG required with the drug to achieve chemosensitizing synergism was much lower than that required of 2,3-DHBA. Bioassays with gene deletion mutants of the model yeast Saccharomyces cerevisiae showed that OG or 2,3-DHBA affect different cellular targets. These assays revealed mitochondrial superoxide dismutase or glutathione homeostasis plays a relatively greater role in fungal tolerance to 2,3-DHBA or OG, respectively. These findings show that application of chemosensitizing compounds that augment MRC debilitation is a promising strategy to antifungal control against yeast pathogens.

  7. Development of a risk-prediction model for Middle East respiratory syndrome coronavirus infection in dialysis patients.

    Science.gov (United States)

    Ahmed, Anwar E; Alshukairi, Abeer N; Al-Jahdali, Hamdan; Alaqeel, Mody; Siddiq, Salma S; Alsaab, Hanan A; Sakr, Ezzeldin A; Alyahya, Hamed A; Alandonisi, Munzir M; Subedar, Alaa T; Aloudah, Nouf M; Baharoon, Salim; Alsalamah, Majid A; Al Johani, Sameera; Alghamdi, Mohammed G

    2018-04-14

    Introduction The Middle East respiratory syndrome coronavirus (MERS-CoV) infection can cause transmission clusters and high mortality in hemodialysis facilities. We attempted to develop a risk-prediction model to assess the early risk of MERS-CoV infection in dialysis patients. Methods This two-center retrospective cohort study included 104 dialysis patients who were suspected of MERS-CoV infection and diagnosed with rRT-PCR between September 2012 and June 2016 at King Fahd General Hospital in Jeddah and King Abdulaziz Medical City in Riyadh. We retrieved data on demographic, clinical, and radiological findings, and laboratory indices of each patient. Findings A risk-prediction model to assess early risk for MERS-CoV in dialysis patients has been developed. Independent predictors of MERS-CoV infection were identified, including chest pain (OR = 24.194; P = 0.011), leukopenia (OR = 6.080; P = 0.049), and elevated aspartate aminotransferase (AST) (OR = 11.179; P = 0.013). The adequacy of this prediction model was good (P = 0.728), with a high predictive utility (area under curve [AUC] = 76.99%; 95% CI: 67.05% to 86.38%). The prediction of the model had optimism-corrected bootstrap resampling AUC of 71.79%. The Youden index yielded a value of 0.439 or greater as the best cut-off for high risk of MERS infection. Discussion This risk-prediction model in dialysis patients appears to depend markedly on chest pain, leukopenia, and elevated AST. The model accurately predicts the high risk of MERS-CoV infection in dialysis patients. This could be clinically useful in applying timely intervention and control measures to prevent clusters of infections in dialysis facilities or other health care settings. The predictive utility of the model warrants further validation in external samples and prospective studies. © 2018 International Society for Hemodialysis.

  8. Glial Draper Rescues Aβ Toxicity in a Drosophila Model of Alzheimer's Disease.

    Science.gov (United States)

    Ray, Arpita; Speese, Sean D; Logan, Mary A

    2017-12-06

    induced downstream of Draper in AD model flies, supporting a model in which glia engulf and destroy Aβ peptides to reduce amyloid-associated toxicity. Copyright © 2017 the authors 0270-6474/17/3711881-13$15.00/0.

  9. Extended biotic ligand model for predicting combined Cu-Zn toxicity to wheat (Triticum aestivum L.): Incorporating the effects of concentration ratio, major cations and pH.

    Science.gov (United States)

    Wang, Xuedong; Ji, Dongxue; Chen, Xiaolin; Ma, Yibing; Yang, Junxing; Ma, Jingxing; Li, Xiaoxiu

    2017-11-01

    Current risk assessment models for metals such as the biotic ligand model (BLM) are usually applied to individual metals, yet toxic metals are rarely found singly in the environment. In the present research, the toxicity of Cu and Zn alone and together were studied in wheat (Triticum aestivum L.) using different Ca 2+ and Mg 2+ concentrations, pH levels and Zn:Cu concentration ratios. The aim of the study was to better understand the toxicity effects of these two metals using BLMs and toxic units (TUs) from single and combined metal toxicity data. The results of single-metal toxicity tests showed that toxicity of Cu and Zn tended to decrease with increasing Ca 2+ or Mg 2+ concentrations, and that the effects of pH on Cu and Zn toxicity were related not only to free Cu 2+ and Zn 2+ activity, respectively, but also to other inorganic metal complex species. For the metal mixture, Cu-Zn interactions based on free ion activities were primarily additive for the different Ca 2+ and Mg 2+ concentrations and levels of pH. The toxicity data of individual metals derived by the BLM, which incorporated Ca 2+ and Mg 2+ competition and toxicity of inorganic metal complexes in a single-metal toxicity assessment, could predict the combined toxicity as a function of TU. There was good performance between the predicted and observed effects (root mean square error [RMSE] = 7.15, R 2  = 0.97) compared to that using a TU method with a model based on free ion activity (RMSE = 14.29, R 2  = 0.86). The overall findings indicated that bioavailability models that include those biochemistry processes may accurately predict the toxicity of metal mixtures. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. An early developmental vertebrate model for nanomaterial safety: bridging cell-based and mammalian toxicity assessment.

    Science.gov (United States)

    Webster, Carl A; Di Silvio, Desire; Devarajan, Aarthi; Bigini, Paolo; Micotti, Edoardo; Giudice, Chiara; Salmona, Mario; Wheeler, Grant N; Sherwood, Victoria; Bombelli, Francesca Baldelli

    2016-03-01

    With the rise in production of nanoparticles (NPs) for an ever-increasing number of applications, there is an urgent need to efficiently assess their potential toxicity. We propose a NP hazard assessment protocol that combines mammalian cytotoxicity data with embryonic vertebrate abnormality scoring to determine an overall toxicity index. We observed that, after exposure to a range of NPs, Xenopus phenotypic scoring showed a strong correlation with cell based in vitro assays. Magnetite-cored NPs, negative for toxicity in vitro and Xenopus, were further confirmed as nontoxic in mice. The results highlight the potential of Xenopus embryo analysis as a fast screening approach for toxicity assessment of NPs, which could be introduced for the routine testing of nanomaterials.

