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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. ADMET Evaluation in Drug Discovery. Part 17: Development of Quantitative and Qualitative Prediction Models for Chemical-Induced Respiratory Toxicity.

    Science.gov (United States)

    Lei, Tailong; Chen, Fu; Liu, Hui; Sun, Huiyong; Kang, Yu; Li, Dan; Li, Youyong; Hou, Tingjun

    2017-07-03

    As a dangerous end point, respiratory toxicity can cause serious adverse health effects and even death. Meanwhile, it is a common and traditional issue in occupational and environmental protection. Pharmaceutical and chemical industries have a strong urge to develop precise and convenient computational tools to evaluate the respiratory toxicity of compounds as early as possible. Most of the reported theoretical models were developed based on the respiratory toxicity data sets with one single symptom, such as respiratory sensitization, and therefore these models may not afford reliable predictions for toxic compounds with other respiratory symptoms, such as pneumonia or rhinitis. Here, based on a diverse data set of mouse intraperitoneal respiratory toxicity characterized by multiple symptoms, a number of quantitative and qualitative predictions models with high reliability were developed by machine learning approaches. First, a four-tier dimension reduction strategy was employed to find an optimal set of 20 molecular descriptors for model building. Then, six machine learning approaches were used to develop the prediction models, including relevance vector machine (RVM), support vector machine (SVM), regularized random forest (RRF), extreme gradient boosting (XGBoost), naïve Bayes (NB), and linear discriminant analysis (LDA). Among all of the models, the SVM regression model shows the most accurate quantitative predictions for the test set (q(2)ext = 0.707), and the XGBoost classification model achieves the most accurate qualitative predictions for the test set (MCC of 0.644, AUC of 0.893, and global accuracy of 82.62%). The application domains were analyzed, and all of the tested compounds fall within the application domain coverage. We also examined the structural features of the compounds and important fragments with large prediction errors. In conclusion, the SVM regression model and the XGBoost classification model can be employed as accurate prediction tools

  3. Respiratory Toxicity Biomarkers

    Science.gov (United States)

    The advancement in high throughput genomic, proteomic and metabolomic techniques have accelerated pace of lung biomarker discovery. A recent growth in the discovery of new lung toxicity/disease biomarkers have led to significant advances in our understanding of pathological proce...

  4. Mobilisation of toxic elements in the human respiratory system

    Energy Technology Data Exchange (ETDEWEB)

    Pinheiro, T. E-mail: murmur@itn1.itn.pt; Alves, L.C.; Palhano, M.J.; Bugalho de Almeida, A

    2001-07-01

    The fate of respired particles in the respiratory system is inferred through the chemical characterisation of individual particles at the tracheal and bronchial mucosas, and the accumulation of toxic elements in lung alveoli and lymph nodes. The particles and tissue elemental distributions were identified and characterised using micro-PIXE elemental mapping of thin frozen sections using the ITN Nuclear Microprobe facility. Significant particle deposits are found at the distal respiratory tract. Al, Si, Ti, V, Cr, Fe, Ni, Cu and Zn are elements detected at these accumulation areas. The elemental distributions in the different cellular environments of lymph nodes vary. The major compartments for Al, Si, Ti, Fe and Cr are the phagocytic cells and capsule of lymph nodes, while V and Ni are in the cortex and paracortex medullar areas which retain more than 70% of these two elements, suggesting high solubility of the latter in the cellular milieu. The elemental mobilisation from particles or deposits to surrounding tissues at the respiratory ducts evidences patterns of diffusion and removal that are different than those for elements in the respiratory tract. Mobilisation of elements such as V, Cr and Ni is more relevant at alveoli areas where gaseous exchange takes place. The apparent high solubility of V and Ni in the respiratory tract tissue points towards a deviation of the lymphatic system filtering efficiency for these elements when compared to others.

  5. 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.

  6. In vitro models of lung toxicity.

    Science.gov (United States)

    Fisher, G L; Placke, M E

    1987-12-01

    In vitro assays that emphasize cellular components critical to the host defense system have been developed to evaluate pulmonary toxicity and define deleterious changes in parenchymal cell populations. Assays that employ pulmonary alveolar macrophages (PAM) have demonstrated good correlation between macrophage toxicity and pulmonary fibrogenicity for many inorganic compounds. The PAM assays provide simple and inexpensive screens of potential respiratory tract toxicity. Many investigators screen chemicals for their ability to alter the mucosal epithelial cell conducting airways by performing tracheal organ cultures. The tracheal assays have also provided useful screens for Vitamin A analogues required for epithelial cell differentiation. Most recently, in vitro respiratory tract models have been extended to include whole-lung explants, an approach that allows for development of fibrosis and epithelial cell toxicity after in vitro exposure to inorganic and organic fibrogens. The whole-lung explant system appears to duplicate the in vivo response to a variety of lung toxins, including bleomycin, silica, and crocidolite asbestos. Together, these assays provide a description of potential toxicity to key components of the lung, emphasizing the pulmonary macrophage, conducting airways, and alveolar septae. It is expected that continued research in these models will enhance their predictive abilities and utility in risk assessment.

  7. Pharmacokinetics and toxicodynamics of pralidoxime effects on paraoxon-induced respiratory toxicity.

    Science.gov (United States)

    Houzé, Pascal; Mager, Donald E; Risède, Patricia; Baud, Frédéric J

    2010-08-01

    Empirical studies suggest that the antidotal effect of pralidoxime depends on plasma concentrations with therapeutic effects associated with concentrations above 4 mg/l. The purpose of this study was to determine the pharmacokinetic-toxicodynamic (PK-TD) relationships for the antidotal effect of pralidoxime on paraoxon-induced toxicity in rats. Diethylparaoxon inactivation of whole-blood cholinesterase activity was studied both in vitro and in male Sprague-Dawley rats. Toxin-induced respiratory effects were measured via whole-body plethysmography in control and pralidoxime-treated animals (50 mg/kg im injection). In the in vitro analysis, cholinesterase reactivation by pralidoxime in blood-poisoned diethylparaoxon (10nM) was proportional to the logarithm of drug concentrations. A mechanism-based TD model was developed, which well described the inhibition of cholinesterases by diethylparaoxon and reactivation with pralidoxime. The in vitro pralidoxime EC(50) was estimated to be 4.67 mg/l. Animals exposed to diethylparaoxon exhibited a decrease in respiratory rate and an increase in expiratory time, and pralidoxime treatment resulted in a rapid complete but transient (antidotal effects, which explained the complex relationship between drug exposure and pharmacological response profile. This study provides insights into the role of oxime-rescue of paraoxon-induced toxicity, and the final PK-TD model might prove useful in optimizing the design and development of such therapy.

  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. Rapid toxicity testing based on yeast respiratory activity

    Energy Technology Data Exchange (ETDEWEB)

    Haubenstricker, M.E. (Environmental Protection Agency, Ann Arbor, MI (USA)); Meier, P.G.; Mancy, K.H. (Univ. of Michigan, Ann Arbor (USA)); Brabec, M.J. (Eastern Michigan Univ., Ypsilanti (USA))

    1990-05-01

    Rapid and economical techniques are needed to determine the effects of environmental contaminants. At present, the main methods to assess the impact of pollutants are based on chemical analysis of the samples. Invertebrate and vertebrate exposures have been used over the last two decades in assessing acute and chronic toxicities. However, these tests are labor intensive and require several days to complete. An alternative to whole organism exposure is to determine toxic effects in monocellular systems. Another approach for assessing toxicity is to monitor sensitive, nonspecific, subcellular target sites such as mitochondria. Changes in mitochondrial function which could indicate a toxic effect can be demonstrated readily after addition of a foreign substance. In initial assessments of various chemicals, rat liver mitochondria (RLM) were evaluated as a biological sensor of toxicity. False toxicity assessments will result if these ions are present even though they are generally considered nontoxic. Because of these disadvantages, an alternative mitochondrial system, such as found in bakers yeast, was evaluated.

  10. Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely.

    Science.gov (United States)

    Ryan, Nicole M; Isbister, Geoffrey K

    2015-07-01

    Tramadol is a commonly used centrally acting analgesic associated with seizures and suspected to cause serotonin toxicity in overdose. This study sought to investigate the effects of tramadol overdose, and included evaluation for serotonin toxicity based on the Hunter Serotonin Toxicity Criteria where the seven clinical features of spontaneous clonus, inducible clonus, ocular clonus, agitation, diaphoresis, tremor and hyperreflexia are examined for in all patients taking serotonergic medications; seizures and central nervous system depression. This was an observational cases series based on a retrospective review of tramadol overdoses (> 400 mg) admitted to a tertiary toxicology unit from November 2000 to June 2013. Demographic details, information on ingestion (dose and co-ingestants), clinical effects, complications (seizures, serotonin toxicity and cardiovascular effects) and intensive care unit (ICU) admission were extracted from a clinical database. There were 71 cases of tramadol overdose (median age: 41 years, range: 17-69 years; and median ingested dose: 1000 mg, interquartile range [IQR]: 800-2000 mg). Seizures were dose related and occurred in 8 patients, one of them co-ingested a benzodiazepine compared with 16 patients without seizures. There were no cases of serotonin toxicity meeting the Hunter Serotonin Toxicity Criteria. Tachycardia occurred in 27 and mild hypertension occurred in 32. The Glasgow Coma Score was tramadol alone (3000 mg and 900 mg). Respiratory depression occurred in 13, median dose: 2500 (IQR: 1600-3000) mg which was significantly different (p = 0.003) to patients without respiratory depression, median dose: 1000 (IQR: 750-1475) mg. Eight patients were admitted to ICU, five due to co-ingestant toxicity and three for respiratory depression. Tramadol overdose was associated with a significant risk of seizures and respiratory depression in more severe cases, both which appear to be related to the ingested dose. There were no cases of

  11. 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

  12. Animal models for diseases of respiratory system

    Directory of Open Access Journals (Sweden)

    R. Adil

    2012-07-01

    Full Text Available Latest trends in understanding of respiratory diseases in human beings can be derived from thorough clinical studies of these diseases occurring in man, but conducting such studies in man is difficult in terms of experimental manipulation. In the last 2 decades, various types of experimental respiratory disease models has been developed and utilized by investigators, which have contributed a lot to the understanding of respiratory diseases in man, but only little investigation has been done on the naturally occurring pulmonary diseases of animals as potential models which could have added to our knowledge. There are certain selected examples of spontaneous pulmonary disease in animals that may serve as exploitable models for human chronic bronchitis, bronchiectasis, emphysema, interstitial lung disease, hypersensitivity pneumonitis, hyaline membrane disease, and bronchial asthma.

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

    Science.gov (United States)

    2014-12-01

    life support (ECLS) in adults with acute respiratory distress syndrome (ARDS) has increased markedly during the past few years after suc- cessful...Extracorporeal Membrane Oxygenation in a Patient With Refractory Acute Respiratory Distress Syndrome Secondary to Toxic Epidermal Necrolysis Christy...COVERED - 4. TITLE AND SUBTITLE Extracorporeal Membrane Oxygenation in a Patient With Refractory Acute Respiratory Distress Syndrome Secondary to

  14. Protection of human upper respiratory tract cell lines against sulphur mustard toxicity by hexamethylenetetramine (HMT).

    Science.gov (United States)

    Andrew, D J; Lindsay, C D

    1998-07-01

    1. Sulphur mustard ('mustard gas', HD) is a highly toxic chemical warfare agent which affects the skin and respiratory tract. The primary targets of inhaled HD are the epithelia of the upper respiratory tract. Hexamethylenetetramine (HMT) has been shown to protect human lung cells against HD toxicity and has also been shown to be effective in vivo against the chemical warfare agent phosgene. The ability of HMT to protect against the toxicity of HD was investigated in the human upper respiratory tract cell lines BEAS-2B and RPMI 2650. 2. HD was highly toxic to both cell lines, with LC50 values of 15-30 microM. HMT, at a concentration of 10 mM, was shown to protect the cell lines against the toxic effects of 20 microM and 40 microM HD. Results demonstrated that it was necessary for HMT to be in situ at the time of exposure to HD for effective cytoprotection. No protection was seen when cells were treated with HMT following exposure to HD, or where HMT was removed prior to HD exposure. 3. Results suggest that HMT may be effective prophylaxis for exposure to HD by inhalation.

  15. ERK1/2 activation modulates pyocyanin-induced toxicity in A549 respiratory epithelial cells.

    Science.gov (United States)

    Forbes, Amanda; Davey, Andrew K; Perkins, Anthony V; Grant, Gary D; McFarland, Amelia J; McDermott, Catherine M; Anoopkumar-Dukie, Shailendra

    2014-02-01

    Pyocyanin (PCN), a virulence factor produced by Pseudomonas aeruginosa, has many damaging effects on mammalian cells. Several lines of evidence suggest that this damage is primarily mediated by its ability to generate oxidative stress. However mechanisms underlying PCN-induced oxidative injury remain unclear. Although oxidative stress and subsequent MAPK signaling has been shown to modulate cell death in other models, its role in PCN-induced cytotoxicity remains unknown. Therefore the aim of this study was to investigate the role of redox-sensitive MAPK in PCN-induced toxicity in A549 cells. Here we show that PCN (50μM) rapidly increased ERK1/2 phosphorylation after 5min. Pre-treatment of A549 cells with the MEK1/2 inhibitor U0126 (10μM) decreased PCN-induced ERK1/2 phosphorylation and protected cells against apoptosis and cell injury suggesting a role for ERK signalling. In contrast, JNK and p38 MAPK phosphorylation remained unchanged following exposure to PCN and pretreatment with either the JNK or p38 MAPK inhibitors (10μM SP600125 and 10μM SB203580, respectively) did not afford protection against PCN toxicity. This would suggest that PCN-induced cytotoxicity appears to occur independently of JNK and p38 MAPK signaling pathways. Finally, although we confirm that oxidative stress contributes to PCN-induced toxicity, our data suggest the contribution of oxidative stress is independent of ERK1/2 signaling. These findings may provide insight for novel targeted therapies to reduce PCN-mediated lung injury in patients with chronic P. aeruginosa respiratory infections.

  16. Respiratory toxicity of multi-wall carbon nanotubes.

    Science.gov (United States)

    Muller, Julie; Huaux, François; Moreau, Nicolas; Misson, Pierre; Heilier, Jean-François; Delos, Monique; Arras, Mohammed; Fonseca, Antonio; Nagy, Janos B; Lison, Dominique

    2005-09-15

    Carbon nanotubes focus the attention of many scientists because of their huge potential of industrial applications, but there is a paucity of information on the toxicological properties of this material. The aim of this experimental study was to characterize the biological reactivity of purified multi-wall carbon nanotubes in the rat lung and in vitro. Multi-wall carbon nanotubes (CNT) or ground CNT were administered intratracheally (0.5, 2 or 5 mg) to Sprague-Dawley rats and we estimated lung persistence, inflammation and fibrosis biochemically and histologically. CNT and ground CNT were still present in the lung after 60 days (80% and 40% of the lowest dose) and both induced inflammatory and fibrotic reactions. At 2 months, pulmonary lesions induced by CNT were characterized by the formation of collagen-rich granulomas protruding in the bronchial lumen, in association with alveolitis in the surrounding tissues. These lesions were caused by the accumulation of large CNT agglomerates in the airways. Ground CNT were better dispersed in the lung parenchyma and also induced inflammatory and fibrotic responses. Both CNT and ground CNT stimulated the production of TNF-alpha in the lung of treated animals. In vitro, ground CNT induced the overproduction of TNF-alpha by macrophages. These results suggest that carbon nanotubes are potentially toxic to humans and that strict industrial hygiene measures should to be taken to limit exposure during their manipulation.

  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. Animal model of Mycoplasma fermentans respiratory infection

    Directory of Open Access Journals (Sweden)

    Yáñez Antonio

    2013-01-01

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

  19. Acute Toxicity and Cardio-Respiratory Effects of 2-Deoxy-D-Glucose: A Promising Radio Sensitiser

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    To evaluate the acute toxicity of 2-deoxy-D-glucose (2DG) by oral (p.o.) and intravenous (i.v.) routes, and also the cardio-respiratory effects following high doses of 2DG in animal models. Methods The LD50 of 2DG (in water)was determined in rats and mice by p.o. route and in mice by i.v. route. The effect of 2-DG (250 mg/kg, 500 mg/kg, and 1000mg/kg, i.v.) was studied on various cardio-respiratory parameters viz., mean arterial blood pressure, heart rate and respiratory rate in anaesthetised rats. The effect of 2DG (500 mg/kg, 1000 mg/kg, and 2000 mg/kg, p.o.) was also studied on various respiratory parameters viz., respiratory rate and tidal volume in conscious rats and mice using a computer program. Results The p.o. LD50 of 2DG was found to be >8000 mg/kg in mice and rats, and at this dose no death was observed. The LD50 in mice by i.v. route was found to be 8000 mg/kg. At this dose 2 out of 4 mice died and the death occurred within 6 h. A significant increase in the body weight was observed after p.o. administration of 2DG in rats at 500 mg/kg, 1000 mg/kg, and 2000 mg/kg doses. There was no significant change in the body weight at 4000 mg/kg and 8000 mg/kg by the p.o. route in rats and up to 8000 mg/kg by p.o. as well as i.v. routes in mice. Intravenous administration of 2DG (250 mg/kg, 500 mg/kg, and 1000 mg/kg)in anaesthetised rats showed a time-dependent decrease in the mean arterial blood pressure. There was no change in the heart rate in any of the treatment groups. The tidal volume was not changed significantly by p.o administration in conscious rats, but a significant decrease in the respiratory frequency at 500 mg/kg and 1000 mg/kg doses was observed. In the mice also there was no change in the tidal volume after p.o, administration, but the respiratory frequency decreased significantly at 2000 mg/kg dose.Conclusion 2DG is a safe compound but can cause a fall in the blood pressure and a decrease in respiratory frequency at high doses.

  20. Predictive Modeling of Developmental Toxicity

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    The use of alternative methods in conjunction with traditional in vivo developmental toxicity testing has the potential to (1) reduce cost and increase throughput of testing the chemical universe, (2) prioritize chemicals for further targeted toxicity testing and risk assessment,...

  1. Association of respiratory complications and elevated serum immunoglobulins with drinking water arsenic toxicity in human.

    Science.gov (United States)

    Islam, Laila N; Nabi, A H M Nurun; Rahman, M Mahfuzur; Zahid, M Shamim H

    2007-10-01

    We assessed the relationship between chronic arsenic exposure through drinking water with respiratory complications and humoral immune response by measuring serum immunoglobulin profiles in the affected subjects (arsenicosis patients) living in the arsenic endemic rural villages of Bangladesh. The duration of exposure was determined through detailed history of the patients (n=125) and the levels of arsenic in the drinking water and urine samples were determined. The mean duration of exposure in the patients was 7.4+/-5.3 y, and the levels of arsenic in the drinking water and urine samples were 216+/-211 and 223+/-302 micro g/L, respectively, compared to 11+/-20 and 29+/-19 microg/L, respectively, in the unexposed subjects. There was high prevalence of respiratory complications like breathing problems including chest sound, asthma, bronchitis and cough associated with drinking water arsenic toxicity. Arsenicosis patients had significantly elevated levels of IgG (Pdiseases, rather it could be due to direct effects of arsenic. We found significant linear relationships between the levels of serum IgE and inorganic phosphorus (Pcaused respiratory complications, induced changes in the humoral as well as mucosal immune responses.

  2. Assessment of geographical variation in the respiratory toxicity of desert dust particles.

    Science.gov (United States)

    Taylor, Karen; Foster, Melanie L; Law, J McHugh; Centeno, Jose A; Fornero, Elisa; Henderson, M Stephen; Trager, Sabrina A; Stockelman, Michael G; Dorman, David C

    2013-06-01

    The health consequences of sand particle inhalation are incompletely understood. This project evaluated the respiratory toxicity of sand particles collected at military bases near Fort Irwin USA, in Iraq (Camp Victory, Taji and Talil), and Khost Afghanistan. Our primary focus was on assessing the role of soluble metals in the respiratory toxicity of the sand particles using in vitro and in vivo methods. Replicating rat type II alveolar cell cultures (RLE-6TN) were exposed to sand extracts or vehicle control in serum-free media for ≤24 h. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and assessment of lactate dehydrogenase leakage. The relative in vitro cytotoxicity of the sand extracts was Taji ≈ Talil > Afghanistan > Camp Victory ≈ Fort Irwin. We also assessed extracts of Camp Victory, Afghanistan, and Taji sand for acute and delayed pulmonary toxicity in rats following intratracheal administration. Assessments included biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung histopathology. The in vitro cytotoxicity assay results were partially predictive of in vivo responses. The more cytotoxic Taji sand extract induced an acute irritant response in rats following intratracheal administration. Rats given the less cytotoxic Camp Victory sand extract had minimal biochemical or cytological BALF changes whereas rats given either the Afghanistan or Taji sand extracts demonstrated BALF changes that were suggestive of mild lung inflammation. Unexpectedly, we observed similar lung pathology in all extract-exposed rats. The results of our study can be used to prioritize future particle inhalation studies or guide epidemiological study design.

  3. Recent advances in theoretical models of respiratory mechanics

    Institute of Scientific and Technical Information of China (English)

    Bo Huo; Rui-Rong Fu

    2012-01-01

    As an important branch of biomedical engineering,respiratory mechanics helps to understand the physiology of the respiratory system and provides fundamental data for developing such clinical technologies as ventilators.To solve different clinical problems,researchers have developed numerous models at various scales that describe biological and mechanical properties of the respiratory system.During the past decade,benefiting from the continuous accumulation of clinical data and the dramatic progress of biomedical technologies (e.g.biomedical imaging),the theoretical modeling of respiratory mechanics has made remarkable progress regarding the macroscopic properties of the respiratory process,complexities of the respiratory system,gas exchange within the lungs,and the coupling interaction between lung and heart.The present paper reviews the advances in the above fields and proposes potential future projects.

  4. The in vitro respiratory toxicity of cristobalite-bearing volcanic ash.

    Science.gov (United States)

    Damby, David E; Murphy, Fiona A; Horwell, Claire J; Raftis, Jennifer; Donaldson, Kenneth

    2016-02-01

    Ash from dome-forming volcanoes poses a unique hazard to millions of people worldwide due to an abundance of respirable cristobalite, a crystalline silica polymorph. Crystalline silica is an established respiratory hazard in other mixed dusts, but its toxicity strongly depends on sample provenance. Previous studies suggest that cristobalite-bearing volcanic ash is not as bio-reactive as may be expected for a dust containing crystalline silica. We systematically address the hazard posed by volcanic cristobalite by analysing a range of dome-related ash samples, and interpret the crystalline silica hazard according to the mineralogical nature of volcanic cristobalite. Samples are sourced from five well-characterized dome-forming volcanoes that span a range of magmatic compositions, specifically selecting samples rich in cristobalite (up to 16wt%). Isolated respirable fractions are used to investigate the in vitro response of THP-1 macrophages and A549 type II epithelial cells in cytotoxicity, cellular stress, and pro-inflammatory assays associated with crystalline silica toxicity. Dome-related ash is minimally reactive in vitro for a range of source compositions and cristobalite contents. Cristobalite-based toxicity is not evident in the assays employed, supporting the notion that crystalline silica provenance influences reactivity. Macrophages experienced minimal ash-induced cytotoxicity and intracellular reduction of glutathione; however, production of IL-1β, IL-6 and IL-8 were sample-dependent. Lung epithelial cells experienced moderate apoptosis, sample-dependent reduction of glutathione, and minimal cytokine production. We suggest that protracted interaction between particles and epithelial cells may never arise due to effective clearance by macrophages. However, volcanic ash has the propensity to incite a low, but significant, and sample-dependent response; the effect of this response in vivo is unknown and prolonged exposure may yet pose a hazard.

  5. ANIMAL MODELS FOR PROTEIN RESPIRATORY SENSITIZERS

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    Protein induced respiratory hypersensitivity, particularly atopic disease in general, and allergic asthma in particular, has increased dramatically over the last several decades in the U.S. and other industrialized nations as a result of ill-defined changes in living conditions i...

  6. 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

  7. A Mathematical Model of the Human Respiratory Control System

    Science.gov (United States)

    Milhorn, Howard T.; Benton, Richard; Ross, Richard; Guyton, Arthur C.