  11. Investigating copper toxicity in the tropical fish cardinal tetra (Paracheirodon axelrodi) in natural Amazonian waters: Measurements, modeling, and reality

    Energy Technology Data Exchange (ETDEWEB)

    Crémazy, Anne, E-mail: acremazy@zoology.ubc.ca [Department of Zoology, University of British Columbia, Vancouver, BC V6T 1Z4 (Canada); Wood, Chris M. [Department of Zoology, University of British Columbia, Vancouver, BC V6T 1Z4 (Canada); Smith, D. Scott [Department of Chemistry and Biochemistry, Wilfrid Laurier University, Waterloo, ON N2L 3C5 (Canada); Ferreira, Márcio S. [Laboratory of Ecophysiology and Molecular Evolution, National Institute for Amazonian Research, Manaus, AM (Brazil); Johannsson, Ora E.; Giacomin, Marina [Department of Zoology, University of British Columbia, Vancouver, BC V6T 1Z4 (Canada); Val, Adalberto L. [Laboratory of Ecophysiology and Molecular Evolution, National Institute for Amazonian Research, Manaus, AM (Brazil)

    2016-11-15

    Highlights: • Copper toxicity to a tropical fish varied greatly in different Amazonian waters. • The biotic ligand model could not capture this variability. • Possible physiological protection was offered by natural organic matter. • Care must be used in applying BLM to fish in tropical waters. - Abstract: Copper at high concentrations is an ionoregulatory toxicant in fish and its toxicity is known to be strongly modulated by the water chemistry. The toxicity of Cu to the tropical fish cardinal tetra (Paracheirodon axelrodi) was investigated in waters from two major rivers of the Amazon watershed: the Rio Negro (filtered <0.45 μm, pH 5.6, DOC = 8.4 mg L{sup −1}, Na = 33 μM, Ca = 8 μM) and the Rio Solimões (filtered <0.45 μm, pH 6.7, DOC = 2.8 mg L{sup −1}, Na = 185 μM, Ca = 340 μM), as well as in a natural “reference water” (groundwater) which was almost DOC-free (pH 6.0, DOC = 0.34 mg L{sup −1}, Na = 53 μM, Ca = 5 μM). Acute 96-h mortality, Cu bioaccumulation and net flux rates of Na{sup +}, Cl{sup −}, K{sup +} and total ammonia were determined in P. axelrodi exposed in each water. Copper speciation in each water was determined by two thermodynamic models and by potentiometry, and its toxicity was predicted based on the biotic ligand model (BLM) framework. Our results indicate that high Na{sup +} loss is the main mode of toxic action of Cu in P. axelrodi, in accordance with general theory. Cardinal tetra showed a particularly high ability to tolerate Cu and to maintain Na{sup +} balance, similar to the ability of this and other endemic Rio Negro species to tolerate low pH and ion-poor conditions. Cu toxicity was lower in Rio Negro than in the other two waters tested, and the free [Cu{sup 2+}] at the LC50, as determined by any of the three speciation methods tested, was approximately 10-fold higher. This variation could not be captured by a realistic set of BLM parameters. At least in part, this observation may be due to gill

  12. Computational Breakthrough of Natural Lead Hits from the Genus ofArisaemaagainst Human Respiratory Syncytial Virus.

    Science.gov (United States)

    Kant, Kamal; Lal, Uma Ranjan; Ghosh, Manik

    2018-01-01

    To date, efforts for the prevention and treatment of human respiratory syncytial virus (RSV) infection have been still vain, and there is no safe and effective clinical accepted vaccine. Arisaema genus has claimed for various traditional bioactivities, but scientific assessments are quite limited. This encouraged us to carry out our present study on around 60 phytoconstituents of different Arisaema species as a natural inhibitor against the human RSV. Selected 60 phytochemical entities were evaluated on the docking behavior of human RSV receptor (PDB: 4UCC) using Maestro 9.3 (Schrödinger, LLC, Cambridge, USA). Furthermore, kinetic properties and toxicity nature of top graded ligands were analyzed through QikProp and ProTox tools. Notably, rutin (glide score: -8.49), schaftoside (glide score: -8.18) and apigenin-6,8-di-C-β-D-galactoside (glide score - 7.29) have resulted in hopeful natural lead hits with an ideal range of kinetic descriptors values. ProTox tool (oral rodent toxicity) has resulted in likely toxicity targets of apex-graded tested ligands. Finally, the whole efforts can be explored further as a model to confirm its anti-human RSV potential with wet laboratory experiments. Rutin, schaftoside, and apigenin-6,8-di-C-β-D-galactoside showed promising top hits docking profile against human respiratory syncytial virusMoreover, absorption, distribution, metabolism, excretion properties (QikProp) of top hits resulted within an ideal range of kinetic descriptorsProTox tool highlighted toxicity class ranges, LD 50 values, and possible toxicity targets of apex-graded tested ligands. Abbreviations used: RSV: Respiratory syncytial virus, PRRSV: Porcine respiratory and reproductive syndrome virus, ADME-T: Absorption, distribution, metabolism, excretion, and toxicity.

  13. A Novel Porcine Model of Septic Shock Induced by Acute Respiratory Distress Syndrome due to Methicillin-resistantStaphylococcus aureus.

    Science.gov (United States)

    Wang, Shuo; Wang, Jun-Yu; Wang, Tao; Hang, Chen-Chen; Shao, Rui; Li, Chun-Sheng

    2017-05-20

    Sepsis is one of the main causes of mortality in critically ill patients following progression to septic shock. To investigate the pathophysiologic changes of sepsis, we developed a novel porcine model of septic shock induced by acute respiratory distress syndrome (ARDS) due to methicillin-resistant Staphylococcus aureus(MRSA) pneumonia. Twenty-six male Landraces (Lvyuanweiye, Beijing, China) weighing 30 ± 2 kg were divided into four groups: sham group (SH; n = 5); cotton smoke inhalation group (SM; n = 6); MRSA pneumonia group (MR; n = 6); and septic shock group with cotton smoke inhalation + MRSA pneumonia (SS; n = 9). Extensive hemodynamics, oxygen dynamics, and lung function were monitored for 24 h following the injury or until death. Tissues were collected, and histopathology evaluations were carried out. Blood cultures from 6 of 9 animals in the SS group were positive for MRSA. Two hours following the injury, decreased mean arterial blood pressure (60-70 mmHg) and cardiac index (septic shock were only observed in the SS group but not significant in the other groups. The PO2/FiO2in the SM and SS groups decreased to 300 and 100, respectively. In the SS group, extravascular lung water index increased to 20 ml/kg, whereas thoracopulmonary compliance decreased to 10 ml/H2O after injury. Deterioration of pulmonary function in the SS group was more serious than the SM and MR groups. Severe lung injury in the SS group was confirmed by the histopathology evaluations. The lung injury confirmed by high-resolution thin-section computed tomography and histopathology in the SS group was more serious than those of other groups. In the present study, we developed a novel porcine model of septic shock induced by ARDS due to severe MRSA pneumonia with characteristic hyperdynamic and hypodynamic phases in 24 h, which mimicked the hemodynamic changing of septic shock in human.

  14. Model of pulmonary fluid traffic homeostasis based on respiratory cycle pressure, bidirectional bronchiolo-pulmonar shunting and water evaporation.

    Science.gov (United States)

    Kurbel, Sven; Kurbel, Beatrica; Gulam, Danijela; Spajić, Borislav

    2010-06-01

    The main puzzle of the pulmonary circulation is how the alveolar spaces remain dry over a wide range of pulmonary vascular pressures and blood flows. Although normal hydrostatic pressure in pulmonary capillaries is probably always below 10 mmHg, well bellow plasma colloid pressure of 25 mmHg, most textbooks state that some fluid filtration through capillary walls does occur, while the increased lymph drainage prevents alveolar fluid accumulation. The lack of a measurable pressure drop along pulmonary capillaries makes the classic description of Starling forces unsuitable to the low pressure, low resistance pulmonary circulation. Here presented model of pulmonary fluid traffic describes lungs as a matrix of small vascular units, each consisting of alveoli whose capillaries are anastomotically linked to the bronchiolar capillaries perfused by a single bronchiolar arteriole. It proposes that filtration and absorption in pulmonary and in bronchiolar capillaries happen as alternating periods of low and of increased perfusion pressures. The model is based on three levels of filtration control: short filtration phases due to respiratory cycle of the whole lung are modulated by bidirectional bronchiolo-pulmonar shunting independently in each small vascular unit, while fluid evaporation from alveolar groups further tunes local filtration. These mechanisms are used to describe a self-sustaining regulator that allows optimal fluid traffic in different settings. The proposed concept is used to describe development of pulmonary edema in several clinical entities (exercise in wet or dry climate, left heart failure, people who rapidly move to high altitudes, acute cyanide and carbon monoxide poisoning, large pulmonary embolisms). .

  15. Quantitative analysis of porcine reproductive and respiratory syndrome (PRRS) viremia profiles from experimental infection: a statistical modelling approach.

    Science.gov (United States)

    Islam, Zeenath U; Bishop, Stephen C; Savill, Nicholas J; Rowland, Raymond R R; Lunney, Joan K; Trible, Benjamin; Doeschl-Wilson, Andrea B

    2013-01-01

    Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically significant viral diseases facing the global swine industry. Viremia profiles of PRRS virus challenged pigs reflect the severity and progression of infection within the host and provide crucial information for subsequent control measures. In this study we analyse the largest longitudinal PRRS viremia dataset from an in-vivo experiment. The primary objective was to provide a suitable mathematical description of all viremia profiles with biologically meaningful parameters for quantitative analysis of profile characteristics. The Wood's function, a gamma-type function, and a biphasic extended Wood's function were fit to the individual profiles using Bayesian inference with a likelihood framework. Using maximum likelihood inference and numerous fit criteria, we established that the broad spectrum of viremia trends could be adequately represented by either uni- or biphasic Wood's functions. Three viremic categories emerged: cleared (uni-modal and below detection within 42 days post infection(dpi)), persistent (transient experimental persistence over 42 dpi) and rebound (biphasic within 42 dpi). The convenient biological interpretation of the model parameters estimates, allowed us not only to quantify inter-host variation, but also to establish common viremia curve characteristics and their predictability. Statistical analysis of the profile characteristics revealed that persistent profiles were distinguishable already within the first 21 dpi, whereas it is not possible to predict the onset of viremia rebound. Analysis of the neutralizing antibody(nAb) data indicated that there was a ubiquitous strong response to the homologous PRRSV challenge, but high variability in the range of cross-protection of the nAbs. Persistent pigs were found to have a significantly higher nAb cross-protectivity than pigs that either cleared viremia or experienced rebound within 42 dpi. Our study provides

  16. Model-based high cell density cultivation of Rhodospirillum rubrum under respiratory dark conditions.

    Science.gov (United States)

    Zeiger, Lisa; Grammel, Hartmut

    2010-03-01

    The potential of facultative photosynthetic bacteria as producers of photosynthetic pigments, vitamins, coenzymes and other valuable products has been recognized for decades. However, mass cultivation under photosynthetic conditions is generally inefficient due to the inevitable limitation of light supply when cell densities become very high. The previous development of a new cultivation process for maximal expression of photosynthetic genes under semi-aerobic dark conditions in common bioreactors offers a new perspective for utilizing the facultative photosynthetic bacterium Rhodospirillum rubrum for large-scale applications. Based on this cultivation system, the present study aimed in determining the maximal achievable cell density of R. rubrum in a bioreactor, thereby providing a major milestone on the way to industrial bioprocesses. As a starting point, we focus on aerobic growth due to higher growth rates and more facile process control under this condition, with the option to extend the process by an anaerobic production phase. Process design and optimization were supported by an unstructured computational process model, based on mixed-substrate kinetics. Key parameters for growth and process control were determined in shake-flask experiments or estimated by simulation studies. For fed-batch cultivation, a computer-controlled exponential feed algorithm in combination with a pH-stat element was implemented. As a result, a maximal cell density of 59 g cell dry weight (CDW) L(-1) was obtained, representing so far not attainable cell densities for photosynthetic bacteria. The applied exponential fed-batch methodology therefore enters a range which is commonly employed for industrial applications with microbial cells. The biochemical analysis of high cell density cultures revealed metabolic imbalances, such as the accumulation and excretion of tetrapyrrole intermediates of the bacteriochlorophyll biosynthetic pathway. (c) 2009 Wiley Periodicals, Inc.