    1965-01-01

    The respiratory system exhibits the properties of a control system of the regulator type. Equations describing this biological control system have been derived. Transient and steady-state solutions for various CO2 and O2 step input disturbances were obtained utilizing a digital computer and are compared with experimental results. The effectiveness of the respiratory system as a regulator is investigated. Further extensions of the model are suggested. PMID:14284328

  8. Modeling neural mechanisms for genesis of respiratory rhythm and pattern. II. Network models of the central respiratory pattern generator.

    Science.gov (United States)

    Rybak, I A; Paton, J F; Schwaber, J S

    1997-04-01

    The present paper describes several models of the central respiratory pattern generator (CRPG) developed employing experimental data and current hypotheses for respiratory rhythmogenesis. Each CRPG model includes a network of respiratory neuron types (e.g., early inspiratory; ramp inspiratory; late inspiratory; decrementing expiratory; postinspiratory; stage II expiratory; stage II constant firing expiratory; preinspiratory) and simplified models of lung and pulmonary stretch receptors (PSR), which provide feedback to the respiratory network. The used models of single respiratory neurons were developed in the Hodgkin-Huxley style as described in the previous paper. The mechanism for termination of inspiration (the inspiratory off-switch) in all models operates via late-I neuron, which is considered to be the inspiratory off-switching neuron. Several two- and three-phase CRPG models have been developed using different accepted hypotheses of the mechanism for termination of expiration. The key elements in the two-phase models are the early-I and dec-E neurons. The expiratory off-switch mechanism in these models is based on the mutual inhibitory connections between early-I and dec-E and adaptive properties of the dec-E neuron. The difference between the two-phase models concerns the mechanism for ramp firing patterns of E2 neurons resulting either from the intrinsic neuronal properties of the E2 neuron or from disinhibition from the adapting dec-E neuron. The key element of the three-phase models is the pre-I neuron, which acts as the expiratory off-switching neuron. The three-phase models differ by the mechanisms used for termination of expiration and for the ramp firing patterns of E2 neurons. Additional CRPG models were developed employing a dual switching neuron that generates two bursts per respiratory cycle to terminate both inspiration and expiration. Although distinctly different each model generates a stable respiratory rhythm and shows physiologically

  9. Acute toxic effects of nerve agent VX on respiratory dynamics and functions following microinsillation inhalation exposure in guinea pigs.

    Science.gov (United States)

    Rezk, Peter E; Graham, Jacob R; Moran, Theodore S; Gordon, Richard K; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2007-03-01

    Exposure to a chemical warfare nerve agent (CWNA) leads to severe respiratory distress, respiratory failure, or death if not treated. We investigated the toxic effects of nerve agent VX on the respiratory dynamics of guinea pigs following exposure to 90.4 mug/m3 of VX or saline by microinstillation inhalation technology for 10 min. Respiratory parameters were monitored by whole-body barometric plethysmography at 4, 24, and 48 h, 7 d, 18 d, and 4 wk after VX exposure. VX-exposed animals showed a significant decrease in the respiratory frequency (RF) at 24 and 48 h of recovery (p value .0329 and .0142, respectively) compared to the saline control. The tidal volume (TV) slightly increased in VX exposed animals at 24 and significantly at 48 h (p = .02) postexposure. Minute ventilation (MV) increased slightly at 4 h but was reduced at 24 h and remained unchanged at 48 h. Animals exposed to VX also showed an increase in expiratory (Te) and relaxation time (RT) at 24 and 48 h and a small reduction in inspiratory time (Ti) at 24 h. A significant increase in end expiratory pause (EEP) was observed at 48 h after VX exposure (p = .049). The pseudo lung resistance (Penh) was significantly increased at 4 h after VX exposure and remained slightly high even at 48 h. Time-course studies reveal that most of the altered respiratory dynamics returned to normal at 7 d after VX exposure except for EEP, which was high at 7 d and returned to normal at 18 d postexposure. After 1 mo, all the monitored respiratory parameters were within normal ranges. Bronchoalveolar lavage (BAL) 1 mo after exposure showed virtually no difference in protein levels, cholinesterase levels, cell number, and cell death in the exposed and control animals. These results indicate that sublethal concentrations of VX induce changes in respiratory dynamics and functions that over time return to normal levels.

  10. 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.

  11. 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.

  12. 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.

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

    Science.gov (United States)

    Zhang, De Lu; Liu, Si Yi; Zhang, Jing; Zhang, Jian Kun; Hu, Chun Xiang; Liu, Yong Ding

    2016-07-01

    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. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. 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.

  15. Computational modeling of aerosol deposition in respiratory tract: a review.

    Science.gov (United States)

    Rostami, Ali A

    2009-02-01

    This review article is intended to serve as an overview of the current status of the computational tools and approaches available for predicting respiratory-tract dosimetry of inhaled particulate matter. There are two groups of computational models available, depending on the intended use. The whole-lung models are designed to provide deposition prediction for the whole lung, from the oronasal cavities to the pulmonary region. The whole-lung models are generally semi-empirical and hence provide more reliable results but within the range of parameters used for empirical correlations. The local deposition or computational fluid dynamics (CFD)-based models, on the other hand, utilize comprehensive theoretical and computational approaches but are often limited to upper respiratory tracts. They are based on theoretical principles and are applicable to a wider range of parameters, but less accurate. One of the difficulties with modeling of aerosol deposition in human lung is related to the complexity of the airways geometry and the limited morphometric data available. Another difficulty corresponds to simulation of the realistic physiological conditions of lung environment. Furthermore, complex physical and chemical phenomena associated with dense and multicomponent aerosols complicate the modeling tasks. All of these issues are addressed in this review. The progress made in each area in the last three decades and the challenges ahead are discussed along with some suggestions for future direction. The following subjects are covered in this review: introduction, aerosol deposition mechanisms, elements of a computational model, respiratory-tract geometry models, whole-lung models, CFD based models, cigarette smoke deposition models, and conclusion.

  16. Modelling toxicity induced Neurological disorders in Zebrafish

    Directory of Open Access Journals (Sweden)

    Benin Joseph

    2012-03-01

    Full Text Available Neurological disorders have become more common and prevalent. Cellular pathology and behavioural symptoms in neurodegenerative diseases although connected are still a mystery to solve with no complete cure available yet. Central pathways in neurodegeneration involves impaired ubiquitin-proteasome machinery, autophagy and mitochondrial oxidative stress. In the case of neurodevlopmental disorders, environmental toxins and genetic factors are main causative agents. We aim to create a toxicity induced zebrafish model of neurological disease focussing on cognition, movement and hyperactivity disorders. Zebra fish embryos at 48 hr post fertilization were treated with different doses of lead, cholesterol and acetyl choline and by 7 days post fertilization pectoral fin movement, swimming behaviour and touch response were compromised in parallel with apoptosis identified in the brain by acridine orange fluorescent staining. A marked window is observed, therefore promising for a drug screening platform. Further characterization of pathology associated protein expression and specific behavioural studies could render this as a simple promising toxic model for preclinical drug screening.

  17. 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.

  18. Iterative integral parameter identification of a respiratory mechanics model

    Directory of Open Access Journals (Sweden)

    Schranz Christoph

    2012-07-01

    Full Text Available Abstract Background Patient-specific respiratory mechanics models can support the evaluation of optimal lung protective ventilator settings during ventilation therapy. Clinical application requires that the individual’s model parameter values must be identified with information available at the bedside. Multiple linear regression or gradient-based parameter identification methods are highly sensitive to noise and initial parameter estimates. Thus, they are difficult to apply at the bedside to support therapeutic decisions. Methods An iterative integral parameter identification method is applied to a second order respiratory mechanics model. The method is compared to the commonly used regression methods and error-mapping approaches using simulated and clinical data. The clinical potential of the method was evaluated on data from 13 Acute Respiratory Distress Syndrome (ARDS patients. Results The iterative integral method converged to error minima 350 times faster than the Simplex Search Method using simulation data sets and 50 times faster using clinical data sets. Established regression methods reported erroneous results due to sensitivity to noise. In contrast, the iterative integral method was effective independent of initial parameter estimations, and converged successfully in each case tested. Conclusion These investigations reveal that the iterative integral method is beneficial with respect to computing time, operator independence and robustness, and thus applicable at the bedside for this clinical application.

  19. Predictive QSAR modelling of algal toxicity of ionic liquids and its interspecies correlation with Daphnia toxicity.

    Science.gov (United States)

    Roy, Kunal; Das, Rudra Narayan; Popelier, Paul L A

    2015-05-01

    Predictive toxicology using chemometric tools can be very useful in order to fill the data gaps for ionic liquids (ILs) with limited available experimental toxicity information, in view of their growing industrial uses. Though originally promoted as green chemicals, ILs have now been shown to possess considerable toxicity against different ecological endpoints. Against this background, quantitative structure-activity relationship (QSAR) models have been developed here for the toxicity of ILs against the green algae Scenedesmus vacuolatus using computed descriptors with definite physicochemical meaning. The final models emerged from E-state indices, extended topochemical atom (ETA) indices and quantum topological molecular similarity (QTMS) indices. The developed partial least squares models support the established mechanism of toxicity of ionic liquids in terms of a surfactant action of cations and chaotropic action of anions. The models have been developed within the guidelines of the Organization of Economic Co-operation and Development (OECD) for regulatory QSAR models, and they have been validated both internally and externally using multiple strategies and also tested for applicability domain. A preliminary attempt has also been made, for the first time, to develop interspecies quantitative toxicity-toxicity relationship (QTTR) models for the algal toxicity of ILs with Daphnia toxicity, which should be interesting while predicting toxicity of ILs for an endpoint when the data for the other are available.

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

    Science.gov (United States)

    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

    2007-03-01

    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.

  1. [Primary peritonitis combined with streptococcal toxic shock syndrome following an upper respiratory tract infection caused by Streptococcus pyogenes].

    Science.gov (United States)

    Van Den Bossche, M J A; Devriendt, D; Weyne, L; Van Ranst, M

    2008-04-12

    A 52-year-old woman with no previous history of major health problems presented with an acute abdomen and symptoms of shock. Three days earlier she had been diagnosed as having acute laryngitis which was treated with steroids. On admission she was suffering from hypotension, renal failure, liver failure and coagulopathy. Emergency laparotomy revealed purulent fluid spread diffusely throughout the abdominal cavity. Streptococcus pyogenes was grown in culture from this fluid, enabling a diagnosis of streptococcal toxic shock syndrome (STSS) with primary peritonitis to be made. This combination is rare, and has been described only a few times. Only one other patient is known in whom this combination was preceded by respiratory symptoms. The treatment consists of abdominal lavage, intravenous administration of antibiotics and immunoglobulins, and support for renal function, liver function, respiration and coagulation.

  2. 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.

  3. 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.

  4. 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.

  5. Comparative respiratory toxicity of particles produced by traffic and sugar cane burning.

    Science.gov (United States)

    Mazzoli-Rocha, Flavia; Magalhães, Clarissa Bichara; Malm, Olaf; Saldiva, Paulo Hilário Nascimento; Zin, Walter Araujo; Faffe, Débora Souza

    2008-09-01

    The impact of particle emissions by biomass burning is increasing throughout the world. We explored the toxicity of particulate matter produced by sugar cane burning and compared these effects with equivalent mass of traffic-derived particles. For this purpose, BALB/c mice received a single intranasal instillation of either distilled water (C) or total suspended particles (15 microg) from an urban area (SP group) or biomass burning-derived particles (Bio group). Lung mechanical parameters (total, resistive and viscoelastic pressures, static elastance, and elastic component of viscoelasticity) and histology were analyzed 24h after instillation. Trace elements and polycyclic aromatic hydrocarbons (PAHs) metabolites of the two sources of particles were determined. All mechanical parameters increased similarly in both pollution groups compared with control, except airway resistive pressure, which increased only in Bio. Both exposed groups showed significantly higher fraction area of alveolar collapse, and influx of polymorphonuclear cells in lung parenchyma than C. The composition analysis of total suspended particles showed higher concentrations of PAHs and lower concentration of metals in traffic than in biomass burning-derived particles. In conclusion, we demonstrated that a single low dose of ambient particles, produced by traffic and sugar cane burning, induced significant alterations in pulmonary mechanics and lung histology in mice. Parenchymal changes were similar after exposure to both particle sources, whereas airway mechanics was more affected by biomass-derived particles. Our results indicate that biomass particles were at least as toxic as those produced by traffic.

  6. 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.

  7. Detection of severe respiratory disease epidemic outbreaks by CUSUM-based overcrowd-severe-respiratory-disease-index model.

    Science.gov (United States)

    Polanco, Carlos; 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.

  8. 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.

  9. [Development of human embryonic stem cell model for toxicity evaluation].

    Science.gov (United States)

    Yu, Guang-yan; Cao, Tong; Ouyang, Hong-wei; Peng, Shuang-qing; Deng, Xu-liang; Li, Sheng-lin; Liu, He; Zou, Xiao-hui; Fu, Xin; Peng, Hui; Wang, Xiao-ying; Zhan, Yuan

    2013-02-18

    The current international standard for toxicity screening of biomedical devices and materials recommend the use of immortalized cell lines because of their homogeneous morphologies and infinite proliferation which provide good reproducibility for in vitro cytotoxicity screening. However, most of the widely used immortalized cell lines are derived from animals and may not be representative of normal human cell behavior in vivo, in particular in terms of the cytotoxic and genotoxic response. Therefore, It is vital to develop a model for toxicity evaluation. In our studies, two Chinese human embryonic stem cell (hESC) lines as toxicity model were established. hESC derived tissue/organ cell model for tissue/organ specific toxicity evaluation were developed. The efficiency and accuracy of using hESC model for cytoxicity, embryotoxicity and genotoxicity evaluation were confirmed. The results indicated that hESCs might be good tools for toxicity testing and biosafety evaluation in vitro.

  10. Numerical stability analysis in respiratory control system models

    Directory of Open Access Journals (Sweden)

    Laszlo E. Kollar

    2005-04-01

    Full Text Available Stability of the unique equilibrium in two mathematical models (based on chemical balance dynamics of human respiration is examined using numerical methods. Due to the transport delays in the respiratory control system these models are governed by delay differential equations. First, a simplified two-state model with one delay is considered, then a five-state model with four delays (where the application of numerical methods is essential is investigated. In particular, software is developed to perform linearized stability analysis and simulations of the model equations. Furthermore, the Matlab package DDE-BIFTOOL v.~2.00 is employed to carry out numerical bifurcation analysis. Our main goal is to study the effects of transport delays on the stability of the model equations. Critical values of the transport delays (i.e., where Hopf bifurcations occur are determined, and stable periodic solutions are found as the delays pass their critical values. The numerical findings are in good agreement with analytic results obtained earlier for the two-state model.

  11. AIR TOXICS MODELING RESEARCH PROGRAM: AN OVERVIEW

    Science.gov (United States)

    This product is a Microsoft Powerpoint slide presentation which was given at the joint EPA Region 3 - Mid-Atlantic Regional Air Management Association (MARAMA) Air Toxic Summit in Philadelphia, Pennsylvania held from October 18, 2005 through October 20, 2005. The slide presentat...

  12. Multisite carcinogenicity and respiratory toxicity of inhaled 1-bromopropane in rats and mice.

    Science.gov (United States)

    Morgan, Daniel L; Nyska, Abraham; Harbo, Sam Jens; Grumbein, Sondra L; Dill, Jeffrey A; Roycroft, Joseph H; Kissling, Grace E; Cesta, Mark F

    2011-10-01

    Two-year 1-bromopropane (1-BP) inhalation studies were conducted because of the potential for widespread exposure, the lack of chronic toxicity and carcinogenicity data, and the known carcinogenicity of structurally related compounds. Male and female F344/N rats and B6C3F1/N mice were exposed by inhalation to 0, 62.5 (mice only), 125, 250, or 500 (rats only) ppm 1-BP for 6 hr/day, 5 days/week for 105 weeks. Exposure of male and female rats to 1-BP resulted in significantly increased incidences of adenomas of the large intestine and skin neoplasms. In male rats, the incidence of malignant mesothelioma of the epididymis was statistically significantly increased at 500 ppm, but the biological significance of this common lesion is unclear. Incidences of pancreatic islet adenoma in male rats were significantly increased at all concentrations relative to concurrent controls but were within the historical control range for inhalation studies. There was no evidence of carcinogenic activity of 1-BP in male B6C3F1 mice; however, significantly increased incidences of alveolar/bronchiolar neoplasms of the lung were present in female mice. Exposure to 1-BP also resulted in increased incidences of nonneoplastic lesions in the nose of rats and mice, the larynx of rats and male mice, the trachea of female rats and male and female mice, and the lungs of mice. Inflammatory lesions with Splendore Hoeppli (S-H) material were present primarily in the nose and skin of exposed male and female rats, indicating that 1-BP caused immunosuppression.

  13. Perinatal Lamb Model of Respiratory Syncytial Virus (RSV) Infection

    Science.gov (United States)

    Derscheid, Rachel J.; Ackermann, Mark R.

    2012-01-01

    Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models are used to study RSV, but most studies investigate disease in adult animals which does not address the unique physiology and immunology that makes infants more susceptible. The perinatal (preterm and term) lamb is a useful model of infant RSV disease as lambs have similar pulmonary structure including airway branching, Clara and type II cells, submucosal glands and Duox/lactoperoxidase (LPO) oxidative system, and prenatal alveologenesis. Lambs can be born preterm (90% gestation) and survive for experimentation although both preterm and term lambs are susceptible to ovine, bovine and human strains of RSV and develop clinical symptoms including fever, tachypnea, and malaise as well as mild to moderate gross and histologic lesions including bronchiolitis with epithelial injury, neutrophil infiltration and syncytial cell formation. RSV disease in preterm lambs is more severe than in term lambs; disease is progressively less in adults and age-dependent susceptibility is a feature similar to humans. Innate and adaptive immune responses by perinatal lambs closely parallel those of infants. The model is used to test therapeutic regimens, risk factors such as maternal ethanol consumption, and formalin inactivated RSV vaccines. PMID:23202468

  14. Perinatal Lamb Model of Respiratory Syncytial Virus (RSV Infection

    Directory of Open Access Journals (Sweden)

    Mark R. Ackermann

    2012-10-01

    Full Text Available Respiratory syncytial virus (RSV is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models are used to study RSV, but most studies investigate disease in adult animals which does not address the unique physiology and immunology that makes infants more susceptible. The perinatal (preterm and term lamb is a useful model of infant RSV disease as lambs have similar pulmonary structure including airway branching, Clara and type II cells, submucosal glands and Duox/lactoperoxidase (LPO oxidative system, and prenatal alveologenesis. Lambs can be born preterm (90% gestation and survive for experimentation although both preterm and term lambs are susceptible to ovine, bovine and human strains of RSV and develop clinical symptoms including fever, tachypnea, and malaise as well as mild to moderate gross and histologic lesions including bronchiolitis with epithelial injury, neutrophil infiltration and syncytial cell formation. RSV disease in preterm lambs is more severe than in term lambs; disease is progressively less in adults and age-dependent susceptibility is a feature similar to humans. Innate and adaptive immune responses by perinatal lambs closely parallel those of infants. The model is used to test therapeutic regimens, risk factors such as maternal ethanol consumption, and formalin inactivated RSV vaccines.

  15. Interspecies Extrapolations of Halocarbon Respiratory and Tissue Kinetics: Applications to Predicting Toxicity in Different Species.

    Science.gov (United States)

    1992-09-04

    Press. 1970 2. Spector, W.S. Handbook of Biological data. Philadelphia, Saunders. 1956 3. Gross. D.R. Animal models in cardiovascular research. Boston...carcinogen. Thus, investigations uti- have resulted in cardiac arrl ’.>ahmms and in lizing laboratory. =nimals must be largely relied central nernous system

  16. Experimental models of the respiratory distress syndrome : lavage and oleic acid

    NARCIS (Netherlands)

    R.M. van der Heijde (Roos); H.P. Grotjohan (Hans)

    1992-01-01

    textabstractSo far the existing animal models have a lack of long lasting stability. Hardly any attention was paid to standardization of the induction of respiratory distress. We aimed at models in which the individual animals have a comparable respiratory distress for several hours to obtain the op

  17. Characterization of a developmental toxicity dose-response model.

    OpenAIRE

    Faustman, E M; Wellington, D G; Smith, W P; Kimmel, C A

    1989-01-01

    The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included ...

  18. A Bidirectional Coupling Procedure Applied to Multiscale Respiratory Modeling.

    Science.gov (United States)

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

  19. A bidirectional coupling procedure applied to multiscale respiratory modeling

    Science.gov (United States)

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

  20. Xenograft model for therapeutic drug testing in recurrent respiratory papillomatosis.

    Science.gov (United States)

    Ahn, Julie; Bishop, Justin A; Akpeng, Belinda; Pai, Sara I; Best, Simon R A

    2015-02-01

    Identifying effective treatment for papillomatosis is limited by a lack of animal models, and there is currently no preclinical model for testing potential therapeutic agents. We hypothesized that xenografting of papilloma may facilitate in vivo drug testing to identify novel treatment options. A biopsy of fresh tracheal papilloma was xenografted into a NOD-scid-IL2Rgamma(null) (NSG) mouse. The xenograft began growing after 5 weeks and was serially passaged over multiple generations. Each generation showed a consistent log-growth pattern, and in all xenografts, the presence of the human papillomavirus (HPV) genome was confirmed by polymerase chain reaction (PCR). Histopathologic analysis demonstrated that the squamous architecture of the original papilloma was maintained in each generation. In vivo drug testing with bevacizumab (5 mg/kg i.p. twice weekly for 3 weeks) showed a dramatic therapeutic response compared to saline control. We report here the first successful case of serial xenografting of a tracheal papilloma in vivo with a therapeutic response observed with drug testing. In severely immunocompromised mice, the HPV genome and squamous differentiation of the papilloma can be maintained for multiple generations. This is a feasible approach to identify therapeutic agents in the treatment of recurrent respiratory papillomatosis. © The Author(s) 2014.

  1. Polymorphisms in the mitochondrial ribosome recycling factor EF-G2mt/MEF2 compromise cell respiratory function and increase atorvastatin toxicity.

    Directory of Open Access Journals (Sweden)

    Sylvie Callegari

    Full Text Available Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.

  2. 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.

  3. A respiratory model for uranium aluminide based on occupational data.

    Science.gov (United States)

    Leggett, R W; Eckerman, K F; Boice, J D

    2005-12-01

    As part of an epidemiological study, doses from intake of radionuclides were estimated for workers employed during a 52-year period at the Rocketdyne/Atomics International facility in California. The facility was involved in a variety of research programmes, including nuclear fuel fabrication, spent nuclear fuel decladding, and reactor operation and disassembly. Most of the documented intakes involved inhalation of enriched uranium (U), fission products, or plutonium (Pu). Highest doses were estimated for a group of workers exposed to airborne uranium aluminide (UAl(x)) during the fabrication of reactor fuel plates. Much of the exposure to UAl(x) occurred early in the fuel fabrication programme, before it was recognised that intake and lung retention were being underestimated from urinary data due to an unexpected delayed dissolution of the inhaled material. In workers who had been removed from exposure, the rate of urinary excretion of U increased for a few months, peaked, and then declined at a rate consistent with moderately soluble material. This pattern differs markedly from the monotonically decreasing absorption rates represented by the default absorption types in the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection (ICRP). This paper summarises the findings on the behaviour of UAl(x) in these workers and describes material-specific parameter values of the HRTM based on this information.

  4. 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.

  5. Understanding Emerging Zoonotic Respiratory Viruses : Animal models for human influenza and coronavirus infections

    NARCIS (Netherlands)

    L.C.M. Wiersma (Lidewij)

    2016-01-01

    markdownabstractThe objective of the work presented in this thesis was to improve understanding of, and response to, emerging zoonotic respiratory viruses. To this end, various animal models were employed to represent respiratory viral infections in humans. The introduction serves to provide a backg

  6. The Revised International Commission on Radiological Protection (ICRP) dosimetric model for the human respiratory tract

    Energy Technology Data Exchange (ETDEWEB)

    Bair, W.J.