  17. In vivo bioluminescence imaging of Burkholderia mallei respiratory infection and treatment in the mouse model

    Directory of Open Access Journals (Sweden)

    Shane eMassey

    2011-08-01

    Full Text Available Bioluminescent imaging (BLI technology is a powerful tool for monitoring infectious disease progression and treatment approaches. BLI is particularly useful for tracking fastidious intracellular pathogens that might be difficult to recover from certain organs. Burkholderia mallei, the causative agent of glanders, is a facultative intracellular pathogen and has been classified by the CDC as a Category B select agent due to its highly infectious nature and potential use as a biological weapon. Very little is known regarding pathogenesis or treatment of glanders. We investigated the use of bioluminescent reporter constructs to monitor the dynamics of infection as well as the efficacy of therapeutics for B. mallei in real time. A stable luminescent reporter B. mallei strain was created using the pUTmini-Tn5::luxKm2 plasmid and used to monitor glanders in the BALB/c murine model. Mice were infected via the intranasal route with 5x103 bacteria and monitored by BLI at 24, 48 and 72 h. We verified that our reporter construct maintained similar virulence and growth kinetics compared to wild-type B. mallei and confirmed that it maintains luminescent stability in the presence or absence of antibiotic selection. The luminescent signal was initially seen in the lungs, and progressed to the liver and spleen over the course of infection. We demonstrated that antibiotic treatment 24 h post-infection resulted in reduction of bioluminescence that can be attributed to decreased bacterial burden in target organs. These findings suggest that BLI can be used to monitor disease progression and efficacy of therapeutics during glanders infections. Finally, we report an alternative method to mini-Tn5::luxKm2 transposon using mini-Tn7-lux elements that insert site-specifically at known genomic attachment sites and that can also be used to tag bacteria.

  18. An examination of quinone toxicity using the yeast Saccharomyces cerevisiae model system.

    Science.gov (United States)

    Rodriguez, Chester E; Shinyashiki, Masaru; Froines, John; Yu, Rong Chun; Fukuto, Jon M; Cho, Arthur K

    2004-09-01

    The toxicity of quinones is generally thought to occur by two mechanisms: the formation of covalent bonds with biological molecules by Michael addition chemistry and the catalytic reduction of oxygen to superoxide and other reactive oxygen species (ROS) (redox cycling). In an effort to distinguish between these general mechanisms of toxicity, we have examined the toxicity of five quinones to yeast cells as measured by their ability to reduce growth rate. Yeast cells can grow in the presence and absence of oxygen and this feature was used to evaluate the role of redox cycling in the toxicity of each quinone. Furthermore, yeast mutants deficient in superoxide dismutase (SOD) activity were used to assess the role of this antioxidant enzyme in protecting cells against quinone-induced reactive oxygen toxicity. The effects of different quinones under different conditions of exposure were compared using IC50 values (the concentration of quinone required to inhibit growth rate by 50%). For the most part, the results are consistent with the chemical properties of each quinone with the exception of 9,10-phenanthrenequinone (9,10-PQ). This quinone, which is not an electrophile, exhibited an unexpected toxicity under anaerobic conditions. Further examination revealed a potent induction of cell viability loss which poorly correlated with decreases in the GSH/2GSSG ratio but highly correlated (r2 > 0.7) with inhibition of the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), suggesting disruption of glycolysis by this quinone. Together, these observations suggest an unexpected oxygen-independent mechanism in the toxicity of 9,10-phenanthrenequinone.

  19. Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity

    International Nuclear Information System (INIS)

    Brenner, Matthew; Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Lemor, Daniel; Ahdout, Rebecca; Boss, Gerry R.; Blackledge, William; Jann, Lauren; Nagasawa, Herbert T.; Patterson, Steven E.

    2010-01-01

    The aim of this study is to investigate the ability of intramuscular and intravenous sulfanegen sodium treatment to reverse cyanide effects in a rabbit model as a potential treatment for mass casualty resulting from cyanide exposure. Cyanide poisoning is a serious chemical threat from accidental or intentional exposures. Current cyanide exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Non-rhodanese mediated sulfur transferase pathways, including 3-mercaptopyruvate sulfurtransferase (3-MPST) catalyze the transfer of sulfur from 3-MP to cyanide, forming pyruvate and less toxic thiocyanate. We developed a water-soluble 3-MP prodrug, 3-mercaptopyruvatedithiane (sulfanegen sodium), with the potential to provide a continuous supply of substrate for CN detoxification. In addition to developing a mass casualty cyanide reversal agent, methods are needed to rapidly and reliably diagnose and monitor cyanide poisoning and reversal. We use non-invasive technology, diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS) to monitor physiologic changes associated with cyanide exposure and reversal. A total of 35 animals were studied. Sulfanegen sodium was shown to reverse the effects of cyanide exposure on oxyhemoglobin and deoxyhemoglobin rapidly, significantly faster than control animals when administered by intravenous or intramuscular routes. RBC cyanide levels also returned to normal faster following both intramuscular and intravenous sulfanegen sodium treatment than controls. These studies demonstrate the clinical potential for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for cyanide detoxification. DOS and CWNIRS demonstrated their usefulness in optimizing the dose of sulfanegen sodium treatment.

  20. Sulfanegen Sodium Treatment in a Rabbit Model of Sub-Lethal Cyanide Toxicity

    Science.gov (United States)

    Brenner, Matthew; Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Lemor, Daniel; Ahdout, Rebecca; Boss, Gerry R.; Blackledge, William; Jann, Lauren; Nagasawa, Herbert T.; Patterson, Steven E.

    2010-01-01

    The aim of this study is to investigate the ability of intramuscular and intravenous sulfanegen sodium treatment to reverse cyanide effects in a rabbit model as a potential treatment for mass casualty resulting from cyanide exposure. Cyanide poisoning is a serious chemical threat from accidental or intentional exposures. Current cyanide exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Non-rhodanese mediated sulfur transferase pathways, including 3-mercaptopyruvate sulfurtransferase (3-MPST) catalyze the transfer of sulfur from 3-MP to cyanide, forming pyruvate and less toxic thiocyanate. We developed a water soluble 3-MP prodrug, 3-mercaptopyruvatedithiane (sulfanegen sodium), with the potential to provide a continuous supply of substrate for CN detoxification. In addition to developing a mass casualty cyanide reversal agent, methods are needed to rapidly and reliably diagnose and monitor cyanide poisoning and reversal. We use non-invasive technology, diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS) to monitor physiologic changes associated with cyanide exposure and reversal. A total of 35 animals were studied. Sulfanegen sodium was shown to reverse the effects of cyanide exposure on oxyhemoglobin and deoxyhemoglobin rapidly, significantly faster than control animals when administered by intravenous or intramuscular routes. RBC cyanide levels also returned to normal faster following both intramuscular and intravenous sulfanegen sodium treatment than controls. These studies demonstrate the clinical potential for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for cyanide detoxification. DOS and CWNIRS demonstrated their usefulness in optimizing the dose of sulfanegen sodium treatment. PMID:20705081

  1. Diffusion dynamics and concentration of toxic materials from quantum dots-based nanotechnologies: an agent-based modeling simulation framework

    International Nuclear Information System (INIS)

    Agusdinata, Datu Buyung; Amouie, Mahbod; Xu, Tao

    2015-01-01

    Due to their favorable electrical and optical properties, quantum dots (QDs) nanostructures have found numerous applications including nanomedicine and photovoltaic cells. However, increased future production, use, and disposal of engineered QD products also raise concerns about their potential environmental impacts. The objective of this work is to establish a modeling framework for predicting the diffusion dynamics and concentration of toxic materials released from Trioctylphosphine oxide-capped CdSe. To this end, an agent-based model simulation with reaction kinetics and Brownian motion dynamics was developed. Reaction kinetics is used to model the stability of surface capping agent particularly due to oxidation process. The diffusion of toxic Cd 2+ ions in aquatic environment was simulated using an adapted Brownian motion algorithm. A calibrated parameter to reflect sensitivity to reaction rate is proposed. The model output demonstrates the stochastic spatial distribution of toxic Cd 2+ ions under different values of proxy environmental factor parameters. With the only chemistry considered was oxidation, the simulation was able to replicate Cd 2+ ion release from Thiol-capped QDs in aerated water. The agent-based method is the first to be developed in the QDs application domain. It adds both simplicity of the solubility and rate of release of Cd 2+ ions and complexity of tracking of individual atoms of Cd at the same time

  2. The mysid Siriella armata as a model organism in marine ecotoxicology: comparative acute toxicity sensitivity with Daphnia magna.

    Science.gov (United States)

    Pérez, Sara; Beiras, Ricardo

    2010-01-01

    Siriella armata (Crustacea, Mysidacea) is a component of the coastal zooplankton that lives in swarms in the shallow waters of the European neritic zone, from the North Sea to the Mediterranean. Juveniles of this species were examined as standard test organisms for use in marine acute toxicity tests. The effects of reference toxicants, three trace metals (Copper, Cadmium and Zinc), and one surfactant, sodium dodecyl sulfate (SDS) were studied on S. armata neonates (\\24 h) reared in the laboratory. Acute toxicity tests were carried out with filtered sea water on individual chambers (microplate wells for metals or glass vials for SDS) incubated in an isothermal room at 20 degrees C, with 16 h light: 8 h dark photoperiod for 96 h. Each neonate was fed daily with 10-15 nauplii of Artemia salina. Acute (96 h) LC50 values, in increasing order, were 46.9 lg/L for Cu, 99.3 lg/L for Cd, 466.7 lg/L for Zn and 8.5 mg/L for SDS. The LC(10), NOEC and LOEC values were also calculated. Results were compared with Daphnia magna, a freshwater cladoceran widely used as a standard ecotoxicological test organism. Acute (48 h) LC(50) values were 56.2 lg/L for Cu, 571.5 lg/L for Cd, 1.3 mg/L for Zn and 27.3 mg/L for SDS. For all the reference toxicants studied, the marine mysid Siriella armata showed higher sensitivity than the freshwater model organism Daphnia magna, validating the use of Siriella mysids as model organisms in marine acute toxicity tests.

  3. Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model.

    Science.gov (United States)

    Steinberg, Jay; Halter, Jeffrey; Schiller, Henry; Gatto, Louis; Carney, David; Lee, Hsi-Ming; Golub, Lorne; Nieman, Gary

    2005-10-01

    Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by

  4. Toxicity assessment and geochemical model of chromium leaching from AOD slag.

    Science.gov (United States)