    1991-09-01

    The new respiratory tract model is based on the premise that the large differences in radiation sensitivity of respiratory tract tissues, and the wide range of doses they receive, argue for calculating specific tissue doses rather than average lung doses for radiation protection purposes. The new model is more complex than the current lung model because it describes deposition of inhaled radioactive material in the clearance from several tissues and regions of the respiratory tract and is applicable to the worldwide population of both workers and the public. 2 refs., 2 figs.

  7. Respiratory dysfunction and proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis.

    Science.gov (United States)

    Bonville, Cynthia A; Bennett, Nicholas J; Koehnlein, Melissa; Haines, Deborah M; Ellis, John A; DelVecchio, Alfred M; Rosenberg, Helene F; Domachowske, Joseph B

    2006-05-25

    We explore relationships linking clinical symptoms, respiratory dysfunction, and local production of proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis. With a reduced inoculum of this natural rodent pathogen, we observe virus clearance by day 9, while clinical symptoms and respiratory dysfunction persist through days 14 and 17 postinoculation, respectively. Via microarray and ELISA, we identify expression profiles of proinflammatory mediators MIP-1alpha, MCP-1, and MIP-2 that correlate with persistent respiratory dysfunction. MIP-1alpha is localized in bronchial epithelium, which is also the major site of PVM replication. Interferon-gamma was detected in lung tissue, but at levels that do not correlate with respiratory dysfunction. Taken together, we present a modification of our pneumovirus infection model that results in improved survival and data that stand in support of a connection between local production of specific mediators and persistent respiratory dysfunction in the setting of acute viral bronchiolitis.

  8. 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.

  9. Literature Review of (Q)SAR Modelling of Nanomaterial Toxicity.

    Science.gov (United States)

    Oksel, Ceyda; Ma, Cai Y; Liu, Jing J; Wilkins, Terry; Wang, Xue Z

    2017-01-01

    Despite the clear benefits that nanotechnology can bring to various sectors of industry, there are serious concerns about the potential health risks associated with engineered nanomaterials (ENMs), intensified by the limited understanding of what makes ENMs toxic and how to make them safe. As the use of ENMs for commercial purposes and the number of workers/end-users being exposed to these materials on a daily basis increases, the need for assessing the potential adverse effects of multifarious ENMs in a time- and cost-effective manner becomes more apparent. One strategy to alleviate the problem of testing a large number and variety of ENMs in terms of their toxicological properties is through the development of computational models that decode the relationships between the physicochemical features of ENMs and their toxicity. Such data-driven models can be used for hazard screening, early identification of potentially harmful ENMs and the toxicity-governing physicochemical properties, and accelerating the decision-making process by maximising the use of existing data. Moreover, these models can also support industrial, regulatory and public needs for designing inherently safer ENMs. This chapter is mainly concerned with the investigation of the applicability of (quantitative) structure-activity relationship ((Q)SAR) methods to modelling of ENMs' toxicity. It summarizes the key components required for successful application of data-driven toxicity prediction techniques to ENMs, the published studies in this field and the current limitations of this approach.

  10. The revised International Commission on Radiological Protection (ICRP) dosimetric model for the human respiratory tract

    Energy Technology Data Exchange (ETDEWEB)

    Bair, W.J.

    1992-05-01

    A task group has revised the dosimetric model of the respiratory tract used to calculate annual limits on intake of radionuclides. The revised model can be used to project respiratory tract doses for workers and members of the public from airborne radionuclides and to assess past exposures. Doses calculated for specific extrathoracic and thoracic tissues can be adjusted to account for differences in radiosensitivity and summed to yield two values of dose for the respiratory tract that are applicable to the ICRP tissue weighted dosimetry system.

  11. 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

  12. 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.

  13. Total liquid ventilation provides superior respiratory support to conventional mechanical ventilation in a large animal model of severe respiratory failure.

    Science.gov (United States)

    Pohlmann, Joshua R; Brant, David O; Daul, Morgan A; Reoma, Junewai L; Kim, Anne C; Osterholzer, Kathryn R; Johnson, Kent J; Bartlett, Robert H; Cook, Keith E; Hirschl, Ronald B

    2011-01-01

    Total liquid ventilation (TLV) has the potential to provide respiratory support superior to conventional mechanical ventilation (CMV) in the acute respiratory distress syndrome (ARDS). However, laboratory studies are limited to trials in small animals for no longer than 4 hours. The objective of this study was to compare TLV and CMV in a large animal model of ARDS for 24 hours. Ten sheep weighing 53 ± 4 (SD) kg were anesthetized and ventilated with 100% oxygen. Oleic acid was injected into the pulmonary circulation until PaO2:FiO2 ≤ 60 mm Hg, followed by transition to a protective CMV protocol (n = 5) or TLV (n = 5) for 24 hours. Pathophysiology was recorded, and the lungs were harvested for histological analysis. Animals treated with CMV became progressively hypoxic and hypercarbic despite maximum ventilatory support. Sheep treated with TLV maintained normal blood gases with statistically greater PO2 (p < 10(-9)) and lower PCO2 (p < 10(-3)) than the CMV group. Survival at 24 hours in the TLV and CMV groups were 100% and 40%, respectively (p < 0.05). Thus, TLV provided gas exchange superior to CMV in this laboratory model of severe ARDS.

  14. A study of IOS data using two mead-related models of respiratory impedance.

    Science.gov (United States)

    Nguyen, T-U; Diong, B; Nazeran, H; Goldman, M

    2007-01-01

    This paper introduces two new respiratory system models, the Mead-Cw model and the Mead-Cl model, which are 6-component models that are intermediate in complexity between the well-known 7-component Mead model and the recently proposed 5-component augmented RIC model (derived from the Mead model by eliminating both Cw and Cl). Their modeling errors were compared to the RIC, extended RIC, augmented RIC and Mead models, for component values estimated from IOS data. The two new models yielded lower errors than all the other models, except for the Mead model. However, the Mead-Cl model and the Mead-Cw model also yielded unreasonably large values for Cw and Cl, respectively, which are known disadvantages of the Mead model. Hence the augmented RIC model appears to be the most useful at present for IOS-based computer-aided detection and diagnosis of respiratory disorders.

  15. Interspecies quantitative structure-toxicity-toxicity (QSTTR) relationship modeling of ionic liquids. Toxicity of ionic liquids to V. fischeri, D. magna and S. vacuolatus.

    Science.gov (United States)

    Das, Rudra Narayan; Roy, Kunal; Popelier, Paul L A

    2015-12-01

    Considering the increasing uses of ionic liquids (ILs) in various industrial processes and chemical engineering operations, a complete assessment of their hazardous profile is essential. In the absence of adequate experimental data, in silico modeling might be helpful in filling data gaps for the toxicity of ILs towards various ecological indicator organisms. Using the rationale of taxonomic relatedness, the development of predictive quantitative structure-toxicity-toxicity relationship (QSTTR) models allows predicting the toxicity of ILs to a particular species using available experimental toxicity data towards a different species. Such studies may employ, along with the available experimental toxicity data to a species, molecular structure features and physicochemical properties of chemicals as independent variables for prediction of the toxicity profile against another closely related species. A few such interspecies toxicity correlation models have been reported in the literature for diverse chemicals in general, but this approach has been rarely applied to the class of ionic liquids. The present study involves the use of IL toxicity data towards the bacteria Vibrio fischeri along with molecular structure derived information or computational descriptors like extended topochemical atom (ETA) indices, quantum topological molecular similarity (QTMS) descriptors and computed lipophilicity measure (logk0) for the interspecies exploration of the toxicity data towards green algae S. vacuolatus and crustacea Daphnia magna, separately. This modeling study has been performed in accordance with the OECD guidelines. Finally, predictions for a true external set have been performed to fill the data gap of toxicity towards daphnids and algae using the Vibrio toxicity data and molecular structure attributes.

  16. Modeling toxic compounds from nitric oxide emission measurements

    Science.gov (United States)

    Vallero, Daniel A.; Peirce, Jeffrey; Cho, Ki Don

    Determining the amount and rate of degradation of toxic pollutants in soil and groundwater is difficult and often requires invasive techniques, such as deploying extensive monitoring well networks. Even with these networks, degradation rates across entire systems cannot readily be extrapolated from the samples. When organic compounds are degraded by microbes, especially nitrifying bacteria, oxides or nitrogen (NO x) are released to the atmosphere. Thus, the flux of nitric oxide (NO) from the soil to the lower troposphere can be used to predict the rate at which organic compounds are degraded. By characterizing and applying biogenic and anthropogenic processes in soils the rates of degradation of organic compounds. Toluene was selected as a representative of toxic aromatic compounds, since it is inherently toxic, it is a substituted benzene compound and is listed as a hazardous air pollutant under Section 12 of the Clean Air Act Amendments of 1990. Measured toluene concentrations in soil, microbial population growth and NO fluxes in chamber studies were used to develop and parameterize a numerical model based on carbon and nitrogen cycling. These measurements, in turn, were used as indicators of bioremediation of air toxic (i.e. toluene) concentrations. The model found that chemical concentration, soil microbial abundance, and NO production can be directly related to the experimental results (significant at P hydrocarbons and oxides of nitrogen. As such, the model may be a tool for decision makers in ozone non-attainment areas.

  17. A Bayesian network model for predicting aquatic toxicity mode ...

    Science.gov (United States)

    The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action 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 data set with the MoA broad classifications as a target node. From cross validation, the overall precision for the model was 80.2% with a R2 of 0.959. 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

  18. The chemical exposure toxicity space (CETS) model: Displaying exposure time, aqueous and organic concentration, activity, and onset of toxicity

    Science.gov (United States)

    Mackay, Donald; Parnis, J. Mark; McCarty, Lynn S.; Arnot, Jon A.; Powell, David E.

    2016-01-01

    Abstract A 1‐compartment toxicokinetic model is used to characterize the chemical exposure toxicity space (CETS), providing a novel graphic tool that can aid in the design of aquatic toxicity tests for fish and for interpreting their results. The graph depicts the solution to the differential equation describing the uptake kinetics of a chemical by a modeled fish under conventional bioassay conditions. The model relates the exposure concentration in the water to a dimensionless time and the onset of toxicity as determined by an estimated or assumed critical body residue or incipient lethal aqueous concentration. These concentration graphs are specific to each chemical and exposure and organism parameters and clearly demonstrate differences in toxicity between chemicals and how factors such as hydrophobicity influence the toxic endpoint. The CETS plots can also be used to assess bioconcentration test conditions to ensure that concentrations are well below toxic levels. Illustrative applications are presented using a recent set of high‐quality toxicity data. Conversion of concentrations to chemical activities in the plots enables results for different baseline toxicants to be superimposed. For chemicals that have different modes of toxic action, the increased toxicity then becomes apparent. Implications for design and interpretation of aquatic toxicity tests are discussed. The model, and pictorial visualization of the time‐course of aquatic toxicity tests, may contribute to improvements in test design, implementation, and interpretation, and to reduced animal usage. Environ Toxicol Chem 2017;36:1389–1396. © 2016 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC. PMID:27801500

  19. Chemical Reactivity and Respiratory Toxicity of the α-Diketone Flavoring Agents: 2,3-Butanedione, 2,3-Pentanedione, and 2,3-Hexanedione.

    Science.gov (United States)

    Morgan, Daniel L; Jokinen, Micheal P; Johnson, Crystal L; Price, Herman C; Gwinn, William M; Bousquet, Ronald W; Flake, Gordon P

    2016-07-01

    Occupational exposure to 2,3-butanedione (BD) vapors has been associated with severe respiratory disease leading to the use of potentially toxic substitutes. We compared the reactivity and respiratory toxicity of BD with that of two structurally related substitutes, 2,3-pentanedione (PD) and 2,3-hexanedione (HD). Chemical reactivity of the diketones with an arginine substrate decreased with increasing chain length (BD > PD > HD). Animals were evaluated the morning after a 2-week exposure to 0, 100, 150, or 200 ppm BD, PD, or HD (postexposure) or 2 weeks later (recovery). Bronchial fibrosis was observed in 5/5 BD and 5/5 PD rats at 200 ppm and in 4/6 BD and 6/6 PD rats at 150 ppm in the postexposure groups. Following recovery, bronchial fibrosis was observed in all surviving rats exposed to 200 ppm BD (5/5) or PD (3/3) and in 2/10 BD and 7/9 PD rats exposed to 150 ppm. Bronchial fibrosis was observed only in 2/12 HD-exposed rats in the 200 ppm postexposure group. Patchy interstitial fibrosis affected lungs of recovery groups exposed to 200 ppm PD (3/3) or BD (1/5) and to 150 ppm PD (4/9) or BD (7/10) and correlated with pulmonary function deficits. BD and PD were more reactive and produced more bronchial fibrosis than HD. © The Author(s) 2016.

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

    OpenAIRE

    Petrica-Adrian Panaite; Thierry Kuntzer; Geneviève Gourdon; Johannes Alexander Lobrinus; Ibtissam Barakat-Walter

    2013-01-01

    SUMMARY 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 p...

  1. 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.

  2. [Amphibians as a model system for the investigation of respiratory control development].

    Science.gov (United States)

    Belzile, Olivier; Simard, Edith; Gulemetova, Roumiana; Bairam, Aida; Kinkead, Richard

    2004-10-01

    Recent medical advances have made it possible for babies to survive premature birth at increasingly earlier developmental stages. This population requires costly and sophisticated medical care to address the problems associated with immaturity of the respiratory system. In addition to pulmonary complications, respiratory instability and apnea reflecting immaturity of the respiratory control system are major causes of hospitalization and morbidity in this highly vulnerable population. These medical concerns, combined with the curiosity of physiologists, have contributed to the expansion of research in respiratory neurobiology. While most researchers working in this field commonly use rodents as an animal model, recent research using in vitro brainstem preparation from bullfrogs (Rana catesbeiana) have revealed the technical advantages of this animal model, and shown that the basic principles underlying respiratory control and its ontogeny are very similar between these two groups of vertebrates. The present review highlights the recent advances in the area of research with a focus on intermittent (episodic) breathing and the role of serotonergic and GABAergic modulation of respiratory activity during development.

  3. Genetic variance of tolerance and the toxicant threshold model.

    Science.gov (United States)

    Tanaka, Yoshinari; Mano, Hiroyuki; Tatsuta, Haruki

    2012-04-01

    A statistical genetics method is presented for estimating the genetic variance (heritability) of tolerance to pollutants on the basis of a standard acute toxicity test conducted on several isofemale lines of cladoceran species. To analyze the genetic variance of tolerance in the case when the response is measured as a few discrete states (quantal endpoints), the authors attempted to apply the threshold character model in quantitative genetics to the threshold model separately developed in ecotoxicology. The integrated threshold model (toxicant threshold model) assumes that the response of a particular individual occurs at a threshold toxicant concentration and that the individual tolerance characterized by the individual's threshold value is determined by genetic and environmental factors. As a case study, the heritability of tolerance to p-nonylphenol in the cladoceran species Daphnia galeata was estimated by using the maximum likelihood method and nested analysis of variance (ANOVA). Broad-sense heritability was estimated to be 0.199 ± 0.112 by the maximum likelihood method and 0.184 ± 0.089 by ANOVA; both results implied that the species examined had the potential to acquire tolerance to this substance by evolutionary change.

  4. Reactor modeling in heterogeneous photocatalysis: toxicity and biodegradability assessment.

    Science.gov (United States)

    Satuf, M L; José, S; Paggi, J C; Brandi, R J; Cassano, A E; Alfano, O M

    2010-01-01

    Photocatalysis employing titanium dioxide is a useful method to degrade a wide variety of organic and inorganic pollutants from water and air. However, the application of this advanced oxidation process at industrial scale requires the development of mathematical models to design and scale-up photocatalytic reactors. In the present work, intrinsic kinetic expressions previously obtained in a laboratory reactor are employed to predict the performance of a bench scale reactor of different configuration and operating conditions. 4-Chlorophenol was chosen as the model pollutant. The toxicity and biodegradability of the irradiated mixture in the bench photoreactor was also assessed. Good agreement was found between simulation and experimental data. The root mean square error of the estimations was 9.9%. The photocatalytic process clearly enhances the biodegradability of the reacting mixture, and the initial toxicity of the pollutant was significantly reduced by the treatment.

  5. A Structural Modelling Study on Marine Sediments Toxicity

    Directory of Open Access Journals (Sweden)

    Sorana D. Bolboacă

    2008-06-01

    Full Text Available Quantitative structure-activity relationship models were obtained by applying the Molecular Descriptor Family approach to eight ordnance compounds with different toxicity on five marine species (arbacia punctulata, dinophilus gyrociliatus, sciaenops ocellatus, opossum shrimp, and ulva fasciata. The selection of the best among molecular descriptors generated and calculated from the ordnance compounds structures lead to accurate monovariate models. The resulting models obtained for six endpoints proved to be accurate in estimation (the squared correlation coefficient varied from 0.8186 to 0.9997 and prediction (the correlation coefficient obtained in leave-one-out analysis varied from 0.7263 to 0.9984.

  6. Adaptive modelling of structured molecular representations for toxicity prediction

    Science.gov (United States)

    Bertinetto, Carlo; Duce, Celia; Micheli, Alessio; Solaro, Roberto; Tiné, Maria Rosaria

    2012-12-01

    We investigated the possibility of modelling structure-toxicity relationships by direct treatment of the molecular structure (without using descriptors) through an adaptive model able to retain the appropriate structural information. With respect to traditional descriptor-based approaches, this provides a more general and flexible way to tackle prediction problems that is particularly suitable when little or no background knowledge is available. Our method employs a tree-structured molecular representation, which is processed by a recursive neural network (RNN). To explore the realization of RNN modelling in toxicological problems, we employed a data set containing growth impairment concentrations (IGC50) for Tetrahymena pyriformis.

  7. Modeling the deposition of bioaerosols with variable size and shape in the human respiratory tract – A review

    Directory of Open Access Journals (Sweden)

    R. Sturm

    2012-10-01

    Full Text Available The behavior of bioaerosol particles with various size and shape in the human respiratory tract was simulated by using a probabilistic model of the lung and an almost realistic mathematical approach to particle deposition. Results obtained from the theoretical computations clearly show that biogenic particle deposition in different lung compartments does not only depend on physical particle properties, but also on breathing mode (nose or mouth breathing and inhalative flow rate (=tidal volume × breathing frequency/30. Whilst ultrafine (5 μm particles tend to accumulate in the extrathoracic region and the uppermost airways of the tracheobronchial tree, particles with intermediate size are characterized by higher penetration depth, leading to their possible accumulation in the lung alveoli. Due to their deposition in deep lung regions and insufficient clearance, some bioaerosol particles may induce severe lung diseases ranging from infections, allergies, and toxic reactions to cancer.

  8. 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.

  9. A test of syndromic surveillance using a severe acute respiratory syndrome model.

    Science.gov (United States)

    Wallace, David J; Arquilla, Bonnie; Heffernan, Richard; Kramer, Martin; Anderson, Todd; Bernstein, David; Augenbraun, Michael

    2009-05-01

    We describe a field simulation that was conducted using volunteers to assess the ability of 3 hospitals in a network to manage a large influx of patients with a potentially communicable disease. This drill provided the opportunity to evaluate the ability of the New York City Department of Health and Mental Hygiene's (NYC-DOHMH) emergency department chief complaint syndromic surveillance system to detect a cluster of patients with febrile respiratory illness. The evaluation was a prospective simulation. The clinical picture was modeled on severe acute respiratory syndrome symptoms. Forty-four volunteers participated in the drill as mock patients. Records from 42 patients (95%) were successfully transmitted to the NYC-DOHMH. The electronic chief complaint for 24 (57%) of these patients indicated febrile or respiratory illness. The drill did not generate a statistical signal in the NYC-DOHMH SaTScan analysis. The 42 drill patients were classified in 8 hierarchical categories based on chief complaints: sepsis (2), cold (3), diarrhea (2), respiratory (20), fever/flu (4), vomit (3), and other (8). The number of respiratory visits, while elevated on the day of the drill, did not appear particularly unusual when compared with the 14-day baseline period used for spatial analyses. This drill with a cluster of patients with febrile respiratory illness failed to trigger a signal from the NYC-DOHMH emergency department chief complaint syndromic surveillance system. This highlighted several limitations and challenges to syndromic surveillance monitoring.

  10. Toxicity of food-relevant nanoparticles in intestinal epithelial models

    Science.gov (United States)

    McCracken, Christie

    Nanoparticles are increasingly being incorporated into common consumer products, including in foods and food packaging, for their unique properties at the nanoscale. Food-grade silica and titania are used as anti-caking and whitening agents, respectively, and these particle size distributions are composed of approximately one-third nanoparticles. Zinc oxide and silver nanoparticles can be used for their antimicrobial properties. However, little is known about the interactions of nanoparticles in the body upon ingestion. This study was performed to investigate the role of nanoparticle characteristics including surface chemistry, dissolution, and material type on toxicity to the intestinal epithelium. Only mild acute toxicity of zinc oxide nanoparticles was observed after 24-hour treatment of intestinal epithelial C2BBe1 cells based on the results of toxicity assays measuring necrosis, apoptosis, membrane damage, and mitochondrial activity. Silica and titanium dioxide nanoparticles were not observed to be toxic although all nanoparticles were internalized by cells. In vitro digestion of nanoparticles in solutions representing the stomach and intestines prior to treatment of cells did not alter nanoparticle toxicity. Long-term repeated treatment of cells weekly for 24 hours with nanoparticles did not change nanoparticle cytotoxicity or the growth rate of the treated cell populations. Thus, silica, titanium dioxide, and zinc oxide nanoparticles were found to induce little toxicity in intestinal epithelial cells. Fluorescent silica nanoparticles were synthesized as a model for silica used in foods that could be tracked in vitro and in vivo. To maintain an exterior of pure silica, a silica shell was hydrolyzed around a core particle of quantum dots or a fluorescent dye electrostatically associated with a commercial silica particle. The quantum dots used were optimized from a previously reported microwave quantum dot synthesis to a quantum yield of 40%. Characterization

  11. 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.

  12. 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.

  13. Baseline toxicity and ion-trapping models to describe the pH-dependence of bacterial toxicity of pharmaceuticals.

    Science.gov (United States)

    Baumer, Andreas; Bittermann, Kai; Klüver, Nils; Escher, Beate I

    2017-07-19

    In numerous studies on the toxicity of ionisable organic chemicals, it has been shown that the toxicity was typically higher, when larger fractions of the neutral species were present. This observation was explained in some cases by slower uptake of charged species. In other cases it was suggested that the neutral species has intrinsically higher toxicity than the charged species or is alone responsible for the toxicity. However, even permanently charged and organic chemicals with multiple acid and base functional groups and zwitterions are toxic. We set out to reconcile the divergent views and to compare the various existing models for describing the pH-dependence of toxicity with the goal to derive one model that is valid independent of the type and number of charges on the molecule. To achieve this goal we measured the cytotoxicity of 18 acidic, 15 basic and 9 multiprotic/zwitterionic pharmaceuticals at pH 5.5 to pH 9 with the bioluminescence inhibition test using Aliivibrio fischeri (Microtox assay). This assay is useful for an evaluation of various models to describe pH-dependent toxicity because the majority of chemicals act as baseline toxicants in this 30 min cytotoxicity assay. Therefore baseline toxicity with constant membrane concentrations of the sum of all chemical species of approximately 200 mmol kglip(-1) served for the validation of the suitability of the various tested models. We confirmed that most tested pharmaceuticals acted as baseline toxicants in this assay at all examined pH values, when toxicity was modeled with a mixture model of concentration addition between the neutral species and all charged species. An ion trapping model, that assumes that the membrane permeability of charged species is kinetically limited, improved model predictions for some pharmaceuticals and pH values. However, neither unhindered uptake nor no uptake of the charged species were ideal models; the reality lies presumably between the two limiting cases with a slower

  14. 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.

  15. 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 ...

  16. High content analysis of an in vitro model for metabolic toxicity: results with the model toxicants 4-aminophenol and cyclophosphamide.