    Liu, Bao; Li, Junguo; Zeng, Yanan; Wang, Ziming

    2016-02-01

    AOD (Argon Oxygen Decarburization) slag is a by-product of the stainless steel refining process. The leaching toxicity of chromium from AOD slag cannot be ignored in the recycling process of the AOD slag. To assess the leaching toxicity of the AOD slag, batch leaching tests have been performed. PHREEQC simulations combined with FactSage were carried out based on the detailed mineralogical analysis and petrophysical data. Moreover, Pourbaix diagram of the Cr-H2O system was protracted by HSC 5.0 software to explore the chromium speciation in leachates. It was found that AOD slag leachate is an alkaline and reductive solution. The Pourbaix diagram of the Cr-H2O system indicated that trivalent chromium, such as Cr(OH)4(-), is the major chromium species in the experimental Eh-pH region considered. However, toxic hexavalent chromium was released with maximum concentrations of 30 µg L(-1) and 18 µg L(-1) at L/S 10 and 100, respectively, during the earlier leaching stage. It concluded that the AOD slag possessed a certain leaching toxicity. After 10 d of leaching, trivalent chromium was the dominant species in the leachates, which corresponded to the results of PHREEQC simulation. Leaching toxicity of AOD slag is based on the chromium speciation and its transformation. Great attention should be focused on such factors as aging, crystal form of chromium-enriched minerals, and electrochemical characteristics of the leachates. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Respiratory Muscle Plasticity

    Science.gov (United States)

    Gransee, Heather M.; Mantilla, Carlos B.; Sieck, Gary C.

    2014-01-01

    Muscle plasticity is defined as the ability of a given muscle to alter its structural and functional properties in accordance with the environmental conditions imposed on it. As such, respiratory muscle is in a constant state of remodeling, and the basis of muscle’s plasticity is its ability to change protein expression and resultant protein balance in response to varying environmental conditions. Here, we will describe the changes of respiratory muscle imposed by extrinsic changes in mechanical load, activity, and innervation. Although there is a large body of literature on the structural and functional plasticity of respiratory muscles, we are only beginning to understand the molecular-scale protein changes that contribute to protein balance. We will give an overview of key mechanisms regulating protein synthesis and protein degradation, as well as the complex interactions between them. We suggest future application of a systems biology approach that would develop a mathematical model of protein balance and greatly improve treatments in a variety of clinical settings related to maintaining both muscle mass and optimal contractile function of respiratory muscles. PMID:23798306

  6. Hydra as a model organism to decipher the toxic effects of copper oxide nanorod: Eco-toxicogenomics approach

    Science.gov (United States)

    Murugadas, Anbazhagan; Zeeshan, Mohammed; Thamaraiselvi, Kaliannan; Ghaskadbi, Surendra; Akbarsha, Mohammad Abdulkader

    2016-01-01

    Nanotechnology has emerged as a powerful field of applied research. However, the potential toxicity of nano-materials is a cause of concern. A thorough toxicological investigation is required before a nanomaterial is evaluated for application of any kind. In this context, there is concerted effort to find appropriate test systems to assess the toxicity of nanomaterials. Toxicity of a nanomaterial greatly depends on its physicochemical properties and the biological system with which it interacts. The present research was carried out with a view to generate data on eco-toxicological impacts of copper oxide nanorod (CuO NR) in Hydra magnipapillata 105 at organismal, cellular and molecular levels. Exposure of hydra to CuO NR resulted in severe morphological alterations in a concentration- as well as duration-dependent manner. Impairment of feeding, population growth, and regeneration was also observed. In vivo and in vitro analyses revealed induction of oxidative stress, genotoxicity, and molecular machinery of apoptotic cell death, accompanied by disruption of cell cycle progression. Taken together, CuO nanorod is potentially toxic to the biological systems. Also, hydra offers potential to be used as a convenient model organism for aquatic ecotoxicological risk assessment of nanomaterials. PMID:27417574

  7. Effects of formalin-inactivated respiratory syncytial virus (FI-RSV in the perinatal lamb model of RSV.

    Directory of Open Access Journals (Sweden)

    Rachel J Derscheid

    Full Text Available Respiratory syncytial virus (RSV is the most frequent cause of bronchiolitis in infants and children worldwide. There are currently no licensed vaccines or effective antivirals. The lack of a vaccine is partly due to increased caution following the aftermath of a failed clinical trial of a formalin-inactivated RSV vaccine (FI-RSV conducted in the 1960's that led to enhanced disease, necessitating hospitalization of 80% of vaccine recipients and resulting in two fatalities. Perinatal lamb lungs are similar in size, structure and physiology to those of human infants and are susceptible to human strains of RSV that induce similar lesions as those observed in infected human infants. We sought to determine if perinatal lambs immunized with FI-RSV would develop key features of vaccine-enhanced disease. This was tested in colostrum-deprived lambs immunized at 3-5 days of age with FI-RSV followed two weeks later by RSV infection. The FI-RSV-vaccinated lambs exhibited several key features of RSV vaccine-enhanced disease, including reduced RSV titers in bronchoalveolar lavage fluid and lung, and increased infiltration of peribronchiolar and perivascular lymphocytes compared to lambs either undergoing an acute RSV infection or naïve controls; all features of RSV vaccine-enhanced disease. These results represent a first step proof-of-principle demonstration that the lamb can develop altered responses to RSV following FI-RSV vaccination. The lamb model may be useful for future mechanistic studies as well as the assessment of RSV vaccines designed for infants.

  8. Surfactant disaturated-phosphatidylcholine kinetics in acute respiratory distress syndrome by stable isotopes and a two compartment model

    Directory of Open Access Journals (Sweden)

    Cogo Paola E

    2007-02-01

    Full Text Available Abstract Background In patients with acute respiratory distress syndrome (ARDS, it is well known that only part of the lungs is aerated and surfactant function is impaired, but the extent of lung damage and changes in surfactant turnover remain unclear. The objective of the study was to evaluate surfactant disaturated-phosphatidylcholine turnover in patients with ARDS using stable isotopes. Methods We studied 12 patients with ARDS and 7 subjects with normal lungs. After the tracheal instillation of a trace dose of 13C-dipalmitoyl-phosphatidylcholine, we measured the 13C enrichment over time of palmitate residues of disaturated-phosphatidylcholine isolated from tracheal aspirates. Data were interpreted using a model with two compartments, alveoli and lung tissue, and kinetic parameters were derived assuming that, in controls, alveolar macrophages may degrade between 5 and 50% of disaturated-phosphatidylcholine, the rest being lost from tissue. In ARDS we assumed that 5–100% of disaturated-phosphatidylcholine is degraded in the alveolar space, due to release of hydrolytic enzymes. Some of the kinetic parameters were uniquely determined, while others were identified as lower and upper bounds. Results In ARDS, the alveolar pool of disaturated-phosphatidylcholine was significantly lower than in controls (0.16 ± 0.04 vs. 1.31 ± 0.40 mg/kg, p de novo synthesis of disaturated-phosphatidylcholine were also significantly lower, while mean resident time in lung tissue was significantly higher in ARDS than in controls. Recycling was 16.2 ± 3.5 in ARDS and 31.9 ± 7.3 in controls (p = 0.08. Conclusion In ARDS the alveolar pool of surfactant is reduced and disaturated-phosphatidylcholine turnover is altered.