    Science.gov (United States)

    Cole, Stephanie D; Madren-Whalley, Janna S; Li, Albert P; Dorsey, Russell; Salem, Harry

    2014-12-01

    In vitro models that accurately and rapidly assess hepatotoxicity and the effects of hepatic metabolism on nonliver cell types are needed by the U.S. Department of Defense and the pharmaceutical industry to screen compound libraries. Here, we report the first use of high content analysis on the Integrated Discrete Multiple Organ Co-Culture (IdMOC) system, a high-throughput method for such studies. We cultured 3T3-L1 cells in the presence and absence of primary human hepatocytes, and exposed the cultures to 4-aminophenol and cyclophosphamide, model toxicants that are respectively detoxified and activated by the liver. Following staining with calcein-AM, ethidium homodimer-1, and Hoechst 33342, high content analysis of the cultures revealed four cytotoxic endpoints: fluorescence intensities of calcein-AM and ethidium homodimer-1, nuclear area, and cell density. Using these endpoints, we observed that the cytotoxicity of 4-aminophenol in 3T3-L1 cells in co-culture was less than that observed for 3T3-L1 monocultures, consistent with the known detoxification of 4-aminophenol by hepatocytes. Conversely, cyclophosphamide cytotoxicity for 3T3-L1 cells was enhanced by co-culturing with hepatocytes, consistent with the known metabolic activation of this toxicant. The use of IdMOC plates combined with high content analysis is therefore a multi-endpoint, high-throughput capability for measuring the effects of metabolism on toxicity.

  17. PABPN1 suppresses TDP-43 toxicity in ALS disease models

    Science.gov (United States)

    Chou, Ching-Chieh; Alexeeva, Olga M.; Yamada, Shizuka; Pribadi, Amy; Zhang, Yi; Mo, Bi; Williams, Kathryn R.; Zarnescu, Daniela C.; Rossoll, Wilfried

    2015-01-01

    TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins. PMID:26130692

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

    Science.gov (United States)

    Katalan, Shahaf; Falach, Reut; Rosner, Amir; Goldvaser, Michael; Brosh-Nissimov, Tal; Dvir, Ayana; Mizrachi, Avi; Goren, Orr; Cohen, Barak; Gal, Yoav; Sapoznikov, Anita; Ehrlich, Sharon; Kronman, Chanoch

    2017-01-01

    ABSTRACT 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. PMID:28067630

  19. 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.

  20. Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene.

    Science.gov (United States)

    Kovalchuk, Nataliia; Kelty, Jacklyn; Li, Lei; Hartog, Matthew; Zhang, Qing-Yu; Edwards, Patricia; Van Winkle, Laura; Ding, Xinxin

    2017-08-15

    We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm. Despite the large increase in circulating and lung tissue NA levels, the level of NA-GSH, a biomarker of NA bioactivation, was either not different, or only slightly higher, in lung and liver tissues of LCN mice, relative to that in WT mice. Furthermore, the extent of NA-induced acute airway injury, judging from high-resolution lung histopathology and morphometry at 20h following NA exposure, was not higher, but lower, in LCN than in WT mice. These results, while confirming the ability of extrahepatic organ to bioactivate inhaled NA and mediate NA's lung toxicity, suggest that liver P450-generated NA metabolites also have a significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Online estimation of respiratory mechanics in non-invasive pressure support ventilation: a bench model study.

    Science.gov (United States)

    Mulqueeny, Qestra; Tassaux, Didier; Vignaux, Laurence; Jolliet, Philippe; Schindhelm, Klaus; Redmond, Stephen; Lovell, Nigel H

    2010-01-01

    An online algorithm for determining respiratory mechanics in patients using non-invasive ventilation (NIV) in pressure support mode was developed and embedded in a ventilator system. Based on multiple linear regression (MLR) of respiratory data, the algorithm was tested on a patient bench model under conditions with and without leak and simulating a variety of mechanics. Bland-Altman analysis indicates reliable measures of compliance across the clinical range of interest (± 11-18% limits of agreement). Resistance measures showed large quantitative errors (30-50%), however, it was still possible to qualitatively distinguish between normal and obstructive resistances. This outcome provides clinically significant information for ventilator titration and patient management.

  2. Construction of kidney phantom model with acoustic shadow by rib bones and respiratory organ motion

    Science.gov (United States)

    Lee, Dongjun; Koizumi, Norihiro; Tsukihara, Hiroyuki; Azuma, Takashi; Nomiya, Akira; Yoshinaka, Kiyoshi; Sugita, Naohiko; Homma, Yukio; Matsumoto, Yoichiro; Mitsuishi, Mamoru

    2017-03-01

    We have been studying the Non-Invasive Ultrasound Theragnostic System (NIUTS), which tracks and follows the affected area while irradiating High Intensity Focused Ultrasound (HIFU). In this report, we propose a phantom model that includes rib bones and respiratory motion.

  3. 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 BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide.

  4. STABILITY AND BIFURCATION OF A HUMAN RESPIRATORY SYSTEM MODEL WITH TIME DELAY

    Institute of Scientific and Technical Information of China (English)

    沈启宏; 魏俊杰

    2004-01-01

    The stability and bifurcation of the trivial solution in the two-dimensional differential equation of a model describing human respiratory system with time delay were investigated. Formulas about the stability of bifurcating periodic solution and the direction of Hopf bifurcation were exhibited by applying the normal form theory and the center manifold theorem. Furthermore, numerical simulation was carried out.

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

    Science.gov (United States)

    Nithiarasu, Perumal; Sazonov, Igor

    2016-11-24

    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.

  6. POPULATION EXPOSURE AND DOSE MODEL FOR AIR TOXICS: A BENZENE CASE STUDY

    Science.gov (United States)

    The EPA's National Exposure Research Laboratory (NERL) is developing a human exposure and dose model called the Stochastic Human Exposure and Dose Simulation model for Air Toxics (SHEDS-AirToxics) to characterize population exposure to air toxics in support of the National Air ...

  7. MOAtox: A Comprehensive Mode of Action and Acute Aquatic Toxicity Database for Predictive Model Development

    Science.gov (United States)

    tThe mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity andas an alternative to chemical class-based predictive toxicity modeling. However, the development ofquantitative structure activity relationship (QSAR) and other models has been limite...

  8. 40 CFR Table 4 to Subpart Dddd of... - Model Rule-Toxic Equivalency Factors

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 6 2010-07-01 2010-07-01 false Model Rule-Toxic Equivalency Factors 4... or Before November 30, 1999 Pt. 60, Subpt. DDDD, Table 4 Table 4 to Subpart DDDD of Part 60—Model Rule—Toxic Equivalency Factors Dioxin/furan congener Toxic equivalency factor 2,3,7,8-tetrachlorinated...

  9. 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

  10. 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

  11. A joint computational respiratory neural network-biomechanical model for breathing and airway defensive behaviors

    Directory of Open Access Journals (Sweden)

    Russell eO'Connor

    2012-07-01

    Full Text Available Data-driven computational neural network models have been used to study mechanisms for generating the motor patterns for breathing and breathing related behaviors such as coughing. These models have commonly been evaluated in open loop conditions or with feedback of lung volume simply represented as a filtered version of phrenic motor output. Limitations of these approaches preclude assessment of the influence of mechanical properties of the musculoskeletal system and motivated development of a biomechanical model of the respiratory muscles, airway, and lungs using published measures from human subjects. Here we describe the model and some aspects of its behavior when linked to a computational brainstem respiratory network model for breathing and airway defensive behavior composed of discrete integrate and fire populations. The network incorporated multiple circuit paths and operations for tuning inspiratory drive suggested by prior work. Results from neuromechanical system simulations included generation of a eupneic-like breathing pattern and the observation that increased respiratory drive and operating volume result in higher peak flow rates during cough, even when the expiratory drive is unchanged, or when the expiratory abdominal pressure is unchanged. Sequential elimination of the model’s sources of inspiratory drive during cough also suggested a role for disinhibitory regulation via tonic expiratory neurons, a result that was subsequently supported by an analysis of in vivo data. Comparisons with antecedent models, discrepancies with experimental results, and some model limitations are noted.

  12. Animal models of peripheral neuropathy due to environmental toxicants.

    Science.gov (United States)

    Rao, Deepa B; Jortner, Bernard S; Sills, Robert C

    2014-01-01

    Despite the progress in our understanding of pathogeneses and the identification of etiologies of peripheral neuropathy, idiopathic neuropathy remains common. Typically, attention to peripheral neuropathies resulting from exposure to environmental agents is limited relative to more commonly diagnosed causes of peripheral neuropathy (diabetes and chemotherapeutic agents). Given that there are more than 80,000 chemicals in commerce registered with the Environmental Protection Agency and that at least 1000 chemicals are known to have neurotoxic potential, very few chemicals have been established to affect the peripheral nervous system (mainly after occupational exposures). A wide spectrum of exposures, including pesticides, metals, solvents, nutritional sources, and pharmaceutical agents, has been related, both historically and recently, to environmental toxicant-induced peripheral neuropathy. A review of the literature shows that the toxicity and pathogeneses of chemicals adversely affecting the peripheral nervous system have been studied using animal models. This article includes an overview of five prototypical environmental agents known to cause peripheral neuropathy--namely, organophosphates, carbon disulfide, pyridoxine (Vitamin B6), acrylamide, and hexacarbons (mainly n-hexane, 2,5-hexanedione, methyl n-butyl ketone). Also included is a brief introduction to the structural components of the peripheral nervous system and pointers on common methodologies for histopathologic evaluation of the peripheral nerves.

  13. Acute toxicity, respiratory reaction, and sensitivity of three cyprinid fish species caused by exposure to four heavy metals.

    Directory of Open Access Journals (Sweden)

    Hongjun Wang

    Full Text Available Using 3 cyprinid fish species zebra fish, rare minnow, and juvenile grass carp, we conducted assays of lethal reaction and ventilatory response to analyze sensitivity of the fish to 4 heavy metals. Our results showed that the 96 h LC50 of Hg(2+ to zebra fish, juvenile grass carp, and rare minnow were 0.14 mg L(-1, 0.23 mg L(-1, and 0.10 mg L(-1, respectively; of Cu(2+0.17 mg L(-1, 0.09 mg L(-1, and 0.12 mg L(-1 respectively; of Cd(2+6.5 mg L(-1, 18.47 mg L(-1, 5.36 mg L(-1, respectively; and of Zn(2+44.48 mg L(-1, 31.37 mg L(-1, and 12.74 mg L(-1, respectively. Under a 1-h exposure, the ventilatory response to the different heavy metals varied. Ventilatory frequency (Vf and amplitude (Va increased in zebra fish, juvenile grass carp, and rare minnows exposed to Hg(2+ and Cu(2+ (P<0.05, and the Vf and Va of the 3 species rose initially and then declined when exposed to Cd(2+. Zn(2+ had markedly different toxic effects than the other heavy metals, whose Vf and Va gradually decreased with increasing exposure concentration (P<0.05. The rare minnow was the most highly susceptible of the 3 fish species to the heavy metals, with threshold effect concentrations (TEC of 0.019 mg L(-1, 0.046 mg L(-1, 2.142 mg L(-1, and 0.633 mg L(-1 for Hg(2+, Cu(2+, Cd(2+, and Zn(2+, respectively. Therefore, it is feasible to use ventilatory parameters as a biomarker for evaluating the pollution toxicity of metals and to recognize early warning signs by using rare minnows as a sensor.

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

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, M.R.; Birchall, A. (National Radiological Protection Board, Chilton (UK)); Cuddihy, R.G. (Inhalation Toxicology Research Inst., Albuquerque, NM (USA)); James, A.C. (Pacific Northwest Lab., Richland, WA (USA)); Roy, M. (CEA Centre d' Etudes Nucleaires de Fontenay-aux-Roses, 92 (France). Inst. de Protection et de Surete Nucleaire)

    1990-07-01

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

  15. Estimates of committed effective dose and annual limit on intake for radioactive dusts using the new ICRP respiratory tract model

    Energy Technology Data Exchange (ETDEWEB)

    O`Brien, R.S. [Australian Radiation Lab., Melbourne, VIC (Australia)

    1996-01-01

    This paper discusses some of the implications of using the new ICRP 66 respiratory tract model for calculation of the committed effective dose(CED), for a period of 50 years post-intake, together with the annual limit on intake(ALI), for radioactive dusts encountered in the uranium and mineral sand mining and processing industries. Some of the differences between the old ICRP 30 respiratory tract model and the LUDEP 1.1 computer code, which is based on the new ICRP 66 respiratory tract model, are discussed and a comparison of values obtained using both models is given. 4 figs; 8 tabs; 16 refs.

  16. Using a human cardiovascular-respiratory model to characterize cardiac tamponade and pulsus paradoxus

    Science.gov (United States)

    Ramachandran, Deepa; Luo, Chuan; Ma, Tony S; Clark, John W

    2009-01-01

    Background Cardiac tamponade is a condition whereby fluid accumulation in the pericardial sac surrounding the heart causes elevation and equilibration of pericardial and cardiac chamber pressures, reduced cardiac output, changes in hemodynamics, partial chamber collapse, pulsus paradoxus, and arterio-venous acid-base disparity. Our large-scale model of the human cardiovascular-respiratory system (H-CRS) is employed to study mechanisms underlying cardiac tamponade and pulsus paradoxus. The model integrates hemodynamics, whole-body gas exchange, and autonomic nervous system control to simulate pressure, volume, and blood flow. Methods We integrate a new pericardial model into our previously developed H-CRS model based on a fit to patient pressure data. Virtual experiments are designed to simulate pericardial effusion and study mechanisms of pulsus paradoxus, focusing particularly on the role of the interventricular septum. Model differential equations programmed in C are solved using a 5th-order Runge-Kutta numerical integration scheme. MATLAB is employed for waveform analysis. Results The H-CRS model simulates hemodynamic and respiratory changes associated with tamponade clinically. Our model predicts effects of effusion-generated pericardial constraint on chamber and septal mechanics, such as altered right atrial filling, delayed leftward septal motion, and prolonged left ventricular pre-ejection period, causing atrioventricular interaction and ventricular desynchronization. We demonstrate pericardial constraint to markedly accentuate normal ventricular interactions associated with respiratory effort, which we show to be the distinct mechanisms of pulsus paradoxus, namely, series and parallel ventricular interaction. Series ventricular interaction represents respiratory variation in right ventricular stroke volume carried over to the left ventricle via the pulmonary vasculature, whereas parallel interaction (via the septum and pericardium) is a result of

  17. 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.

  18. Development of an ex vivo human-porcine respiratory model for preclinical studies.

    Science.gov (United States)

    Perinel, Sophie; Pourchez, Jérémie; Leclerc, Lara; Avet, John; Durand, Marc; Prévôt, Nathalie; Cottier, Michèle; Vergnon, Jean M

    2017-02-24

    Anatomical models to study aerosol delivery impose huge limitations and extrapolation to humans remains controversial. This study aimed to develop and validate an ex vivo human-like respiratory tract model easy to use and relevant to compare to in vivo human data. A human plastinated head is connected to an ex vivo porcine pulmonary tract ventilated artificially by passive expansion. A physiological study measures "pleural" depressions, tidal volumes, and minute ventilation for the respiratory rates chosen (10, 15, and 20 per minute) with three inspiratory/expiratory ratios (1/1, 1/2, and 1/3). Scintigraphy with (81m)Krypton assesses the homogeneity of the ventilation. Forty different experiments were set for validation, with 36 (90%) ventilating successfully. At a respiratory rate of 15/minute with inspiratory/expiratory ratio of 1/2, the tidal volume average was 824 mL (standard deviation, 207 mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity to human physiological studies. Ratio of the peripheral to central count rates were equally correlated with human data published in the literature. This new model, combining research feasibility and human physiology likeness, provides a realistic approach to human inhalation and therefore can be an interesting tool in aerosol regional deposition studies.

  19. Model for the respiratory modulation of the heart beat-to-beat time interval series

    Science.gov (United States)

    Capurro, Alberto; Diambra, Luis; Malta, C. P.

    2005-09-01

    In this study we present a model for the respiratory modulation of the heart beat-to-beat interval series. The model consists of a set of differential equations used to simulate the membrane potential of a single rabbit sinoatrial node cell, excited with a periodic input signal with added correlated noise. This signal, which simulates the input from the autonomous nervous system to the sinoatrial node, was included in the pacemaker equations as a modulation of the iNaK current pump and the potassium current iK. We focus at modeling the heart beat-to-beat time interval series from normal subjects during meditation of the Kundalini Yoga and Chi techniques. The analysis of the experimental data indicates that while the embedding of pre-meditation and control cases have a roughly circular shape, it acquires a polygonal shape during meditation, triangular for the Kundalini Yoga data and quadrangular in the case of Chi data. The model was used to assess the waveshape of the respiratory signals needed to reproduce the trajectory of the experimental data in the phase space. The embedding of the Chi data could be reproduced using a periodic signal obtained by smoothing a square wave. In the case of Kundalini Yoga data, the embedding was reproduced with a periodic signal obtained by smoothing a triangular wave having a rising branch of longer duration than the decreasing branch. Our study provides an estimation of the respiratory signal using only the heart beat-to-beat time interval series.

  20. Fluid-structure interaction including volumetric coupling with homogenised subdomains for modeling respiratory mechanics.

    Science.gov (United States)

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

    2017-04-01

    In this article, a novel approach is presented for combining standard fluid-structure interaction with additional volumetric constraints to model fluid flow into and from homogenised solid domains. The proposed algorithm is particularly interesting for investigations in the field of respiratory mechanics as it enables the mutual coupling of airflow in the conducting part and local tissue deformation in the respiratory part of the lung by means of a volume constraint. In combination with a classical monolithic fluid-structure interaction approach, a comprehensive model of the human lung can be established that will be useful to gain new insights into respiratory mechanics in health and disease. To illustrate the validity and versatility of the novel approach, three numerical examples including a patient-specific lung model are presented. The proposed algorithm proves its capability of computing clinically relevant airflow distribution and tissue strain data at a level of detail that is not yet achievable, neither with current imaging techniques nor with existing computational models. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Development of an ex vivo human-porcine respiratory model for preclinical studies

    Science.gov (United States)

    Perinel, Sophie; Pourchez, Jérémie; Leclerc, Lara; Avet, John; Durand, Marc; Prévôt, Nathalie; Cottier, Michèle; Vergnon, Jean M.

    2017-01-01

    Anatomical models to study aerosol delivery impose huge limitations and extrapolation to humans remains controversial. This study aimed to develop and validate an ex vivo human-like respiratory tract model easy to use and relevant to compare to in vivo human data. A human plastinated head is connected to an ex vivo porcine pulmonary tract ventilated artificially by passive expansion. A physiological study measures “pleural” depressions, tidal volumes, and minute ventilation for the respiratory rates chosen (10, 15, and 20 per minute) with three inspiratory/expiratory ratios (1/1, 1/2, and 1/3). Scintigraphy with 81mKrypton assesses the homogeneity of the ventilation. Forty different experiments were set for validation, with 36 (90%) ventilating successfully. At a respiratory rate of 15/minute with inspiratory/expiratory ratio of 1/2, the tidal volume average was 824 mL (standard deviation, 207 mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity to human physiological studies. Ratio of the peripheral to central count rates were equally correlated with human data published in the literature. This new model, combining research feasibility and human physiology likeness, provides a realistic approach to human inhalation and therefore can be an interesting tool in aerosol regional deposition studies. PMID:28233793

  2. 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.

  3. Toxicity of copper and cadmium in combinations to Duckweed analyzed by the biotic ligand model.

    Science.gov (United States)

    Hatano, Ayumi; Shoji, Ryo

    2008-06-01

    The biotic ligand model (BLM) of acute toxicity to aquatic organisms is based on the concept that metals binding onto biotic ligand may cause toxic effect on the organism. The BLM can take into incorporation between metal speciation and the protective effects of competing cations account. The demonstrated BLM can provide a good estimation of the amount of single metal effect under various conditions such as pH, coexistence of other non toxic cations. However, toxic metals are often found as mixture in nature. This study estimated combined toxicity of Cu and Cd examined by growth inhibition of Duckweed (Lemna paucicostata) by using single toxicity data as toxic unit (TU) derived by three types of model, BLM and two conventional models, free ion activity model (FIAM), and total metal concentration model. According to our results, single toxicity data derived by the BLM can estimate combined toxicity described as a function of TU. Particularly under the high level of heavy metals stress, BLM clearly predicted toxicity of heavy metals compared with other two models. According to numeric correlation (R(2), root mean square error), the order is BLM (R=0.83, RMSE=13.5)> total metal concentration model (R=0.41, RMSE=24.9)> FIAM (R=0.36, RMSE=26.1).

  4. Joint PET-MR respiratory motion models for clinical PET motion correction

    Science.gov (United States)

    Manber, Richard; Thielemans, Kris; Hutton, Brian F.; Wan, Simon; McClelland, Jamie; Barnes, Anna; Arridge, Simon; Ourselin, Sébastien; Atkinson, David

    2016-09-01

    Patient motion due to respiration can lead to artefacts and blurring in positron emission tomography (PET) images, in addition to quantification errors. The integration of PET with magnetic resonance (MR) imaging in PET-MR scanners provides complementary clinical information, and allows the use of high spatial resolution and high contrast MR images to monitor and correct motion-corrupted PET data. In this paper we build on previous work to form a methodology for respiratory motion correction of PET data, and show it can improve PET image quality whilst having minimal impact on clinical PET-MR protocols. We introduce a joint PET-MR motion model, using only 1 min per PET bed position of simultaneously acquired PET and MR data to provide a respiratory motion correspondence model that captures inter-cycle and intra-cycle breathing variations. In the model setup, 2D multi-slice MR provides the dynamic imaging component, and PET data, via low spatial resolution framing and principal component analysis, provides the model surrogate. We evaluate different motion models (1D and 2D linear, and 1D and 2D polynomial) by computing model-fit and model-prediction errors on dynamic MR images on a data set of 45 patients. Finally we apply the motion model methodology to 5 clinical PET-MR oncology patient datasets. Qualitative PET reconstruction improvements and artefact reduction are assessed with visual analysis, and quantitative improvements are calculated using standardised uptake value (SUVpeak and SUVmax) changes in avid lesions. We demonstrate the capability of a joint PET-MR motion model to predict respiratory motion by showing significantly improved image quality of PET data acquired before the motion model data. The method can be used to incorporate motion into the reconstruction of any length of PET acquisition, with only 1 min of extra scan time, and with no external hardware required.

  5. 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

    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....

  6. Estimation of exposure to toxic releases using spatial interaction modeling

    Directory of Open Access Journals (Sweden)

    Conley Jamison F

    2011-03-01

    Full Text Available Abstract Background The United States Environmental Protection Agency's Toxic Release Inventory (TRI data are frequently used to estimate a community's exposure to pollution. However, this estimation process often uses underdeveloped geographic theory. Spatial interaction modeling provides a more realistic approach to this estimation process. This paper uses four sets of data: lung cancer age-adjusted mortality rates from the years 1990 through 2006 inclusive from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER database, TRI releases of carcinogens from 1987 to 1996, covariates associated with lung cancer, and the EPA's Risk-Screening Environmental Indicators (RSEI model. Results The impact of the volume of carcinogenic TRI releases on each county's lung cancer mortality rates was calculated using six spatial interaction functions (containment, buffer, power decay, exponential decay, quadratic decay, and RSEI estimates and evaluated with four multivariate regression methods (linear, generalized linear, spatial lag, and spatial error. Akaike Information Criterion values and P values of spatial interaction terms were computed. The impacts calculated from the interaction models were also mapped. Buffer and quadratic interaction functions had the lowest AIC values (22298 and 22525 respectively, although the gains from including the spatial interaction terms were diminished with spatial error and spatial lag regression. Conclusions The use of different methods for estimating the spatial risk posed by pollution from TRI sites can give different results about the impact of those sites on health outcomes. The most reliable estimates did not always come from the most complex methods.

  7. Feasibility of a 3D human airway epithelial model to study respiratory absorption.

    Science.gov (United States)

    Reus, Astrid A; Maas, Wilfred J M; Jansen, Harm T; Constant, Samuel; Staal, Yvonne C M; van Triel, Jos J; Kuper, C Frieke

    2014-03-01

    The respiratory route is an important portal for human exposure to a large variety of substances. Consequently, there is an urgent need for realistic in vitro strategies for evaluation of the absorption of airborne substances with regard to safety and efficacy assessment. The present study investigated feasibility of a 3D human airway epithelial model to study respiratory absorption, in particular to differentiate between low and high absorption of substances. Bronchial epithelial models (MucilAir™), cultured at the air-liquid interface, were exposed to eight radiolabeled model substances via the apical epithelial surface. Absorption was evaluated by measuring radioactivity in the apical compartment, the epithelial cells and the basolateral culture medium. Antipyrine, caffeine, naproxen and propranolol were highly transported across the epithelial cell layer (>5%), whereas atenolol, mannitol, PEG-400 and insulin were limitedly transported (absorption. The intra-experimental reproducibility of the results was considered adequate based on an average coefficient of variation (CV) of 15%. The inter-experimental reproducibility of highly absorbed compounds was in a similar range (CV of 15%), but this value was considerably higher for those compounds that were limitedly absorbed. No statistical significant differences between different donors and experiments were observed. The present study provides a simple method transposable in any lab, which can be used to rank the absorption of chemicals and pharmaceuticals, and is ready for further validation with respect to reproducibility and capacity of the method to predict respiratory transport in humans.

  8. Statistical modeling of 4D respiratory lung motion using diffeomorphic image registration.

    Science.gov (United States)

    Ehrhardt, Jan; Werner, René; Schmidt-Richberg, Alexander; Handels, Heinz

    2011-02-01

    Modeling of respiratory motion has become increasingly important in various applications of medical imaging (e.g., radiation therapy of lung cancer). Current modeling approaches are usually confined to intra-patient registration of 3D image data representing the individual patient's anatomy at different breathing phases. We propose an approach to generate a mean motion model of the lung based on thoracic 4D computed tomography (CT) data of different patients to extend the motion modeling capabilities. Our modeling process consists of three steps: an intra-subject registration to generate subject-specific motion models, the generation of an average shape and intensity atlas of the lung as anatomical reference frame, and the registration of the subject-specific motion models to the atlas in order to build a statistical 4D mean motion model (4D-MMM). Furthermore, we present methods to adapt the 4D mean motion model to a patient-specific lung geometry. In all steps, a symmetric diffeomorphic nonlinear intensity-based registration method was employed. The Log-Euclidean framework was used to compute statistics on the diffeomorphic transformations. The presented methods are then used to build a mean motion model of respiratory lung motion using thoracic 4D CT data sets of 17 patients. We evaluate the model by applying it for estimating respiratory motion of ten lung cancer patients. The prediction is evaluated with respect to landmark and tumor motion, and the quantitative analysis results in a mean target registration error (TRE) of 3.3 ±1.6 mm if lung dynamics are not impaired by large lung tumors or other lung disorders (e.g., emphysema). With regard to lung tumor motion, we show that prediction accuracy is independent of tumor size and tumor motion amplitude in the considered data set. However, tumors adhering to non-lung structures degrade local lung dynamics significantly and the model-based prediction accuracy is lower in these cases. The statistical respiratory

  9. 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.

  10. Three dimensional quantitative structure-toxicity relationship modeling and prediction of acute toxicity for organic contaminants to algae.

    Science.gov (United States)

    Jin, Xiangqin; Jin, Minghao; Sheng, Lianxi

    2014-08-01

    Although numerous chemicals have been identified to have significant toxicological effect on aquatic organisms, there is still lack of a reliable, high-throughput approach to evaluate, screen and monitor the presence of organic contaminants in aquatic system. In the current study, we proposed a synthetic pipeline to automatically model and predict the acute toxicity of chemicals to algae. In the procedure, a new alignment-free three dimensional (3D) structure characterization method was described and, with this method, several 3D-quantitative structure-toxicity relationship (3D-QSTR) models were developed, from which two were found to exhibit strong internal fitting ability and high external predictive power. The best model was established by Gaussian process (GP), which was further employed to perform extrapolation on a random compound library consisting of 1014 virtually generated substituted benzenes. It was found that (i) substitution number can only exert slight influence on chemical׳s toxicity, but low-substituted benzenes seem to have higher toxicity than those of high-substituted entities, and (ii) benzenes substituted by nitro group and halogens exhibit high acute toxicity as compared to other substituents such as methyl and carboxyl groups. Subsequently, several promising candidates suggested by computational prediction were assayed by using a standard algal growth inhibition test. Consequently, four substituted benzenes, namely 2,3-dinitrophenol, 2-chloro-4-nitroaniline, 1,2,3-trinitrobenzene and 3-bromophenol, were determined to have high acute toxicity to Scenedesmus obliquus, with their EC50 values of 2.5±0.8, 10.5±2.1, 1.4±0.2 and 42.7±5.4μmol/L, respectively.

  11. A study of IOS data using the aRIC+I(p) model of respiratory impedance.

    Science.gov (United States)

    Nguyen, T-U; Diong, B; Goldman, M

    2009-01-01

    Development of better methods to assess human lung function has been continuing since the existing standard lung function test of spirometry requires subjects to inhale and exhale with maximum effort, which may be troublesome especially for the elderly and young children, leading to unreliable results. Therefore, the method of forced oscillation, and the Impulse Oscillometry System (IOS) in particular, has been developed to lessen the effort of the patients while obtaining valid measurements. The applied pressure waves and the resulting airflow responses are recorded to provide information about the respiratory system's input impedance, which can be fit by electric circuit models to possibly serve as a means to detect and diagnose respiratory diseases. Presently, research continues to find a more accurate model that also provides reasonable component values. This paper proposes the augmented RIC+I(p)(aRIC+I(p)) model and compares it to five other well-known models (the RIC, extended RIC, augmented RIC, DuBois and Mead models) in fitting the IOS data from adult COPD patients and healthy subjects. While the aRIC+I(p) model yielded slightly higher fitting error than the Mead and DuBois models, it did not produce unphysiologically large values for any of its components, unlike the Mead and DuBois models. Hence, the aRIC+(p) model appears to be the most reasonable one for use, at this point in time, in studying IOS-based computer-aided detection and diagnosis of COPD.

  12. 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.

  13. Evaluation of residual abdominal tumour motion in carbon ion gated treatments through respiratory motion modelling.

    Science.gov (United States)

    Meschini, Giorgia; Seregni, Matteo; Pella, Andrea; Ciocca, Mario; Fossati, Piero; Valvo, Francesca; Riboldi, Marco; Baroni, Guido

    2017-02-01

    At the Italian National Centre for Oncologic Hadrontherapy (CNAO) patients with upper-abdominal tumours are being treated with carbon ion therapy, adopting the respiratory gating technique in combination with layered rescanning and abdominal compression to mitigate organ motion. Since online imaging of the irradiated volume is not feasible, this study proposes a modelling approach for the estimation of residual motion of the target within the gating window. The model extracts a priori respiratory motion information from the planning 4DCT using deformable image registration (DIR), then combines such information with the external surrogate signal recorded during dose delivery. This provides estimation of a CT volume corresponding to any given respiratory phase measured during treatment. The method was applied for the retrospective estimation of tumour residual motion during irradiation, considering 16 patients treated at CNAO with the respiratory gating protocol. The estimated tumour displacement, calculated with respect to the reference end-exhale position, was always limited (average displacement is 0.32±0.65mm over all patients) and below the maximum motion defined in the treatment plan. This supports the hypothesis of target position reproducibility, which is the crucial assumption in the gating approach. We also demonstrated the use of the model as a simulation tool to establish a patient-specific relationship between residual motion and the width of the gating window. In conclusion, the implemented method yields an estimation of the repeatability of the internal anatomy configuration during gated treatments, which can be used for further studies concerning the dosimetric impact of the estimated residual organ motion.

  14. Modelling acute oral mammalian toxicity. 1. Definition of a quantifiable baseline effect.

    Science.gov (United States)

    Koleva, Yana K; Cronin, Mark T D; Madden, Judith C; Schwöbel, Johannes A H

    2011-10-01

    Quantitative structure-activity relationships (QSARs) provide a useful tool to define a relationship between chemical structure and toxicity and allow for the prediction of the toxicity of untested chemicals. QSAR models based upon an anaesthetic or narcosis mechanism represent a baseline, or minimum, toxicity, i.e. unless a chemical acts by another, more specific, mechanism, its toxicity will be predicted by such models. The aim of this investigation was to develop baseline models for the acute toxicity of chemicals to mammals (rat and mouse) following the oral route of administration. The availability of such baseline toxicity models for mammalian species can provide a probe for testing new chemicals with respect to their molecular mechanism of toxicity. Multiple-regression type structure-toxicity relationships were derived . (i.e., from oral log LD(50)(-1) data for mammalian species (rat and mouse) and the 1-octanol/water partition coefficient (log P) of classic non-polar narcotics). Subsequently, these models were used to distinguish between reactive chemicals of different mechanistic domains and baseline toxic chemicals. Comparison of measured toxicity data for oral rat and mouse LD(50) with predictions from baseline QSAR provides a means of identifying mechanistic categories and for categorising more specific acute mechanisms. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Assessing pneumococcal meningitis association with viral respiratory infections and antibiotics: insights from statistical and mathematical models.

    Science.gov (United States)

    Opatowski, Lulla; Varon, Emmanuelle; Dupont, Claire; Temime, Laura; van der Werf, Sylvie; Gutmann, Laurent; Boëlle, Pierre-Yves; Watier, Laurence; Guillemot, Didier

    2013-08-01

    Pneumococcus is an important human pathogen, highly antibiotic resistant and a major cause of bacterial meningitis worldwide. Better prevention requires understanding the drivers of pneumococcal infection incidence and antibiotic susceptibility. Although respiratory viruses (including influenza) have been suggested to influence pneumococcal infections, the underlying mechanisms are still unknown, and viruses are rarely considered when studying pneumococcus epidemiology. Here, we propose a novel mathematical model to examine hypothetical relationships between Streptococcus pneumoniae meningitis incidence (SPMI), acute viral respiratory infections (AVRIs) and antibiotic exposure. French time series of SPMI, AVRI and penicillin consumption over 2001-2004 are analysed and used to assess four distinct virus-bacteria interaction submodels, ascribing the interaction on pneumococcus transmissibility and/or pathogenicity. The statistical analysis reveals strong associations between time series: SPMI increases shortly after AVRI incidence and decreases overall as the antibiotic-prescription rate rises. Model simulations require a combined impact of AVRI on both pneumococcal transmissibility (up to 1.3-fold increase at the population level) and pathogenicity (up to threefold increase) to reproduce the data accurately, along with diminished epidemic fitness of resistant pneumococcal strains causing meningitis (0.97 (0.96-0.97)). Overall, our findings suggest that AVRI and antibiotics strongly influence SPMI trends. Consequently, vaccination protecting against respiratory virus could have unexpected benefits to limit invasive pneumococcal infections.

  16. 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...

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

    Science.gov (United States)

    Panaite, Petrica-Adrian; Kuntzer, Thierry; Gourdon, Geneviève; Lobrinus, Johannes Alexander; Barakat-Walter, Ibtissam

    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

  18. 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

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

    Science.gov (United States)

    Ghio, Andrew J.; Kummarapurugu, Suryanaren T.; Tong, Haiyan; Soukup, Joleen M.; Dailey, Lisa A.; Boykin, Elizabeth; Gilmour, M. Ian; Ingram, Peter; Roggli, Victor L.; Goldstein, Harland L.; Reynolds, Richard L.

    2014-01-01

    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 imparts a biological effect in respiratory epithelial cells and an animal model. Two samples of surface sediment were collected from separate dust sources in northeastern Arizona. Analysis of the PM20 fraction demonstrated that the majority of both dust samples were quartz and clay minerals (total SiO2 of 52 and 57%). Using respiratory epithelial and monocytic cell lines, the two desert dusts increased oxidant generation, measured by Amplex Red fluorescence, along with carbon black (a control particle), silica, and NIST 1649 (an ambient air pollution particle). Cell oxidant generation was greatest following exposures to silica and the desert dusts. Similarly, changes in RNA for superoxide dismutase-1, heme oxygenase-1, and cyclooxygenase-2 were also greatest after silica and the desert dusts supporting an oxidative stress after cell exposure. Silica, desert dusts, and the ambient air pollution particle NIST 1649 demonstrated a capacity to activate the p38 and ERK1/2 pathways and release pro-inflammatory mediators. Mice, instilled with the same particles, showed the greatest lavage concentrations of pro-inflammatory mediators, neutrophils, and lung injury following silica and desert dusts. We conclude that, comparable to other particles, desert dusts have a capacity to (1) influence oxidative stress and release of pro-inflammatory mediators in respiratory epithelial cells and (2) provoke an inflammatory injury in the lower respiratory tract of an animal model. The biological effects of desert dusts approximated those of silica.

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

    Energy Technology Data Exchange (ETDEWEB)

    James, A.C.; Briant, J.K. (Pacific Northwest Lab., Richland, WA (USA)); Stahlhofen, W.; Rudolf, G. (Gesellschaft fuer Strahlen- und Umweltforschung mbH Muenchen, Frankfurt am Main (Germany, F.R.). Abt. fuer Biophysikalische Strahlenforschung); Egan, M.J.; Nixon, W. (AEA Safety and Reliability, Culcheth (UK)); Gehr, P. (Bern Univ. (Switzerland). Anatomisches Inst.)

    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 {mu}m. 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.

  1. Direct Visuo-Haptic 4D Volume Rendering Using Respiratory Motion Models.

    Science.gov (United States)

    Fortmeier, Dirk; Wilms, Matthias; Mastmeyer, Andre; Handels, Heinz

    2015-01-01

    This article presents methods for direct visuo-haptic 4D volume rendering of virtual patient models under respiratory motion. Breathing models are computed based on patient-specific 4D CT image data sequences. Virtual patient models are visualized in real-time by ray casting based rendering of a reference CT image warped by a time-variant displacement field, which is computed using the motion models at run-time. Furthermore, haptic interaction with the animated virtual patient models is provided by using the displacements computed at high rendering rates to translate the position of the haptic device into the space of the reference CT image. This concept is applied to virtual palpation and the haptic simulation of insertion of a virtual bendable needle. To this aim, different motion models that are applicable in real-time are presented and the methods are integrated into a needle puncture training simulation framework, which can be used for simulated biopsy or vessel puncture in the liver. To confirm real-time applicability, a performance analysis of the resulting framework is given. It is shown that the presented methods achieve mean update rates around 2,000 Hz for haptic simulation and interactive frame rates for volume rendering and thus are well suited for visuo-haptic rendering of virtual patients under respiratory motion.

  2. Respiratory recovery following organophosphate poisoning in a rat model is suppressed by isolated hypoxia at the point of apnea.

    Science.gov (United States)

    Gaspari, Romolo J; Paydarfar, David

    2012-12-16

    Normal respiratory activity (eupnea) and gasping represent different types of respiratory activity, one of which is supported by oxygen (eupnea) and the other suppressed by oxygen (gasping). There is a loss of respiratory activity post-organophosphate (OP) poisoning that returns following treatment. It is not clear if post-OP respiratory activity represents eupnea or gasping. Depending on the type of respiratory activity, oxygenation during recovery from OP poisoning may have the potential to either support or suppress respiratory activity. We hypothesize that respiratory recovery following OP-induced central apnea represents a resumption of eupnea and is supported by oxygenation. We used an animal model of acute OP poisoning with detailed physiologic recordings. Animals were poisoned with dichlorvos and allowed to recover during a period of mechanical ventilation. Two experimental models were analyzed: (1) animals supported with 100% oxygen and (2) animals supported with a normoxic gas mixture titrated to a PaO(2) of 115 mmHg. Rats in this study demonstrated breathing that resumes spontaneously following OP-induced apnea with characteristics of both eupnea and gasping. The post-OP respiratory activity was suppressed by hypoxia, a characteristic of eupneic respiration and not gasping respiration. However, the respiratory rate during post-apneic breathing corresponded more closely to gasping. Analysis of phrenic nerve discharge activity was distinct from both eupnea and gasping, with peak inspiratory and post-inspiratory discharge activities significantly reduced compared to both eupnea and gasping. In summary, in this animal model post-apneic breathing distinct from eupnea and gasping that emerges following prolonged OP-induced central apnea is suppressed by hypoxia.

  3. Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length.

    OpenAIRE

    Panaite, P.A.; Kuntzer, T; Gourdon, G; Barakat-Walter, I.

    2013-01-01

    Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control an...

  4. Neurochemical and Behavioral Characteristics of Toxic Milk Mice: An Animal Model of Wilson’s Disease

    OpenAIRE

    2013-01-01

    Toxic milk mice have an inherited defect of copper metabolism. Hepatic phenotype of the toxic milk mice is similar to clinical findings in humans suffering from Wilson’s disease (WND). In the present study, neurotransmitter system and locomotor performance in toxic milk mice was examined to verify the feasibility of this animal model for studying neuropathology of WND. Mice aged 2 and 12 months were used in the experiment. The mice were tested according to rotarod and footprint protocols. Mon...

  5. Optimal Determination of Respiratory Airflow Patterns Using a Nonlinear Multicompartment Model for a Lung Mechanics System

    Directory of Open Access Journals (Sweden)

    Hancao Li

    2012-01-01

    Full Text Available We develop optimal respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system. Specifically, we use classical calculus of variations minimization techniques to derive an optimal airflow pattern for inspiratory and expiratory breathing cycles. The physiological interpretation of the optimality criteria used involves the minimization of work of breathing and lung volume acceleration for the inspiratory phase, and the minimization of the elastic potential energy and rapid airflow rate changes for the expiratory phase. Finally, we numerically integrate the resulting nonlinear two-point boundary value problems to determine the optimal airflow patterns over the inspiratory and expiratory breathing cycles.

  6. Optimal determination of respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system.

    Science.gov (United States)

    Li, Hancao; Haddad, Wassim M

    2012-01-01

    We develop optimal respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system. Specifically, we use classical calculus of variations minimization techniques to derive an optimal airflow pattern for inspiratory and expiratory breathing cycles. The physiological interpretation of the optimality criteria used involves the minimization of work of breathing and lung volume acceleration for the inspiratory phase, and the minimization of the elastic potential energy and rapid airflow rate changes for the expiratory phase. Finally, we numerically integrate the resulting nonlinear two-point boundary value problems to determine the optimal airflow patterns over the inspiratory and expiratory breathing cycles.

  7. Influences of parameter uncertainties within the ICRP 66 respiratory tract model: particle deposition.

    Science.gov (United States)

    Bolch, W E; Farfán, E B; Huh, C; Huston, T E; Bolch, W E

    2001-10-01

    Risk assessment associated with the inhalation of radioactive aerosols requires as an initial step the determination of particle deposition within the various anatomic regions of the respiratory tract. The model outlined in ICRP Publication 66 represents to date one of the most complete overall descriptions of not only particle deposition, but of particle clearance and local radiation dosimetry of lung tissues. In this study, a systematic review of the deposition component within the ICRP 66 respiratory tract model was conducted in which probability density functions were assigned to all input parameters. These distributions were subsequently incorporated within a computer code LUDUC (LUng Dose Uncertainty Code) in which Latin hypercube sampling techniques are used to generate multiple (e.g., 1,000) sets of input vectors (i.e., trials) for all of the model parameters needed to assess particle deposition within the extrathoracic (anterior and posterior), bronchial, bronchiolar, and alveolar-interstitial regions of the ICRP 66 respiratory tract model. Particle deposition values for the various trial simulations were shown to be well described by lognormal probability distributions. Geometric mean deposition fractions from LUDUC were found to be within approximately +/- 10% of the single-value estimates from the LUDEP computer code for each anatomic region and for particle diameters ranging from 0.001 to 50 microm. In all regions of the respiratory tract, LUDUC simulations for an adult male at light exertion show that uncertainties in particle deposition fractions are distributed only over a range of about a factor of approximately 2-4 for particle sizes between 0.005 to 0.2 microm. Below 0.005 microm, uncertainties increase only for deposition within the alveolar region. At particle sizes exceeding 1 microm, uncertainties in the deposition fraction within the extrathoracic regions are relatively small, but approach a factor of 20 for deposition in the bronchial

  8. 4D-CT motion estimation using deformable image registration and 5D respiratory motion modeling

    OpenAIRE

    2008-01-01

    Four-dimensional computed tomography (4D-CT) imaging technology has been developed for radiation therapy to provide tumor and organ images at the different breathing phases. In this work, a procedure is proposed for estimating and modeling the respiratory motion field from acquired 4D-CT imaging data and predicting tissue motion at the different breathing phases. The 4D-CT image data consist of series of multislice CT volume segments acquired in ciné mode. A modified optical flow deformable i...

  9. Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length.

    Science.gov (United States)

    Panaite, Petrica-Adrian; Kuntzer, Thierry; Gourdon, Geneviève; Barakat-Walter, Ibtissam

    2013-10-01

    Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.

  10. A patient-specific respiratory model of anatomical motion for radiation treatment planning

    CERN Document Server

    Zhang, Qinghui; Hertanto, Agung; Hu, Yu-Chi; Rosenzweig, Kenneth E; Ling, C Clifton; Mageras, Gig S

    2007-01-01

    Modeling of respiratory motion is important for a more accurate understanding and accounting of its effect on dose to cancers in the thorax and abdomen by radiotherapy. We have developed a model of respiration-induced organ motion in the thorax, without the commonly adopted assumption of repeatable breath cycles. The model describes the motion of a volume of interest within the patient, based on a reference 3-dimensional image (at end-expiration), and the diaphragm positions at different time points. The input data are respiration-correlated CT images of patients treated for nonsmall cell lung cancer, consisting of 3D images, including the diaphragm positions, at 10 phases of the respiratory cycle. A deformable image registration algorithm calculates the deformation field that maps each 3D image to the reference 3D image. A principle component analysis is performed to parameterize the 3D deformation field in terms of the diaphragm motion. We show that the first two principal components are adequate to accurat...

  11. 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.

  12. Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis.

    Science.gov (United States)

    Kolli, V K; Natarajan, K; Isaac, B; Selvakumar, D; Abraham, P

    2014-10-01

    The efficacy of methotrexate (MTX), a widely used chemotherapeutic drug, is limited by its gastrointestinal toxicity and the mechanism of which is not clear. The present study investigates the possible role of mitochondrial damage in MTX-induced enteritis. Small intestinal injury was induced in Wistar rats by the administration of 7 mg kg(-1) body wt. MTX intraperitoneally for 3 consecutive days. MTX administration resulted in severe small intestinal injury and extensive damage to enterocyte mitochondria. Respiratory control ratio, the single most useful and reliable test of mitochondrial function, and 3-(4,5-dimethylthiazol-2-yll)-2,5-diphenyltetrazolium bromide reduction, a measure of cell viability were significantly reduced in all the fractions of MTX-treated rat enterocytes. A massive decrease (nearly 70%) in the activities of complexes II and IV was also observed. The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis. MTX-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes. MTX-induced mitochondrial damage can result in reduced adenosine triphosphate synthesis, thereby interfering with nutrient absorption and enterocyte renewal. This derangement may contribute to malabsorption of nutrients, diarrhea, and weight loss seen in patients on MTX chemotherapy.

  13. 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...

  14. 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...

  15. 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...

  16. 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.

  17. 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.

  18. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-24

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

  20. 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...

  1. In Silico Model for Developmental Toxicity: How to Use QSAR Models and Interpret Their Results.

    Science.gov (United States)

    Marzo, Marco; Roncaglioni, Alessandra; Kulkarni, Sunil; Barton-Maclaren, Tara S; Benfenati, Emilio

    2016-01-01

    Modeling developmental toxicity has been a challenge for (Q)SAR model developers due to the complexity of the endpoint. Recently, some new in silico methods have been developed introducing the possibility to evaluate the integration of existing methods by taking advantage of various modeling perspectives. It is important that the model user is aware of the underlying basis of the different models in general, as well as the considerations and assumptions relative to the specific predictions that are obtained from these different models for the same chemical. The evaluation on the predictions needs to be done on a case-by-case basis, checking the analogs (possibly using structural, physicochemical, and toxicological information); for this purpose, the assessment of the applicability domain of the models provides further confidence in the model prediction. In this chapter, we present some examples illustrating an approach to combine human-based rules and statistical methods to support the prediction of developmental toxicity; we also discuss assumptions and uncertainties of the methodology.

  2. 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

  3. 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

  4. 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

  5. Modeling the Early Events of Severe Acute Respiratory Syndrome Coronavirus Infection In Vitro

    Science.gov (United States)

    Yen, Yu-Ting; Liao, Fang; Hsiao, Cheng-Hsiang; Kao, Chuan-Liang; Chen, Yee-Chun; Wu-Hsieh, Betty A.