  9. The sea urchin, a versatile model for eco-toxicity studies and ecological experimental research

    Directory of Open Access Journals (Sweden)

    D. Privitera

    2011-01-01

    Full Text Available Echinoderm early developmental stages represent a good tool for toxicity testing in different fields, ranging from environment to food contamination, and in full respect of the 3Rs objectives (Reduction, Refinement, Replacement of animal experiments, that will lead to the reduction of vertebrate use for toxicity testing. Further, sea urchins are key species in a wide range of marine habitats, as they are able to structure algal community. Experiments and observations aiming at the  characterization of anthropogenic or climate changes effects on their settlement, population structure, feeding behaviour and reproductive condition, may be useful to describe future scenarios regarding the whole marine community. The present paper represents a short review of the possible applications of eco-toxicity bioassays using Paracentrotus lividus gametes and embryos. Further, examples of ecological researches, involving sea urchins, aiming at the definition of future scenarios will be preserved.

  10. Testing an application of a biotic ligand model to predict acute toxicity of metal mixtures to rainbow trout.

    Science.gov (United States)

    Iwasaki, Yuichi; Kamo, Masashi; Naito, Wataru

    2015-04-01

    The authors tested the applicability of a previously developed biotic ligand model (BLM) to predict acute toxicity of single metals and metal mixtures (cadmium, lead, and zinc) to rainbow trout fry (Oncorhynchus mykiss) from a single available dataset. The BLM used in the present study hypothesizes that metals inhibit an essential cation (calcium) and organisms die as a result of its deficiency, leading to an assumption that the proportion of metal-binding ligand (f) is responsible for the toxic effects of metals on the survival of rainbow trout. The f value is a function of free-ion concentrations of metals computed by a chemical speciation model, and the function has affinity constants as model parameters. First, the survival effects of single metals were statistically modeled separately (i.e., f-survival relationship) by using the generalized linear mixed model with binomial distribution. The modeled responses of survival rates to f overlapped reasonably irrespective of metals tested, supporting the theoretical prediction from the BLM that f-survival relationships are comparable regardless of metal species. The authors thus developed the generalized linear mixed model based on all data pooled across the single-metal tests. The best-fitted model well predicted the survival responses observed in mixture tests (r = 0.97), providing support for the applicability of the BLM to predict effects of metal mixtures. © 2014 SETAC.

  11. A multi-compartment model for slow bronchial clearance of insoluble particles - Extension of the ICRP human respiratory tract models

    International Nuclear Information System (INIS)

    Sturm, R.; Hofmann, W.

    2006-01-01

    To incorporate the various mechanisms that are presently assumed to be responsible for the experimentally observed slow bronchial clearance into the HRTM, a multi-compartment model was developed to simulate the clearance of insoluble particles in the tracheobronchial tree of the human lung. The new model considers specific mass transfer paths that may play an important role for slow bronchial clearance. These include the accumulation of particulate mass in the peri-ciliary sol layer, phagocytosis of stored particles by airway macrophages and uptake of deposited mass by epithelial cells. Besides the gel layer representing fast mucociliary clearance, all cellular and non-cellular units involved in the slow clearance process are described by respective compartments that are connected by specific transfer rates. The gastrointestinal tract and lymph nodes are included into the model as final accumulation compartments, to which mass is transferred via the airway route and the transepithelial path. Predicted retention curves correspond well with previously published data. (authors)

  12. A dynamic approach for the impact of a toxic gas dispersion hazard considering human behaviour and dispersion modelling.

    Science.gov (United States)

    Lovreglio, Ruggiero; Ronchi, Enrico; Maragkos, Georgios; Beji, Tarek; Merci, Bart

    2016-11-15

    The release of toxic gases due to natural/industrial accidents or terrorist attacks in populated areas can have tragic consequences. To prevent and evaluate the effects of these disasters different approaches and modelling tools have been introduced in the literature. These instruments are valuable tools for risk managers doing risk assessment of threatened areas. Despite the significant improvements in hazard assessment in case of toxic gas dispersion, these analyses do not generally include the impact of human behaviour and people movement during emergencies. This work aims at providing an approach which considers both modelling of gas dispersion and evacuation movement in order to improve the accuracy of risk assessment for disasters involving toxic gases. The approach is applied to a hypothetical scenario including a ship releasing Nitrogen dioxide (NO2) on a crowd attending a music festival. The difference between the results obtained with existing static methods (people do not move) and a dynamic approach (people move away from the danger) which considers people movement with different degrees of sophistication (either a simple linear path or more complex behavioural modelling) is discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Analysis and modeling of ensemble recordings from respiratory pre-motor neurons indicate changes in functional network architecture after acute hypoxia

    Directory of Open Access Journals (Sweden)

    Roberto F Galán

    2010-09-01

    Full Text Available We have combined neurophysiologic recording, statistical analysis, and computational modeling to investigate the dynamics of the respiratory network in the brainstem. Using a multielectrode array, we recorded ensembles of respiratory neurons in perfused in situ rat preparations that produce spontaneous breathing patterns, focusing on inspiratory pre-motor neurons. We compared firing rates and neuronal synchronization among these neurons before and after a brief hypoxic stimulus. We observed a significant decrease in the number of spikes after stimulation, in part due to a transient slowing of the respiratory pattern. However, the median interspike interval did not change, suggesting that the firing threshold of the neurons was not affected but rather the synaptic input was. A bootstrap analysis of synchrony between spike trains revealed that, both before and after brief hypoxia, up to 45 % (but typically less than 5 % of coincident spikes across neuronal pairs was not explained by chance. Most likely, this synchrony resulted from common synaptic input to the pre-motor population, an example of stochastic synchronization. After brief hypoxia most pairs were less synchronized, although some were more, suggesting that the respiratory network was “rewired” transiently after the stimulus. To investigate this hypothesis, we created a simple computational model with feed-forward divergent connections along the inspiratory pathway. Assuming that 1 the number of divergent projections was not the same for all presynaptic cells, but rather spanned a wide range and 2 that the stimulus increased inhibition at the top of the network; this model reproduced the reduction in firing rate and bootstrap-corrected synchrony subsequent to hypoxic stimulation observed in our experimental data.