    2006-01-01

    The clinical picture of severe acute respiratory syndrome (SARS) is characterized by pulmonary inflammation and respiratory failure, resembling that of acute respiratory distress syndrome. However, the events that lead to the recruitment of leukocytes are poorly understood. To study the cellular response in the acute phase of SARS coronavirus (SARS-CoV)-host cell interaction, we investigated the induction of chemokines, adhesion molecules, and DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin) by SARS-CoV. Immunohistochemistry revealed neutrophil, macrophage, and CD8 T-cell infiltration in the lung autopsy of a SARS patient who died during the acute phase of illness. Additionally, pneumocytes and macrophages in the patient's lung expressed P-selectin and DC-SIGN. In in vitro study, we showed that the A549 and THP-1 cell lines were susceptible to SARS-CoV. A549 cells produced CCL2/monocyte chemoattractant protein 1 (MCP-1) and CXCL8/interleukin-8 (IL-8) after interaction with SARS-CoV and expressed P-selectin and VCAM-1. Moreover, SARS-CoV induced THP-1 cells to express CCL2/MCP-1, CXCL8/IL-8, CCL3/MIP-1α, CXCL10/IP-10, CCL4/MIP-1β, and CCL5/RANTES, which attracted neutrophils, monocytes, and activated T cells in a chemotaxis assay. We also demonstrated that DC-SIGN was inducible in THP-1 as well as A549 cells after SARS-CoV infection. Our in vitro experiments modeling infection in humans together with the study of a lung biopsy of a patient who died during the early phase of infection demonstrated that SARS-CoV, through a dynamic interaction with lung epithelial cells and monocytic cells, creates an environment conducive for immune cell migration and accumulation that eventually leads to lung injury. PMID:16501078

  6. 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.

  7. 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.

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

    DEFF Research Database (Denmark)

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

    Influenza A virus infections have great impact on human health and welfare and significant resources are linked to influenza epidemics due to excess hospitalizations and lost productivity. Up to 15% of the human population is affected when Influenza spreads around the world in seasonal epidemics...... 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...... 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...

  9. Platelets can neutralize hydrogen peroxide in an acute toxicity model with cells involved in granulation tissue formation.

    Science.gov (United States)

    Kandler, Barbara; Maitz, Philipp; Fischer, Michael B; Watzek, Georg; Gruber, Reinhard

    2005-04-01

    Platelets play a key role in the replacement of the blood clot with granulation tissue during the early steps of bone regeneration. We hypothesized that activated platelets can neutralize locally produced reactive oxygen species, thereby protecting cells involved in granulation tissue formation. The potential of platelet-released supernatant (PRS) to neutralize hydrogen peroxide (H(2)O(2)) was tested in an acute toxicity model with osteogenic, inflammatory, and endothelial cells. In the human fetal osteoblastic cell line 1.19 (hFOB), considerable morphological changes, cell shedding, and dysfunction of the respiratory chain were observed when cells were exposed to 3 mM H(2)O(2). Caspase-3 and poly-(ADP-ribose)-polymerase were not activated, suggesting that cell death occurred by necrosis. Preincubation of osteogenic cells, leukocytes, or endothelial cells with PRS decreased the acute toxicity of H(2)O(2). The capacity of platelets to release H(2)O(2)-detoxifying activity was retained for up to 72 h. Aminotriazole, an inhibitor of catalase, decreased the cytoprotective activity of PRS, whereas blocking of glutathione peroxidase by mercaptosuccinate had no effect. These results suggest that platelet-released catalase can rapidly neutralize cytotoxic amounts of H(2)O(2), a process that may play a role during the early stages of bone regeneration.

  10. Expression of the alternative oxidase mitigates beta-amyloid production and toxicity in model systems.

    Science.gov (United States)

    El-Khoury, Riyad; Kaulio, Eveliina; Lassila, Katariina A; Crowther, Damian C; Jacobs, Howard T; Rustin, Pierre

    2016-07-01

    Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease.

  11. 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.

  12. Semiconductor quantum dot toxicity in a mouse in vivo model

    Science.gov (United States)

    Bozrova, Svetlana V.; Baryshnikova, Maria A.; Nabiev, Igor; Sukhanova, Alyona

    2017-01-01

    Quantum dots (QDs) are increasingly widely used in clinical medicine. Their most promising potential applications are cancer diagnosis, including in vivo tumour imaging and targeted drug delivery. In this connection, the main questions are whether or not QDs are toxic for humans and, if they are, what concentration is relatively harmless. We have carried out in vivo experiments with CdSe/ZnS fluorescent semiconductor core/shell QDs, which are currently the most widely used in research.

  13. 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...

  14. Periodicity in a "Food-limited" Population Model with Toxicants and Time Delays

    Institute of Scientific and Technical Information of China (English)

    Meng Fan; Ke Wang

    2002-01-01

    With the help of a continuation theorem based on Gaines and Mawhin's coincidence degree, we study the global existence of positive periodic solutions of a "food-limited" population model with toxicants and time delays. Some new results are obtained.

  15. 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...

  16. 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 pulmonary fibrosis , ...

  17. A biophysical model of the mitochondrial respiratory system and oxidative phosphorylation.

    Directory of Open Access Journals (Sweden)

    Daniel A Beard

    2005-09-01

    Full Text Available A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at complexes I, III, and IV of the electron transport system, ATP synthesis at F1F0 ATPase, substrate transporters including adenine nucleotide translocase and the phosphate-hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K+/H+ antiporter and passive H+ and K+ permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphate-dependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.

  18. A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation.

    Directory of Open Access Journals (Sweden)

    2005-09-01

    Full Text Available A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at complexes I, III, and IV of the electron transport system, ATP synthesis at F(1F(0 ATPase, substrate transporters including adenine nucleotide translocase and the phosphate-hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K/H antiporter and passive H and K permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphate-dependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.

  19. Modeling the toxicity of aromatic compounds to tetrahymena pyriformis: the response surface methodology with nonlinear methods.

    Science.gov (United States)

    Ren, Shijin

    2003-01-01

    Response surface models based on multiple linear regression had previously been developed for the toxicity of aromatic chemicals to Tetrahymena pyriformis. However, a nonlinear relationship between toxicity and one of the molecular descriptors in the response surface model was observed. In this study, response surface models were established using six nonlinear modeling methods to handle the nonlinearity exhibited in the aromatic chemicals data set. All models were validated using the method of cross-validation, and prediction accuracy was tested on an external data set. Results showed that response surface models based on locally weighted regression scatter plot smoothing (LOESS), multivariate adaptive regression splines (MARS), neural networks (NN), and projection pursuit regression (PPR) provided satisfactory power of model fitting and prediction and had similar applicabilities. The response surface models based on nonlinear methods were difficult to interpret and conservative in discriminating toxicity mechanisms.

  20. Development of a new toxic-unit model for the bioassessment of metals in streams

    Science.gov (United States)

    Schmidt, T.S.; Clements, W.H.; Mitchell, K.A.; Church, S.E.; Wanty, R.B.; Fey, D.L.; Verplanck, P.L.; San, Juan C.A.

    2010-01-01

    Two toxic-unit models that estimate the toxicity of trace-metal mixtures to benthic communities were compared. The chronic criterion accumulation ratio (CCAR), a modification of biotic ligand model (BLM) outputs for use as a toxic-unit model, accounts for the modifying and competitive influences of major cations (Ca2+, Mg2+, Na+, K+, H+), anions (HCO3−, CO32−,SO42−, Cl−, S2−) and dissolved organic carbon (DOC) in determining the free metal ion available for accumulation on the biotic ligand. The cumulative criterion unit (CCU) model, an empirical statistical model of trace-metal toxicity, considers only the ameliorative properties of Ca2+ and Mg2+ (hardness) in determining the toxicity of total dissolved trace metals. Differences in the contribution of a metal (e.g., Cu, Cd, Zn) to toxic units as determined by CCAR or CCU were observed and attributed to how each model incorporates the influences of DOC, pH, and alkalinity. Akaike information criteria demonstrate that CCAR is an improved predictor of benthic macroinvertebrate community metrics as compared with CCU. Piecewise models depict great declines (thresholds) in benthic macroinvertebrate communities at CCAR of 1 or more, while negative changes in benthic communities were detected at a CCAR of less than 1. We observed a 7% reduction in total taxa richness and a 43% decrease in Heptageniid abundance between background (CCAR = 0.1) and the threshold of chronic toxicity on the basis of continuous chronic criteria (CCAR = 1). In this first application of the BLM as a toxic-unit model, we found it superior to CCU.

  1. 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

  2. Correlation of Klebsiella pneumoniae comparative genetic analyses with virulence profiles in a murine respiratory disease model.

    Directory of Open Access Journals (Sweden)

    Ramy A Fodah

    Full Text Available Klebsiella pneumoniae is a bacterial pathogen of worldwide importance and a significant contributor to multiple disease presentations associated with both nosocomial and community acquired disease. ATCC 43816 is a well-studied K. pneumoniae strain which is capable of causing an acute respiratory disease in surrogate animal models. In this study, we performed sequencing of the ATCC 43816 genome to support future efforts characterizing genetic elements required for disease. Furthermore, we performed comparative genetic analyses to the previously sequenced genomes from NTUH-K2044 and MGH 78578 to gain an understanding of the conservation of known virulence determinants amongst the three strains. We found that ATCC 43816 and NTUH-K2044 both possess the known virulence determinant for yersiniabactin, as well as a Type 4 secretion system (T4SS, CRISPR system, and an acetonin catabolism locus, all absent from MGH 78578. While both NTUH-K2044 and MGH 78578 are clinical isolates, little is known about the disease potential of these strains in cell culture and animal models. Thus, we also performed functional analyses in the murine macrophage cell lines RAW264.7 and J774A.1 and found that MGH 78578 (K52 serotype was internalized at higher levels than ATCC 43816 (K2 and NTUH-K2044 (K1, consistent with previous characterization of the antiphagocytic properties of K1 and K2 serotype capsules. We also examined the three K. pneumoniae strains in a novel BALB/c respiratory disease model and found that ATCC 43816 and NTUH-K2044 are highly virulent (LD50<100 CFU while MGH 78578 is relatively avirulent.

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

    Science.gov (United States)

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

    2014-03-01

    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 (pI), inspiration and expiration time (tI, tE) 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 pI and adequate tE 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-expiratory pressure.

  4. 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.

  5. Respiratory mechanics during high-frequency oscillatory ventilation: a physical model and preterm infant study.

    Science.gov (United States)

    Singh, Rachana; Courtney, Sherry E; Weisner, Michael D; Habib, Robert H

    2012-04-01

    Accurate mechanics measurements during high-frequency oscillatory ventilation (HFOV) facilitate optimizing ventilator support settings. Yet, these are influenced substantially by endotracheal tube (ETT) contributions, which may dominate when leaks around uncuffed ETT are present. We hypothesized that 1) the effective removal of ETT leaks may be confirmed via direct comparison of measured vs. model-predicted mean intratracheal pressure [mPtr (meas) vs. mPtr (pred)], and 2) reproducible respiratory system resistance (Rrs) and compliance (Crs) may be derived from no-leak oscillatory Ptr and proximal flow. With the use of ETT test-lung models, proximal airway opening (Pao) and distal (Ptr) pressures and flows were measured during slow-cuff inflations until leaks are removed. These were repeated for combinations of HFOV settings [frequency, mean airway pressure (Paw), oscillation amplitudes (ΔP), and inspiratory time (%t(I))] and varying test-lung Crs. Results showed that leaks around the ETT will 1) systematically reduce the effective distending pressures and lung-delivered oscillatory volumes, and 2) derived mechanical properties are increasingly nonphysiologic as leaks worsen. Mean pressures were systematically reduced along the ventilator circuit and ETT (Paw > Pao > Ptr), even for no-leak conditions. ETT size-specific regression models were then derived for predicting mPtr based on mean Pao (mPao), ΔP, %t(I), and frequency. Next, in 10 of 11 studied preterm infants (0.77 ± 0.24 kg), no-to-minimal leak was confirmed based on excellent agreement between mPtr (meas) and mPtr (pred), and consequently, their oscillatory respiratory mechanics were evaluated. Infant resistance at the proximal ETT (R(ETT); resistance airway opening = R(ETT) + Rrs; P mechanical properties that can objectively guide ventilatory management of HFOV-treated preterm infants.

  6. An attraction-repulsion point process model for respiratory syncytial virus infections.

    Science.gov (United States)

    Goldstein, Joshua; Haran, Murali; Simeonov, Ivan; Fricks, John; Chiaromonte, Francesca

    2015-06-01

    How is the progression of a virus influenced by properties intrinsic to individual cells? We address this question by studying the susceptibility of cells infected with two strains of the human respiratory syncytial virus (RSV-A and RSV-B) in an in vitro experiment. Spatial patterns of infected cells give us insight into how local conditions influence susceptibility to the virus. We observe a complicated attraction and repulsion behavior, a tendency for infected cells to lump together or remain apart. We develop a new spatial point process model to describe this behavior. Inference on spatial point processes is difficult because the likelihood functions of these models contain intractable normalizing constants; we adapt an MCMC algorithm called double Metropolis-Hastings to overcome this computational challenge. Our methods are computationally efficient even for large point patterns consisting of over 10,000 points. We illustrate the application of our model and inferential approach to simulated data examples and fit our model to various RSV experiments. Because our model parameters are easy to interpret, we are able to draw meaningful scientific conclusions from the fitted models.

  7. Lung toxicity of biodegradable nanoparticles.

    Science.gov (United States)

    Fattal, Elias; Grabowski, Nadége; Mura, Simona; Vergnaud, Juliette; Tsapis, Nicolas; Hillaireau, Hervé

    2014-10-01

    Biodegradable nanoparticles exhibit high potentialities for local or systemic drug delivery through lung administration making them attractive as nanomedicine carriers. However, since particulate matter or some inorganic manufactured nanoparticles exposed to lung cells have provoked cytotoxic effects, inflammatory and oxidative stress responses, it becomes important to investigate nanomedicine toxicity towards the lungs. This is the reason why, in the present review, the behavior of biodegradable nanoparticles towards the different parts of the respiratory tract as well as the toxicological consequences, measured on several models in vitro, ex vivo or in vivo, are described. Taken all together, the different studies carried out so far conclude on no or slight toxicity of biodegradable nanoparticles.

  8. Predicting aquatic toxicities of chemical pesticides in multiple test species using nonlinear QSTR modeling approaches.

    Science.gov (United States)

    Basant, Nikita; Gupta, Shikha; Singh, Kunwar P

    2015-11-01

    In this study, we established nonlinear quantitative-structure toxicity relationship (QSTR) models for predicting the toxicities of chemical pesticides in multiple aquatic test species following the OECD (Organization for Economic Cooperation and Development) guidelines. The decision tree forest (DTF) and decision tree boost (DTB) based QSTR models were constructed using a pesticides toxicity dataset in Selenastrum capricornutum and a set of six descriptors. Other six toxicity data sets were used for external validation of the constructed QSTRs. Global QSTR models were also constructed using the combined dataset of all the seven species. The diversity in chemical structures and nonlinearity in the data were evaluated. Model validation was performed deriving several statistical coefficients for the test data and the prediction and generalization abilities of the QSTRs were evaluated. Both the QSTR models identified WPSA1 (weighted charged partial positive surface area) as the most influential descriptor. The DTF and DTB QSTRs performed relatively better than the single decision tree (SDT) and support vector machines (SVM) models used as a benchmark here and yielded R(2) of 0.886 and 0.964 between the measured and predicted toxicity values in the complete dataset (S. capricornutum). The QSTR models applied to six other aquatic species toxicity data yielded R(2) of >0.92 (DTF) and >0.97 (DTB), respectively. The prediction accuracies of the global models were comparable with those of the S. capricornutum models. The results suggest for the appropriateness of the developed QSTR models to reliably predict the aquatic toxicity of chemicals and can be used for regulatory purpose.

  9. Study of airflow during respiratory cycle in semi-realistic model of human tracheobronchial tree

    Science.gov (United States)

    Elcner, Jakub; Zaremba, M.; Maly, M.; Jedelsky, J.; Lizal, F.; Jicha, M.

    2016-06-01

    This article deals with study of airflow under breathing process, which is characteristic by unsteady behavior. Simulations provided by computational fluid dynamics (CFD) was compared with experiments performed on similar geometry of human upper airways. This geometry was represented by mouth cavity of realistic shape connected to an idealized tracheobronchial tree up to fourth generation of branching. Commercial CFD software Star-CCM+ was used to calculate airflow inside investigated geometry and method of Reynolds averaging of Navier-Stokes equations was used for subscribing the turbulent behavior through model geometry. Conditions corresponding to resting state were considered. Comparisons with experiments were provided on several points through trachea and bronchial tree and results with respect to inspiratory and respiratory part of breathing cycle was discussed.

  10. Bayesian model averaging method for evaluating associations between air pollution and respiratory mortality: a time-series study

    Science.gov (United States)

    Fang, Xin; Li, Runkui; Kan, Haidong; Bottai, Matteo; Fang, Fang

    2016-01-01

    Objective To demonstrate an application of Bayesian model averaging (BMA) with generalised additive mixed models (GAMM) and provide a novel modelling technique to assess the association between inhalable coarse particles (PM10) and respiratory mortality in time-series studies. Design A time-series study using regional death registry between 2009 and 2010. Setting 8 districts in a large metropolitan area in Northern China. Participants 9559 permanent residents of the 8 districts who died of respiratory diseases between 2009 and 2010. Main outcome measures Per cent increase in daily respiratory mortality rate (MR) per interquartile range (IQR) increase of PM10 concentration and corresponding 95% confidence interval (CI) in single-pollutant and multipollutant (including NOx, CO) models. Results The Bayesian model averaged GAMM (GAMM+BMA) and the optimal GAMM of PM10, multipollutants and principal components (PCs) of multipollutants showed comparable results for the effect of PM10 on daily respiratory MR, that is, one IQR increase in PM10 concentration corresponded to 1.38% vs 1.39%, 1.81% vs 1.83% and 0.87% vs 0.88% increase, respectively, in daily respiratory MR. However, GAMM+BMA gave slightly but noticeable wider CIs for the single-pollutant model (−1.09 to 4.28 vs −1.08 to 3.93) and the PCs-based model (−2.23 to 4.07 vs −2.03 vs 3.88). The CIs of the multiple-pollutant model from two methods are similar, that is, −1.12 to 4.85 versus −1.11 versus 4.83. Conclusions The BMA method may represent a useful tool for modelling uncertainty in time-series studies when evaluating the effect of air pollution on fatal health outcomes. PMID:27531727

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

    Science.gov (United States)

    Berman, Nathaniel; Lectura, Melisa; Thurman, Joshua M; Reinecke, James; Raff, Amanda C; Melamed, Michal L; 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.

  12. Spatio-temporal and stochastic modelling of severe acute respiratory syndrome

    Directory of Open Access Journals (Sweden)

    Poh-Chin Lai

    2013-11-01

    Full Text Available This study describes the development of a spatio-temporal disease model based on the episodes of severe acute respiratory syndrome (SARS that took place in Hong Kong in 2003. In contrast to conventional, deterministic modelling approaches, the model described here is predominantly spatial. It incorporates stochastic processing of environmental and social variables that interact in space and time to affect the patterns of disease transmission in a community. The model was validated through a comparative assessment between actual and modelled distribution of diseased locations. Our study shows that the inclusion of location-specific characteristics satisfactorily replicates the spatial dynamics of an infectious disease. The Pearson’s correlation coefficients for five trials based on 3-day aggregation of disease counts for 1-3, 4-6 and 7-9 day forecasts were 0.57- 0.95, 0.54-0.86 and 0.57-0.82, respectively, while the correlation based on 5-day aggregation for the 1-5 day forecast was 0.55- 0.94 and 0.58-0.81 for the 6-10 day forecast. The significant and strong relationship between actual results and forecast is encouraging for the potential development of an early warning system for detecting this type of disease outbreaks.

  13. A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors

    Science.gov (United States)

    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 pu...

  14. MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development (SETAC abstract)

    Science.gov (United States)

    The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, the development of quantitative structure activity relationship (QSAR) and other models has been limit...

  15. Gene expression patterns in Rainbow Trout, Oncorhynchus mykiss, exposed to a suite of model toxicants

    Energy Technology Data Exchange (ETDEWEB)

    Hook, Sharon E.; Skillman, Ann D.; Small, Jonathan A.; Schultz, Irv R.

    2006-05-25

    The increased availability and use of DNA microarrays has allowed the characterization of gene expression patterns associated with different toxicants. An important question is whether toxicant induced changes in gene expression in fish are sufficiently diverse to allow for identification of specific modes of action and/or specific contaminants. In theory, each class of toxicant may generate a gene expression profile unique to its mode of toxic action. We exposed isogenic (cloned) rainbow trout Oncorhyncus mykiss, to sublethal levels of a series of model toxicants with varying modes of action, including ethynylestradiol (xeno-estrogen), trenbolone (anabolic steroid; model androgen), 2,2,4,4´tetrabromodiphenyl ether (BDE-47, thyroid active), diquat (oxidant stressor), chromium VI, and benzo[a]pyrene (BaP) for a period of 1-3 weeks. Following exposure, fish were euthanized, livers harvested and RNA extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon / Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNA’s. The slides were scanned to measure abundance of a given transcript in each sample relative to controls. Data were analyzed via Genespring (Silicon Genetics) to identify a list of up and down regulated genes, as well as to determine gene clustering patterns that can be used as “expression signatures”. Our analysis indicates each toxicant generated specific gene expression profiles. Most genes exhibiting altered expression responded to only one of the toxicants. Relatively few genes are co-expressed in multiple treatments. For example, BaP and Diquat, both of which exert toxicity via oxidative stress, up-regulated 28 of the same genes, of over 100 genes altered by ether treatment. Other genes associated with steroidogenesis, p450 and estrogen responsive genes appear to be useful for selectively identifying toxicant mode of in fish, suggesting a link between gene expression

  16. Use of a (Quantitative) Structure-Activity Relationship [(Q)SAR] model to predict the toxicity of naphthenic acids

    DEFF Research Database (Denmark)

    Frank, Richard; Sanderson, Hans; Kavanagh, Richard

    2010-01-01

    -Activity Relationship ((Q)SAR) model to accurately predict the toxicity of NA-like surrogates was investigated.  The USEPA’s ECOSAR model predicted the toxicity of NA-like surrogates with acceptable accuracy in comparison to observed toxicity values from Vibrio fischeri and Daphnia magna assays, indicating...... that the model has potential to serve as a prioritization tool for identifying NA structures likely to have an increased toxicity.  Investigating NAs of equal MW, the ECOSAR model predicted increased toxic potency for NAs containing fewer carbon rings.  Furthermore, NA structures with a linear grouping of carbon...

  17. Prediction of organ toxicity endpoints by QSAR modeling based on precise chemical-histopathology annotations.

    Science.gov (United States)

    Myshkin, Eugene; Brennan, Richard; Khasanova, Tatiana; Sitnik, Tatiana; Serebriyskaya, Tatiana; Litvinova, Elena; Guryanov, Alexey; Nikolsky, Yuri; Nikolskaya, Tatiana; Bureeva, Svetlana

    2012-09-01

    The ability to accurately predict the toxicity of drug candidates from their chemical structure is critical for guiding experimental drug discovery toward safer medicines. Under the guidance of the MetaTox consortium (Thomson Reuters, CA, USA), which comprised toxicologists from the pharmaceutical industry and government agencies, we created a comprehensive ontology of toxic pathologies for 19 organs, classifying pathology terms by pathology type and functional organ substructure. By manual annotation of full-text research articles, the ontology was populated with chemical compounds causing specific histopathologies. Annotated compound-toxicity associations defined histologically from rat and mouse experiments were used to build quantitative structure-activity relationship models predicting subcategories of liver and kidney toxicity: liver necrosis, liver relative weight gain, liver lipid accumulation, nephron injury, kidney relative weight gain, and kidney necrosis. All models were validated using two independent test sets and demonstrated overall good performance: initial validation showed 0.80-0.96 sensitivity (correctly predicted toxic compounds) and 0.85-1.00 specificity (correctly predicted non-toxic compounds). Later validation against a test set of compounds newly added to the database in the 2 years following initial model generation showed 75-87% sensitivity and 60-78% specificity. General hepatotoxicity and nephrotoxicity models were less accurate, as expected for more complex endpoints.

  18. Nanoparticle toxicity assessment using an in vitro 3-D kidney organoid culture model.

    Science.gov (United States)

    Astashkina, Anna I; Jones, Clint F; Thiagarajan, Giridhar; Kurtzeborn, Kristen; Ghandehari, Hamid; Brooks, Benjamin D; Grainger, David W

    2014-08-01

    Nanocarriers and nanoparticles remain an intense pharmaceutical and medical imaging technology interest. Their entry into clinical use is hampered by the lack of reliable in vitro models that accurately predict in vivo toxicity. This study evaluates a 3-D kidney organoid proximal tubule culture to assess in vitro toxicity of the hydroxylated generation-5 PAMAM dendrimer (G5-OH) compared to previously published preclinical in vivo rodent nephrotoxicity data. 3-D kidney proximal tubule cultures were created using isolated murine proximal tubule fractions suspended in a biomedical grade hyaluronic acid-based hydrogel. Toxicity in these cultures to neutral G5-OH dendrimer nanoparticles and gold nanoparticles in vitro was assessed using clinical biomarker generation. Neutral PAMAM nanoparticle dendrimers elicit in vivo-relevant kidney biomarkers and cell viability in a 3-D kidney organoid culture that closely reflect toxicity markers reported in vivo in rodent nephrotoxicity models exposed to this same nanoparticle.

  19. The effects of salbutamol in an experimental model with acute respiratory distress syndrome

    Institute of Scientific and Technical Information of China (English)

    Sema Yilmaz; Diner Yildizdas; Kenan Daglioglu; Arbil Acikalin; Can Acipayam; Ibrahim Bayram; Derya Gumurdulu; Atila Tanyeli

    2012-01-01

    Objective: To investigate salbutamol effects on histopathologic features of acute respiratory distress syndrome (ARDS). Methods: ARDS was designed in Wistar albino male rats, 250-300 g in weight, by intratracheal instillation of physiological saline solution. Anesthezied and tracheotomized rats with ARDS were pressure-controlled ventilated. At the end of the 210 minutes, two hours past and nebulized salbutamol inhalation was tried. All rats were assigned to two groups: Group 1 (n=10) control group, given no treatment, group 2 (n=10) received salbutamol. Nebulized salbutamol inhalation was given in the dosage of 0, 15 mg/kg/dose. Rats were continued to be on ventilator through the experiment. After the last inhalation, two hours past and their both lungs were excised for histopathological examination. Results: Rat-model ARDS had similar histopathological appearance occuring during the acute phase of the acute respiratory distress syndrome in humans. A statistical difference was seen between control and salbutamol group (P=0.002) for HM. The margination of leukocytes was decreased in salbutamol group. The difference was significant (P<0.042). Hemorrhage and interstitial/intraalveolar edema were much lower in 0.15 mg/dose nebulized salbutamol group than that of control group. There was a significant difference statistically between two groups (P<0.001). Conclusions: Inhaled salbutamol therapy for ARDS is may be associated with the improvement of inflamation. Besides known effects of salbutamol, the reducing of infiltration of polymorphonuclear neutrophil leukocytes, interstitial/intraalveolar edema, perivascular and/or intraalveolar hemorrhage and hyaline membrane formation should be emphasized.

  20. 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

  1. Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants.

    Science.gov (United States)

    You, Dahui; Saravia, Jordy; Siefker, David; Shrestha, Bishwas; Cormier, Stephania A

    2015-10-07

    The infant immune response to respiratory syncytial virus (RSV) remains incompletely understood. Here we review the use of a neonatal mouse model of RSV infection to mimic severe infection in human infants. We describe numerous age-specific responses, organized by cell type, observed in RSV-infected neonatal mice and draw comparisons (when possible) to human infants.

  2. A MURINE MODEL FOR LOW MOLECULAR WEIGHT CHEMICALS: DIFFERENTIATION OF RESPIRATORY SENSITIZERS (TMA) FROM CONTACT SENSITIZERS (DNFB)

    Science.gov (United States)

    Exposure to low molecular weight (LMW) chemicals contributes to both dermal and respiratory sensitization and is an important occupational health problem. Our goal was to establish an in vivo murine model for hazard identification of LMW chemicals that have the potential to indu...

  3. Isoflurane anesthetic hypersensitivity and progressive respiratory depression in a mouse model with isolated mitochondrial complex I deficiency

    NARCIS (Netherlands)

    Roelofs, S.; Manjeri, G.R.; Willems, P.H.G.M.; Scheffer, G.J.; Smeitink, J.A.M.; Driessen, J.J.

    2014-01-01

    BACKGROUND: Children with mitochondrial disorders are frequently anesthetized for a wide range of operations. These disorders may interfere with the response to surgery and anesthesia. We examined anesthetic sensitivity to and respiratory effects of isoflurane in the Ndufs4 knockout (KO) mouse model

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

    Directory of Open Access Journals (Sweden)

    Oluyemi Toyinbo

    2016-03-01

    Full Text Available Background: 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. Methods: 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. Results: 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. Conclusions: 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.

  5. Multispecies QSAR modeling for predicting the aquatic toxicity of diverse organic chemicals for regulatory toxicology.

    Science.gov (United States)

    Singh, Kunwar P; Gupta, Shikha; Kumar, Anuj; Mohan, Dinesh

    2014-05-19

    The research aims to develop multispecies quantitative structure-activity relationships (QSARs) modeling tools capable of predicting the acute toxicity of diverse chemicals in various Organization for Economic Co-operation and Development (OECD) recommended test species of different trophic levels for regulatory toxicology. Accordingly, the ensemble learning (EL) approach based classification and regression QSAR models, such as decision treeboost (DTB) and decision tree forest (DTF) implementing stochastic gradient boosting and bagging algorithms were developed using the algae (P. subcapitata) experimental toxicity data for chemicals. The EL-QSAR models were successfully applied to predict toxicities of wide groups of chemicals in other test species including algae (S. obliguue), daphnia, fish, and bacteria. Structural diversity of the selected chemicals and those of the end-point toxicity data of five different test species were tested using the Tanimoto similarity index and Kruskal-Wallis (K-W) statistics. Predictive and generalization abilities of the constructed QSAR models were compared using statistical parameters. The developed QSAR models (DTB and DTF) yielded a considerably high classification accuracy in complete data of model building (algae) species (97.82%, 99.01%) and ranged between 92.50%-94.26% and 92.14%-94.12% in four test species, respectively, whereas regression QSAR models (DTB and DTF) rendered high correlation (R(2)) between the measured and model predicted toxicity end-point values and low mean-squared error in model building (algae) species (0.918, 0.15; 0.905, 0.21) and ranged between 0.575 and 0.672, 0.18-0.51 and 0.605-0.689 and 0.20-0.45 in four different test species. The developed QSAR models exhibited good predictive and generalization abilities in different test species of varied trophic levels and can be used for predicting the toxicities of new chemicals for screening and prioritization of chemicals for regulation.

  6. Induced respiratory system modeling by high frequency chest compression using lumped system identification method.

    Science.gov (United States)

    Lee, Jongwon; Lee, Yong Wan; O'Clock, George; Zhu, Xiaoming; Parhi, Keshab K; Warwick, Warren J

    2009-01-01

    High frequency chest compression (HFCC) treatment systems are used to promote mucus transport and mitigate pulmonary system clearance problems to remove sputum from the airways in patients with Cystic Fibrosis (CF) and at risk of developing chronic obstructive pulmonary disease (COPD). Every HFCC system consists of a pump generator, one or two hoses connected to a vest, to deliver the pulsation. There are three different waveforms in use; symmetric sine, the asymmetric sine and the trapezoid waveforms. There have been few studies that compared the efficacy of a sine waveform with the HFCC pulsations. In this study we present a model of the respiratory system for a young normal subject who is one of co-authors. The input signal is the pressure applied by the vest to chest, at a frequency of 6Hz. Using the system model simulation, the effectiveness of different source waveforms is evaluated and compared by observing the waveform response associated with air flow at the mouth. Also the study demonstrated that the ideal rectangle wave produced the maximum peak air flow, and followed by the trapezoid, triangle and sine waveform. The study suggests that a pulmonary system evaluation or modeling effort for CF patient might be useful as a method to optimize frequency and waveform structure choices for HFCC therapeutic intervention.

  7. Comparison of a priori calibration models for respiratory inductance plethysmography during running.

    Science.gov (United States)

    Leutheuser, Heike; Heyde, Christian; Gollhofer, Albert; Eskofier, Bjoern M

    2014-01-01

    Respiratory inductive plethysmography (RIP) has been introduced as an alternative for measuring ventilation by means of body surface displacement (diameter changes in rib cage and abdomen). Using a posteriori calibration, it has been shown that RIP may provide accurate measurements for ventilatory tidal volume under exercise conditions. Methods for a priori calibration would facilitate the application of RIP. Currently, to the best knowledge of the authors, none of the existing ambulant procedures for RIP calibration can be used a priori for valid subsequent measurements of ventilatory volume under exercise conditions. The purpose of this study is to develop and validate a priori calibration algorithms for ambulant application of RIP data recorded in running exercise. We calculated Volume Motion Coefficients (VMCs) using seven different models on resting data and compared the root mean squared error (RMSE) of each model applied on running data. Least squares approximation (LSQ) without offset of a two-degree-of-freedom model achieved the lowest RMSE value. In this work, we showed that a priori calibration of RIP exercise data is possible using VMCs calculated from 5 min resting phase where RIP and flowmeter measurements were performed simultaneously. The results demonstrate that RIP has the potential for usage in ambulant applications.

  8. A Predictive Model for Toxicity Effects Assessment of Biotransformed Hepatic Drugs Using Iterative Sampling Method.

    Science.gov (United States)

    Tharwat, Alaa; Moemen, Yasmine S; Hassanien, Aboul Ella

    2016-12-09

    Measuring toxicity is one of the main steps in drug development. Hence, there is a high demand for computational models to predict the toxicity effects of the potential drugs. In this study, we used a dataset, which consists of four toxicity effects:mutagenic, tumorigenic, irritant and reproductive effects. The proposed model consists of three phases. In the first phase, rough set-based methods are used to select the most discriminative features for reducing the classification time and improving the classification performance. Due to the imbalanced class distribution, in the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling and Synthetic Minority Oversampling Technique are used to solve the problem of imbalanced datasets. ITerative Sampling (ITS) method is proposed to avoid the limitations of those methods. ITS method has two steps. The first step (sampling step) iteratively modifies the prior distribution of the minority and majority classes. In the second step, a data cleaning method is used to remove the overlapping that is produced from the first step. In the third phase, Bagging classifier is used to classify an unknown drug into toxic or non-toxic. The experimental results proved that the proposed model performed well in classifying the unknown samples according to all toxic effects in the imbalanced datasets.

  9. 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...

  10. 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.

  11. 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.

  12. A Computer Model for the Simulation of Nonspherical Particle Dynamics in the Human Respiratory Tract

    Directory of Open Access Journals (Sweden)

    Robert Sturm

    2012-01-01

    Full Text Available In the study presented here deposition of spheres and nonspherical particles with various aspect ratios (0.01–100 in the human respiratory tract was theoretically modeled. Shape of the nonspherical particles was considered by the application of the latest aerodynamic diameter concepts. Particle deposition was predicted by using a stochastic model of the lung geometry and simulating particle transport trajectories according to the random-walk algorithm. Concerning fibers total deposition is significantly enhanced with respect to that of spheres for μm-sized particles, whereby at normal breathing conditions peripheral lung compartments serve as primary deposition targets. In the case of oblate disks, total deposition becomes mostly remarkable for submicron particles, with the bronchioli and alveoli being targeted to a high extent. Enhancement of the aerodynamic diameter and/or flow rate generally causes a displacement of deposition maxima from peripheral to more proximal lung regions. From these findings, it can be concluded that these particle classes may represent tremendous occupational hazards, especially if they are attached with radioactive elements or heavy metals.

  13. Ecotoxicogenomic approaches for understanding molecular mechanisms of environmental chemical toxicity using aquatic invertebrate, Daphnia model organism.

    Science.gov (United States)

    Kim, Hyo Jeong; Koedrith, Preeyaporn; Seo, Young Rok

    2015-05-29

    Due to the rapid advent in genomics technologies and attention to ecological risk assessment, the term "ecotoxicogenomics" has recently emerged to describe integration of omics studies (i.e., transcriptomics, proteomics, metabolomics, and epigenomics) into ecotoxicological fields. Ecotoxicogenomics is defined as study of an entire set of genes or proteins expression in ecological organisms to provide insight on environmental toxicity, offering benefit in ecological risk assessment. Indeed, Daphnia is a model species to study aquatic environmental toxicity designated in the Organization for Economic Co-operation and Development's toxicity test guideline and to investigate expression patterns using ecotoxicology-oriented genomics tools. Our main purpose is to demonstrate the potential utility of gene expression profiling in ecotoxicology by identifying novel biomarkers and relevant modes of toxicity in Daphnia magna. These approaches enable us to address adverse phenotypic outcomes linked to particular gene function(s) and mechanistic understanding of aquatic ecotoxicology as well as exploration of useful biomarkers. Furthermore, key challenges that currently face aquatic ecotoxicology (e.g., predicting toxicant responses among a broad spectrum of phytogenetic groups, predicting impact of temporal exposure on toxicant responses) necessitate the parallel use of other model organisms, both aquatic and terrestrial. By investigating gene expression profiling in an environmentally important organism, this provides viable support for the utility of ecotoxicogenomics.

  14. Ecotoxicogenomic Approaches for Understanding Molecular Mechanisms of Environmental Chemical Toxicity Using Aquatic Invertebrate, Daphnia Model Organism

    Directory of Open Access Journals (Sweden)

    Hyo Jeong Kim

    2015-05-01

    Full Text Available Due to the rapid advent in genomics technologies and attention to ecological risk assessment, the term “ecotoxicogenomics” has recently emerged to describe integration of omics studies (i.e., transcriptomics, proteomics, metabolomics, and epigenomics into ecotoxicological fields. Ecotoxicogenomics is defined as study of an entire set of genes or proteins expression in ecological organisms to provide insight on environmental toxicity, offering benefit in ecological risk assessment. Indeed, Daphnia is a model species to study aquatic environmental toxicity designated in the Organization for Economic Co-operation and Development’s toxicity test guideline and to investigate expression patterns using ecotoxicology-oriented genomics tools. Our main purpose is to demonstrate the potential utility of gene expression profiling in ecotoxicology by identifying novel biomarkers and relevant modes of toxicity in Daphnia magna. These approaches enable us to address adverse phenotypic outcomes linked to particular gene function(s and mechanistic understanding of aquatic ecotoxicology as well as exploration of useful biomarkers. Furthermore, key challenges that currently face aquatic ecotoxicology (e.g., predicting toxicant responses among a broad spectrum of phytogenetic groups, predicting impact of temporal exposure on toxicant responses necessitate the parallel use of other model organisms, both aquatic and terrestrial. By investigating gene expression profiling in an environmentally important organism, this provides viable support for the utility of ecotoxicogenomics.

  15. Ecotoxicogenomic Approaches for Understanding Molecular Mechanisms of Environmental Chemical Toxicity Using Aquatic Invertebrate, Daphnia Model Organism

    Science.gov (United States)

    Kim, Hyo Jeong; Koedrith, Preeyaporn; Seo, Young Rok

    2015-01-01

    Due to the rapid advent in genomics technologies and attention to ecological risk assessment, the term “ecotoxicogenomics” has recently emerged to describe integration of omics studies (i.e., transcriptomics, proteomics, metabolomics, and epigenomics) into ecotoxicological fields. Ecotoxicogenomics is defined as study of an entire set of genes or proteins expression in ecological organisms to provide insight on environmental toxicity, offering benefit in ecological risk assessment. Indeed, Daphnia is a model species to study aquatic environmental toxicity designated in the Organization for Economic Co-operation and Development’s toxicity test guideline and to investigate expression patterns using ecotoxicology-oriented genomics tools. Our main purpose is to demonstrate the potential utility of gene expression profiling in ecotoxicology by identifying novel biomarkers and relevant modes of toxicity in Daphnia magna. These approaches enable us to address adverse phenotypic outcomes linked to particular gene function(s) and mechanistic understanding of aquatic ecotoxicology as well as exploration of useful biomarkers. Furthermore, key challenges that currently face aquatic ecotoxicology (e.g., predicting toxicant responses among a broad spectrum of phytogenetic groups, predicting impact of temporal exposure on toxicant responses) necessitate the parallel use of other model organisms, both aquatic and terrestrial. By investigating gene expression profiling in an environmentally important organism, this provides viable support for the utility of ecotoxicogenomics. PMID:26035755

  16. A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors-abstract

    Science.gov (United States)

    The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action using a recently published dataset contain...

  17. Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity

    Directory of Open Access Journals (Sweden)

    William Dott

    2014-01-01

    Full Text Available Mitochondrial toxicity is increasingly being implicated as a contributing factor to many xenobiotic-induced organ toxicities, including skeletal muscle toxicity. This has necessitated the need for predictive in vitro models that are able to sensitively detect mitochondrial toxicity of chemical entities early in the research and development process. One such cell model involves substituting galactose for glucose in the culture media. Since cells cultured in galactose are unable to generate sufficient ATP from glycolysis they are forced to rely on mitochondrial oxidative phosphorylation for ATP generation and consequently are more sensitive to mitochondrial perturbation than cells grown in glucose. The aim of this study was to characterise cellular growth, bioenergetics and mitochondrial toxicity of the L6 rat skeletal muscle cell line cultured in either high glucose or galactose media. L6 myoblasts proliferated more slowly when cultured in galactose media, although they maintained similar levels of ATP. Galactose cultured L6 cells were significantly more sensitive to classical mitochondrial toxicants than glucose-cultured cells, confirming the cells had adapted to galactose media. Analysis of bioenergetic function with the XF Seahorse extracellular flux analyser demonstrated that oxygen consumption rate (OCR was significantly increased whereas extracellular acidification rate (ECAR, a measure of glycolysis, was decreased in cells grown in galactose. Mitochondria operated closer to state 3 respiration and had a lower mitochondrial membrane potential and basal mitochondrial O2·– level compared to cells in the glucose model. An antimycin A (AA dose response revealed that there was no difference in the sensitivity of OCR to AA inhibition between glucose and galactose cells. Importantly, cells in glucose were able to up-regulate glycolysis, while galactose cells were not. These results confirm that L6 cells are able to adapt to growth in a

  18. Establishment of a new dynamic RRC model in smoke toxicity evaluation and engineering application

    Institute of Scientific and Technical Information of China (English)

    YANG Lizhong; FANG Tingyong; ZHOU Xiaodong; FENG Wenxing; HUANG Rui; ZHAI Guanglong; FAN Weicheng

    2005-01-01

    It is by now a well established fact that the overwhelming hazard from fire is smoke as far as the death of people in the fire is concerned. There are many methodologies for addressing the smoke toxicity component of fire hazard such as CO stochastic model,FED (fractional effective dose) model, FEC (fractional effective concentration) model, N-gas model and so on. None of these models can reflect spatio-temporal variation of the smoke concentration. A new dynamic smoke toxicity evaluation model, RRC (respiration, route and concentration) model, is proposed in this paper concerning the three decisive factors in real fire such as the respiration, movement route of people and the distribution of smoke concentration in the building. Furthermore, an example of the model is presented.

  19. Sorption of toxic organic compounds on wastewater solids: Mechanism and modeling

    Energy Technology Data Exchange (ETDEWEB)

    Wang, L.; Govind, R.; Dobbs, R.A.

    1992-01-01

    Sorption of toxic organic compounds on wastewater solids is an important process in conventional biological wastewater treatment systems. The extent of accumulation of toxic organic compounds by sorption onto wastewater solids not only affects the efficiency of the treatment system, but also impacts the management of wastewater solids. The study is an attempt to propose a mechanism for understanding the sorption phenomenon and to develop a model for sorption on wastewater solids based on the proposed mechanism. It was postulated that sorption was a combination of two processes: adsorption and partitioning. A sorption model was developed for both single component and multicomponent systems. The model was tested using single component experimental isotherm data of eight toxic organic compounds.

  20. SU-E-J-163: A Biomechanical Lung Model for Respiratory Motion Study

    Energy Technology Data Exchange (ETDEWEB)

    Liu, X; Belcher, AH; Grelewicz, Z; Wiersma, RD [The University of Chicago, Chicago, IL (United States)

    2015-06-15

    Purpose: This work presents a biomechanical model to investigate the complex respiratory motion for the lung tumor tracking in radiosurgery by computer simulation. Methods: The models include networked massspring-dampers to describe the tumor motion, different types of surrogate signals, and the force generated by the diaphragm. Each mass-springdamper has the same mechanical structure and each model can have different numbers of mass-spring-dampers. Both linear and nonlinear stiffness parameters were considered, and the damping ratio was tuned in a range so that the tumor motion was over-damped (no natural tumor oscillation occurs without force from the diaphragm). The simulation was run by using ODE45 (ordinary differential equations by Runge-Kutta method) in MATLAB, and all time courses of motions and inputs (force) were generated and compared. Results: The curvature of the motion time courses around their peaks was sensitive to the damping ratio. Therefore, the damping ratio can be determined based on the clinical data of a high sampling rate. The peak values of different signals and the time the peaks occurred were compared, and it was found that the diaphragm force had a time lead over the tumor motion, and the lead time (0.1–0.4 seconds) depended on the distance between the tumor and the diaphragm. Conclusion: We reported a model based analysis approach for the spatial and temporal relation between the motion of the lung tumor and the surrogate signals. Due to the phase lead of the diaphragm in comparing with the lung tumor motion, the measurement of diaphragm motion (or its electromyography signal) can be used as a beam gating signal in radiosurgery, and it can also be an additional surrogate signal for better tumor motion tracking. The research is funded by the American Cancer Society (ACS) grant. The grant name is: Frameless SRS Based on Robotic Head Motion Cancellation. The grant number is: RSG-13-313-01-CCE.

  1. Multi-Scale Computational Analyses of JP-8 Fuel Droplets and Vapors in Human Respiratory Airway Models

    Science.gov (United States)

    2007-10-31

    Deposition Clearance and Effects in the Lung 20, 294-309. Kleinstreuer, C., Zhang, Z., 2003. Laminar-to-turbulent fluid-particle flows in a human airway ...FA9550-04-1-0422 Vapors in Human Respiratory Airway Models 5b. GRANT NUMBER Sc. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Kleinstreuer...tracheobronchial airway models, transient 3- D as well as equivalent steady-state solutions have been obtained for the transport and deposition of

  2. 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

  3. Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model

    NARCIS (Netherlands)

    Schijf, Marcel A.; Kruijsen, Debby; Bastiaans, Jacqueline; Coenjaerts, Frank E. J.; Garssen, Johan; van Bleek, Grada M.; van't Land, Belinda

    2012-01-01

    Breast feeding reduces the risk of developing severe respiratory syncytial virus (RSV) infections in infants. In addition to maternal antibodies, other immune-modulating factors in human milk contribute to this protection. Specific dietary prebiotic oligosaccharides, similar to oligosaccharides pres

  4. QSTR modeling for qualitative and quantitative toxicity predictions of diverse chemical pesticides in honey bee for regulatory purposes.

    Science.gov (United States)

    Singh, Kunwar P; Gupta, Shikha; Basant, Nikita; Mohan, Dinesh

    2014-09-15

    Pesticides are designed toxic chemicals for specific purposes and can harm nontarget species as well. The honey bee is considered a nontarget test species for toxicity evaluation of chemicals. Global QSTR (quantitative structure-toxicity relationship) models were established for qualitative and quantitative toxicity prediction of pesticides in honey bee (Apis mellifera) based on the experimental toxicity data of 237 structurally diverse pesticides. Structural diversity of the chemical pesticides and nonlinear dependence in the toxicity data were evaluated using the Tanimoto similarity index and Brock-Dechert-Scheinkman statistics. Probabilistic neural network (PNN) and generalized regression neural network (GRNN) QSTR models were constructed for classification (two and four categories) and function optimization problems using the toxicity end point in honey bees. The predictive power of the QSTR models was tested through rigorous validation performed using the internal and external procedures employing a wide series of statistical checks. In complete data, the PNN-QSTR model rendered a classification accuracy of 96.62% (two-category) and 95.57% (four-category), while the GRNN-QSTR model yielded a correlation (R(2)) of 0.841 between the measured and predicted toxicity values with a mean squared error (MSE) of 0.22. The results suggest the appropriateness of the developed QSTR models for reliably predicting qualitative and quantitative toxicities of pesticides in honey bee. Both the PNN and GRNN based QSTR models constructed here can be useful tools in predicting the qualitative and quantitative toxicities of the new chemical pesticides for regulatory purposes.