  14. Spatial analysis of toxic emissions in LCA: a sub-continental nested USEtox model with freshwater archetypes.

    Science.gov (United States)

    Kounina, Anna; Margni, Manuele; Shaked, Shanna; Bulle, Cécile; Jolliet, Olivier

    2014-08-01

    This paper develops continent-specific factors for the USEtox model and analyses the accuracy of different model architectures, spatial scales and archetypes in evaluating toxic impacts, with a focus on freshwater pathways. Inter-continental variation is analysed by comparing chemical fate and intake fractions between sub-continental zones of two life cycle impact assessment models: (1) the nested USEtox model parameterized with sub-continental zones and (2) the spatially differentiated IMPACTWorld model with 17 interconnected sub-continental regions. Substance residence time in water varies by up to two orders of magnitude among the 17 zones assessed with IMPACTWorld and USEtox, and intake fraction varies by up to three orders of magnitude. Despite this variation, the nested USEtox model succeeds in mimicking the results of the spatially differentiated model, with the exception of very persistent volatile pollutants that can be transported to polar regions. Intra-continental variation is analysed by comparing fate and intake fractions modelled with the a-spatial (one box) IMPACT Europe continental model vs. the spatially differentiated version of the same model. Results show that the one box model might overestimate chemical fate and characterisation factors for freshwater eco-toxicity of persistent pollutants by up to three orders of magnitude for point source emissions. Subdividing Europe into three archetypes, based on freshwater residence time (how long it takes water to reach the sea), improves the prediction of fate and intake fractions for point source emissions, bringing them within a factor five compared to the spatial model. We demonstrated that a sub-continental nested model such as USEtox, with continent-specific parameterization complemented with freshwater archetypes, can thus represent inter- and intra-continental spatial variations, whilst minimizing model complexity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Multiple linear regression models for predicting chronic aluminum toxicity to freshwater aquatic organisms and developing water quality guidelines.

    Science.gov (United States)

    DeForest, David K; Brix, Kevin V; Tear, Lucinda M; Adams, William J

    2018-01-01

    The bioavailability of aluminum (Al) to freshwater aquatic organisms varies as a function of several water chemistry parameters, including pH, dissolved organic carbon (DOC), and water hardness. We evaluated the ability of multiple linear regression (MLR) models to predict chronic Al toxicity to a green alga (Pseudokirchneriella subcapitata), a cladoceran (Ceriodaphnia dubia), and a fish (Pimephales promelas) as a function of varying DOC, pH, and hardness conditions. The MLR models predicted toxicity values that were within a factor of 2 of observed values in 100% of the cases for P. subcapitata (10 and 20% effective concentrations [EC10s and EC20s]), 91% of the cases for C. dubia (EC10s and EC20s), and 95% (EC10s) and 91% (EC20s) of the cases for P. promelas. The MLR models were then applied to all species with Al toxicity data to derive species and genus sensitivity distributions that could be adjusted as a function of varying DOC, pH, and hardness conditions (the P. subcapitata model was applied to algae and macrophytes, the C. dubia model was applied to invertebrates, and the P. promelas model was applied to fish). Hazardous concentrations to 5% of the species or genera were then derived in 2 ways: 1) fitting a log-normal distribution to species-mean EC10s for all species (following the European Union methodology), and 2) fitting a triangular distribution to genus-mean EC20s for animals only (following the US Environmental Protection Agency methodology). Overall, MLR-based models provide a viable approach for deriving Al water quality guidelines that vary as a function of DOC, pH, and hardness conditions and are a significant improvement over bioavailability corrections based on single parameters. Environ Toxicol Chem 2018;37:80-90. © 2017 SETAC. © 2017 SETAC.

  16. In vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing: Application of a generic PBK modelling approach.

    Science.gov (United States)

    Fragki, Styliani; Piersma, Aldert H; Rorije, Emiel; Zeilmaker, Marco J

    2017-10-01

    Incorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at the target site is accepted to be an indispensable element for such purposes. Nonetheless, PBK models are usually designed for a single or a group of compounds and are considered demanding, with respect to experimental data needed for model parameterization. Alternatively, we evaluate here the use of a more generic approach, i.e. the so-called IndusChemFate model, which is based on incorporated QSAR model parametrization. The model was used to simulate the in vivo kinetics of three diverse classes of developmental toxicants: triazoles, glycol ethers' alkoxyacetic acid metabolites and phthalate primary metabolites. The model required specific input per each class of compounds. These compounds were previously tested in three alternative assays: the whole-embryo culture (WEC), the zebrafish embryo test (ZET), and the mouse embryonic stem cell test (EST). Thereafter, the PBK-simulated blood levels at toxic in vivo doses were compared to the respective in vitro effective concentrations. Comparisons pertaining to relative potency and potency ranking with integration of kinetics were similar to previously obtained comparisons. Additionally, all three in vitro systems produced quite comparable results, and hence, a combination of alternative tests is still preferable for predicting the endpoint of developmental toxicity in vivo. This approach is put forward as biologically more plausible since plasma concentrations, rather than external administered doses, constitute the most direct in vivo dose metric. Copyright © 2017 Elsevier Inc. All rights reserved.