  5. The combination of PRRS virus and bacterial endotoxin as a model for multifactorial respiratory disease in pigs.

    Science.gov (United States)

    Van Gucht, Steven; Labarque, Geoffrey; Van Reeth, Kristien

    2004-12-08

    This paper reviews in vivo studies on the interaction between porcine reproductive and respiratory syndrome virus (PRRSV) and LPS performed in the authors' laboratory. The main aim was to develop a reproducible model to study the pathogenesis of PRRSV-induced multifactorial respiratory disease. The central hypothesis was that respiratory disease results from an overproduction of proinflammatory cytokines in the lungs. In a first series of studies, PRRSV was shown to be a poor inducer of TNF-alpha and IFN-alpha in the lungs, whereas IL-1 and the anti-inflammatory cytokine IL-10 were produced consistently during infection. We then set up a dual inoculation model in which pigs were inoculated intratracheally with PRRSV and 3-14 days later with LPS. PRRSV-infected pigs developed acute respiratory signs for 12-24h upon intratracheal LPS inoculation, in contrast to pigs inoculated with PRRSV or LPS only. Moreover, peak TNF-alpha, IL-1 and IL-6 titers were 10-100 times higher in PRRSV-LPS inoculated pigs than in the singly inoculated pigs and the cytokine overproduction was associated with disease. To further prove the role of proinflammatory cytokines, we studied the effect of pentoxifylline, a known inhibitor of TNF-alpha and IL-1, on PRRSV-LPS induced cytokine production and disease. The clinical effects of two non-steroidal anti-inflammatory drugs (NSAIDs), meloxicam and flunixin meglumine, were also examined. Pentoxifylline, but not the NSAIDs, significantly reduced fever and respiratory signs from 2 to 6h after LPS. The levels of TNF-alpha and IL-1 in the lungs of pentoxifylline-treated pigs were moderately reduced, but were still 26 and 3.5-fold higher than in pigs inoculated with PRRSV or LPS only. This indicates that pathways other than inhibition of cytokine production contributed to the clinical improvement. Finally, we studied a mechanism by which PRRSV may sensitize the lungs for LPS. We hypothesized that PRRSV would increase the amount of LPS receptor

  6. Using Online Tool (iPrior) for Modeling ToxCast™ Assays Towards Prioritization of Animal Toxicity Testing.

    Science.gov (United States)

    Abdelaziz, Ahmed; Sushko, Yurii; Novotarskyi, Sergii; Körner, Robert; Brandmaier, Stefan; Tetko, Igor V

    2015-01-01

    The use of long-term animal studies for human and environmental toxicity estimation is more discouraged than ever before. Alternative models for toxicity prediction, including QSAR studies, are gaining more ground. A recent approach is to combine in vitro chemical profiling and in silico chemical descriptors with the knowledge about toxicity pathways to derive a unique signature for toxicity endpoints. In this study we investigate the ToxCast™ Phase I data regarding their ability to predict long-term animal toxicity. We investigated thousands of models constructed in an effort to predict 61 toxicity endpoints using multiple descriptor packages and hundreds of in vitro assays. We investigated the use of in vitro assays and biochemical pathways on model performance. We identified 10 toxicity endpoints where biologically derived descriptors from in vitro assays or pathway perturbations improved the model prediction ability. In vivo toxicity endpoints proved generally challenging to model. Few models were possible to readily model with a balanced accuracy (BA) above 0.7. We also constructed in silico models to predict the outcome of 144 in vitro assays. This showed better statistical metrics with 79 out of 144 assays having median balanced accuracy above 0.7. This suggests that the in vitro datasets have a better modelability than in vivo animal toxicities for the given datasets. Moreover, we published an online platform (http://iprior.ochem.eu) that automates large-scale model building and analysis.

  7. Modelling the Tox21 10 K chemical profiles for in vivo toxicity prediction and mechanism characterization.

    Science.gov (United States)

    Huang, Ruili; Xia, Menghang; Sakamuru, Srilatha; Zhao, Jinghua; Shahane, Sampada A; Attene-Ramos, Matias; Zhao, Tongan; Austin, Christopher P; Simeonov, Anton

    2016-01-26

    Target-specific, mechanism-oriented in vitro assays post a promising alternative to traditional animal toxicology studies. Here we report the first comprehensive analysis of the Tox21 effort, a large-scale in vitro toxicity screening of chemicals. We test ∼ 10,000 chemicals in triplicates at 15 concentrations against a panel of nuclear receptor and stress response pathway assays, producing more than 50 million data points. Compound clustering by structure similarity and activity profile similarity across the assays reveals structure-activity relationships that are useful for the generation of mechanistic hypotheses. We apply structural information and activity data to build predictive models for 72 in vivo toxicity end points using a cluster-based approach. Models based on in vitro assay data perform better in predicting human toxicity end points than animal toxicity, while a combination of structural and activity data results in better models than using structure or activity data alone. Our results suggest that in vitro activity profiles can be applied as signatures of compound mechanism of toxicity and used in prioritization for more in-depth toxicological testing.

  8. Influence of respiratory substrate in carbon steel corrosion by a Sulphate Reducing Prokaryote model organism.

    Science.gov (United States)

    Dall'agnol, Leonardo T; Cordas, Cristina M; Moura, José J G

    2014-06-01

    Sulphate Reducing Prokaryotes (SRP) are an important group of microorganisms involved in biocorrosion processes. Sulphide production is recognized as a fundamental cause of corrosion and nitrate is often used as treatment. The present work analyses the influence of respiratory substrates in the metal, from off-shore installations, SRP influenced corrosion, using Desulfovibrio desulfuricans ATTC 27774 as model organism, since this can switch from sulphate to nitrate. Open Circuit Potential over 6days in different conditions was measured, showing an increase around 200 and 90mV for the different media. Tafel plots were constructed allowing Ecorr and jcorr calculations. For SRP in sulphate and nitrate media Ecorr values of -824 and -728mV, and jcorr values of 2.5 and 3.7μAcm(-2), respectively, were attained indicating that in nitrate, the resultant corrosion rate is larger than in sulphate. Also, it is shown that the equilibrium of sulphide in the solution/gas phases is a key factor to the evolution of corrosion Nitrate prevents pitting but promotes general corrosion and increases the corrosion potential and iron dissolution 40 times when compared to sulphate. Our results demonstrate that nitrate injection strategy in oil fields has to be considered carefully as option to reduce souring and localized corrosion.

  9. Comparison of heart and respiratory rate variability measures using an intermittent incremental submaximal exercise model.

    Science.gov (United States)

    Barrera-Ramirez, Juliana; Bravi, Andrea; Green, Geoffrey; Seely, Andrew J; Kenny, Glen P

    2013-11-01

    To better understand the alterations in cardiorespiratory variability during exercise, the present study characterized the patterns of change in heart rate variability (HRV), respiratory rate variability (RRV), and combined cardiorespiratory variability (HRV-RRV) during an intermittent incremental submaximal exercise model. Six males and six females completed a submaximal exercise protocol consisting of an initial baseline resting period followed by three 10-min bouts of exercise at 20%, 40%, and 60% of maximal aerobic capacity (V̇O2max). The R-R interval and interbreath interval variability were measured at baseline rest and throughout the submaximal exercise. A group of 93 HRV, 83 RRV, and 28 HRV-RRV measures of variability were tracked over time through a windowed analysis using a 5-min window size and 30-s window step. A total of 91 HRV measures were able to detect the presence of exercise, whereas only 46 RRV and 3 HRV-RRV measures were able to detect the same stimulus. Moreover, there was a loss of overall HRV and RRV, loss of complexity of HRV and RRV, and loss of parasympathetic modulation of HRV (up to 40% V̇O2max) with exercise. Conflicting changes in scale-invariant structure of HRV and RRV with increases in exercise intensity were also observed. In summary, in this simultaneous evaluation of HRV and RRV, we found more consistent changes across HRV metrics compared with RRV and HRV-RRV.

  10. Development and application of a multimetal multibiotic ligand model for assessing aquatic toxicity of metal mixtures.

    Science.gov (United States)

    Santore, Robert C; Ryan, Adam C

    2015-04-01

    A multimetal, multiple binding site version of the biotic ligand model (mBLM) has been developed for predicting and explaining the bioavailability and toxicity of mixtures of metals to aquatic organisms. The mBLM was constructed by combining information from single-metal BLMs to preserve compatibility between the single-metal and multiple-metal approaches. The toxicities from individual metals were predicted by assuming additivity of the individual responses. Mixture toxicity was predicted based on both dissolved metal and mBLM-normalized bioavailable metal. Comparison of the 2 prediction methods indicates that metal mixtures frequently appear to have greater toxicity than an additive estimation of individual effects on a dissolved metal basis. However, on an mBLM-normalized basis, mixtures of metals appear to be additive or less than additive. This difference results from interactions between metals and ligands in solutions including natural organic matter, processes that are accounted for in the mBLM. As part of the mBLM approach, a technique for considering variability was developed to calculate confidence bounds (called response envelopes) around the central concentration-response relationship. Predictions using the mBLM and response envelope were compared with observed toxicity for a number of invertebrate and fish species. The results show that the mBLM is a useful tool for considering bioavailability when assessing the toxicity of metal mixtures.

  11. Phlorizin pretreatment reduces acute renal toxicity in a mouse model for diabetic nephropathy.

    Science.gov (United States)

    Brouwers, Bas; Pruniau, Vincent P E G; Cauwelier, Elisa J G; Schuit, Frans; Lerut, Evelyne; Ectors, Nadine; Declercq, Jeroen; Creemers, John W M

    2013-09-20

    Streptozotocin (STZ) is widely used as diabetogenic agent in animal models for diabetic nephropathy (DN). However, it is also directly cytotoxic to kidneys, making it difficult to distinguish between DN-related and STZ-induced nephropathy. Therefore, an improved protocol to generate mice for DN studies, with a quick and robust achievement of the diabetic state, without direct kidney toxicity is required. To investigate the mechanism leading to STZ-induced nephropathy, kidney damage was induced with a high dose of STZ. This resulted in delayed gastric emptying, at least partially caused by impaired desacyl ghrelin clearance. STZ uptake in the kidneys is to a large extent mediated by the sodium/glucose cotransporters (Sglts) because the Sglt inhibitor phlorizin could reduce STZ uptake in the kidneys. Consequently, the direct toxic effects in the kidney and the gastric dilatation were resolved without interfering with the β-cell toxicity. Furthermore, pancreatic STZ uptake was increased, hereby decreasing the threshold for β-cell toxicity, allowing for single low non-nephrotoxic STZ doses (70 mg/kg). In conclusion, this study provides novel insights into the mechanism of STZ toxicity in kidneys and suggests a more efficient regime to induce DN with little or no toxic side effects.

  12. Comparative pathology of rhesus macaque and common marmoset animal models with Middle East respiratory syndrome coronavirus

    Science.gov (United States)

    Yu, Pin; Xu, Yanfeng; Deng, Wei; Bao, Linlin; Huang, Lan; Xu, Yuhuan; Yao, Yanfeng; Qin, Chuan

    2017-01-01

    Middle East respiratory syndrome (MERS), which is caused by a newly discovered coronavirus (CoV), has recently emerged. It causes severe viral pneumonia and is associated with a high fatality rate. However, the pathogenesis, comparative pathology and inflammatory cell response of rhesus macaques and common marmosets experimentally infected with MERS-CoV are unknown. We describe the histopathological, immunohistochemical, and ultrastructural findings from rhesus macaque and common marmoset animal models of MERS-CoV infection. The main histopathological findings in the lungs of rhesus macaques and common marmosets were varying degrees of pulmonary lesions, including pneumonia, pulmonary oedema, haemorrhage, degeneration and necrosis of the pneumocytes and bronchial epithelial cells, and inflammatory cell infiltration. The characteristic inflammatory cells in the lungs of rhesus macaques and common marmosets were eosinophils and neutrophils, respectively. Based on these observations, the lungs of rhesus macaques and common marmosets appeared to develop chronic and acute pneumonia, respectively. MERS-CoV antigens and viral RNA were identified in type I and II pneumocytes, alveolar macrophages and bronchial epithelial cells, and ultrastructural observations showed that viral protein was found in type II pneumocytes and inflammatory cells in both species. Correspondingly, the entry receptor DDP4 was found in type I and II pneumocytes, bronchial epithelial cells, and alveolar macrophages. The rhesus macaque and common marmoset animal models of MERS-CoV can be used as a tool to mimic the oncome of MERS-CoV infections in humans. These models can help to provide a better understanding of the pathogenic process of this virus and to develop effective medications and prophylactic treatments. PMID:28234937

  13. A multi-tiered time-series modelling approach to forecasting respiratory syncytial virus incidence at the local level.

    Science.gov (United States)

    Spaeder, M C; Fackler, J C

    2012-04-01

    Respiratory syncytial virus (RSV) is the most common cause of documented viral respiratory infections, and the leading cause of hospitalization, in young children. We performed a retrospective time-series analysis of all patients aged Forecasting models of weekly RSV incidence for the local community, inpatient paediatric hospital and paediatric intensive-care unit (PICU) were created. Ninety-five percent confidence intervals calculated around our models' 2-week forecasts were accurate to ±9·3, ±7·5 and ±1·5 cases/week for the local community, inpatient hospital and PICU, respectively. Our results suggest that time-series models may be useful tools in forecasting the burden of RSV infection at the local and institutional levels, helping communities and institutions to optimize distribution of resources based on the changing burden and severity of illness in their respective communities.

  14. 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.

  15. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts.

    Science.gov (United States)

    Ding, Xinxin; Kaminsky, Laurence S

    2003-01-01

    Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in these tissues, as well as future research needs, are discussed.

  16. Modeling of TCE and Toluene Toxicity to Pseudomonas putida F1

    Science.gov (United States)

    Singh, R.; Olson, M. S.

    2009-12-01

    Prediction of viable bacterial distribution with respect to contaminants is important for efficient bioremediation of contaminated ground-water aquifers, particularly those contaminated with residual NAPLs. While bacterial motility and chemotaxis may help situate bacteria close to high concentrations of contaminant thereby enhancing bioremediation, prolonged exposure to high concentrations of contaminates is toxic to contaminant-degrading bacteria. The purpose of this work is to model the toxicity of trichloroethylene and toluene to Pseudomonas putida F1. The Live/Dead® bacterial viability assay was used to determine the toxic effect of chemical contaminants on the viability of P. putida F1 in a sealed zero head-space experimental environment. Samples of bacterial suspensions were exposed to common ground-water pollutants, TCE and toluene, for different durations. Changes in live and dead cell populations were monitored over the course of experiments using fluorescence microscopy. Data obtained from these toxicity experiments were fit to simple linear and exponential bacterial decay models using non-linear regression to describe loss of bacterial viability. TCE toxicity to P. putida F1 was best described with an exponential decay model (Figure 1a), with a decay constant kTCE = 0.025 h-4.95 (r2 = 0.956). Toluene toxicity showed a marginally better fit to the linear decay model (Figure 1b) (r2 = 0.971), with a decay constant ktoluene = 0.204 h-1. Best-fit model parameters obtained for both TCE and toluene were used to predict bacterial viability in toxicity experiments with higher contaminant concentrations and matched well with experimental data. Results from this study can be used to predict bacterial accumulation and viability near NAPL sources, and thus may be helpful in improving bioremediation performance assessment of contaminated sites. Figure 1: Survival ratios (S = N/No) of P. putida F1 in TCE- (a) and toluene- (b) stressed samples (observed (

  17. Characterization of an animal model of severe sepsis associated with respiratory dysfunction

    Directory of Open Access Journals (Sweden)

    Luciano Cesar Pontes de Azevedo

    2007-01-01

    Full Text Available PURPOSE: Pathophysiological studies in humans regarding sepsis are difficult to perform due to ethical and methodological concerns. In this context, animal models of sepsis can be useful to better understand this condition and to test therapeutic strategies. The purpose of this study was to characterize a feasible and clinically relevant model of sepsis in pigs that could be useful for testing different therapeutic interventions. METHODS: 5 White Large pigs were anesthetized, arterial and pulmonary catheters were introduced, and sepsis was induced by fecal peritonitis. Several biochemical indicators of organ dysfunction and infectious parameters were measured. The pigs were monitored until death, when fragments of organs were removed for pathology. Three animals without peritonitis served as controls and were sacrificed 24 hours after surgery without developing significant changes in organ function. RESULTS: Septic pigs survived 17 hours on average (range, 16-18 h, and Escherichia coli was recovered from blood cultures. They developed a significant decrease in left ventricular work and a nonsignificant reduction in mixed venous oxygen saturation. Respiratory dysfunction was characterized by a decrease in the PaO2/FiO2 ratio and respiratory compliance. Pathology of the lungs revealed areas of pulmonary collapse, hemorrhage, pulmonary congestion, and discrete neutrophil infiltrate. CONCLUSIONS: Fecal peritonitis in pigs is a clinically relevant model of sepsis associated with acute lung injury without direct pulmonary insult. This model may prove to be useful for studying pathogenic aspects of secondary lung injury as well as for validating ventilatory or pharmacologic interventions.PROPOSTA: Estudos sobre sepse envolvendo sua fisiopatologia são difíceis de serem realizados devido a razões éticas e metodológicas. Neste sentido, modelos animais criam oportunidades de estudos para entender a fisiopatologia e testar estratégias terapêuticas. O

  18. Lamb Model of Respiratory Syncytial Virus–Associated Lung Disease: Insights to Pathogenesis and Novel Treatments

    Science.gov (United States)

    Ackermann, Mark R.

    2014-01-01

    Preterm birth is a risk factor for respiratory syncytial virus (RSV) bronchiolitis and hospitalization. The pathogenesis underlying this is not fully understood, and in vivo studies are needed to better clarify essential cellular features and molecular mechanisms. Such studies include analysis of lung tissue from affected human infants and various animal models. The preterm and newborn lamb lung has developmental, structural, cellular, physiologic, and immunologic features similar to that of human infants. Also, the lamb lung is susceptible to various strains of RSV that infect infants and cause similar bronchiolar lesions. Studies in lambs suggest that viral replication in airways (especially bronchioles) is extensive by 4 days after infection, along with bronchiolitis characterized by degeneration and necrosis of epithelial cells, syncytial cell formation, neutrophil infiltration, epithelial cell hypertrophy and hyperplasia, and innate and adaptive immune responses. RSV bronchiolitis greatly affects airflow and gaseous exchange. RSV disease severity is increased in preterm lambs compared with full-term lambs; similar to human infants. The lamb is conducive to experimental assessment of novel, mechanistic therapeutic interventions such as delivery of vascular endothelial growth factor and enhancement of airway epithelial oxidative responses, Club (Clara) cell protein 10, and synthesized compounds such as nanobodies. In contrast, exposure of the fetal ovine lung in vivo to ethanol, a risk factor for preterm birth, reduces pulmonary alveolar development and surfactant protein A expression. Because the formalin-inactivated RSV vaccination enhances some inflammatory responses to RSV infection in lambs, this model has the potential to assess mechanisms of formalin-inactivated RSV enhanced disease as well as newly developed vaccines. PMID:24936027

  19. Aerosol deposition in the respiratory tract of the rat. Experimental results and mathematical modelling.

    Science.gov (United States)

    Halík, J; Lenger, V; Kliment, V; Voboril, P

    1980-01-01

    The deposition fraction in the respiratory tract of rats were determined experimentally using aerosol 85Srl2 in saline. The dimensions of the particles [MMD 1.63 /+- /+- 0.47 micron, Sg = 1.29] were measured by two independent methods. Rats weighing 200 g were exposed for a period of 60 min [t] in the inhalation apparatus PIANO 3 with a generator according to Lauterbach. From the volume activity [A] of 3 - 11 Bq/litre air a depot of 35-129 kBq was formed in the animals. Spirometric values measured with a modified Jäger ergospirometer were: V = 178.8 /+- 42.9 ml, VT = = 1.18 /+- 0.24 ml. f = 163.1 /+- 28.1 cycles/min. The total amount inhaled [Q] was calculated [Q = V.A.t], the deposited amount [D] was measured by a whole body counter. THe mean deposition fraction was 0.570 /+- 0.052 and was not related either to exposure time or to aerosol activity. In view of the broad validity of the conclusions for aerosols of round-shaped particles, the mean deposition fraction was determined with the help of a mathematical model according to Landahl. The theoretical values amounted to 0.609 [from 0.522 to 0.686]. The good agreement between the mean deposition fractions estimated by two independent methods indicates that on the basis of the probability theory and dimensional analysis, the mathematical model can also be used in humans for simulation deposition as one of the basis foundations for a quantitative evaluation of inhalation risk from any kind of aerosol.

  20. 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

    2014-11-21

    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.

  1. Expression of Prothrombinase/fibroleukin Gene fg12 in Lung Impairment in a Murine Severe Acute Respiratory Syndrome Model

    Institute of Scientific and Technical Information of China (English)

    Wei-ming YAN; Jia-quan HUANG; Xiao-ping LUO; Qin NING

    2007-01-01

    To evaluate the role of murine fibrinogen like protein 2 (mfgl2) /fibroleukin in lung impairment in Severe acute respiratory syndrome (SARS), a murine SARS model induced by Murine hepatitis virus strain 3 (MHV-3) through trachea was established. Impressively, all the animals developed interstitial pneumonia with extensive hyaline membranes formation within alveoli, and presence of micro-vascular thrombosis in the pulmonary vessels. MHV-3 nucleocapsid gene transcripts were identified in multiple organs including lungs, spleen etc. As a representative proinflammatory gene, mfgl2 prothrombinase expression was evident in terminal and respiratory bronchioles, alveolar epithelia and infiltrated cells in the lungs associated with fibrin deposition and micro-vascular thrombosis. In summary, the established murine SARS model could mimic the pathologic characteristics of lungs in patients with SARS. Besides the physical damages due to virus replication in organs, the up-regulation of novel gene mfgl2 in lungs may play a vital role in the development of SARS associated lung damage.

  2. Acute toxicity of metals and reference toxicants to a freshwater ostracod, Cypris subglobosa Sowerby, 1840 and correlation to EC{sub 50} values of other test models

    Energy Technology Data Exchange (ETDEWEB)

    Khangarot, B.S., E-mail: bkhangarot@hotmail.com [Ecotoxicology Division, Indian Institute of Toxicology Research (Formerly: Industrial Toxicology Research Centre), Post Box No. 80, Mahatma Gandhi Marg, Lucknow 226001 (India); Das, Sangita [Ecotoxicology Division, Indian Institute of Toxicology Research (Formerly: Industrial Toxicology Research Centre), Post Box No. 80, Mahatma Gandhi Marg, Lucknow 226001 (India)

    2009-12-30

    The ostracod Cypris subglobosa Sowerby, 1840 static bioassay test on the basis of a 48 h of 50% of immobilization (EC{sub 50}) has been used to measure the toxicity of 36 metals and metalloids and 12 reference toxicants. Among the 36 metals and metalloids, osmium (Os) was found to be the most toxic in the test while boron (B), the least toxic. The EC{sub 50} values of this study revealed positive linear relationship with the established test models of cladoceran (Daphnia magna), sludge worm (Tubifex tubifex), chironomid larvae (Chironomus tentans), protozoan (Tetrahymena pyriformis), fathead minnow (Pimephales promelas), bluegill sunfish (Lepomis macrochirus), and aquatic macrophyte duckweed (Lemna minor). Correlation coefficients (r{sup 2}) for 17 physicochemical properties of metals or metal ions and EC{sub 50}s (as pM) were examined by linear regression analysis. The electronegativity, ionization potential, melting point, solubility product of metal sulfides (pK{sub sp}), softness parameter and some other physicochemical characteristics were significantly correlated with EC{sub 50}s of metals to C. subglobosa. The reproducibility of toxicity test was determined using 12 reference toxicants. The coefficient of variability of the EC{sub 50}s ranged from 6.95% to 55.37% and variability was comparable to that noticed for D. magna and other aquatic test models. The study demonstrated the need to include crustacean ostracods in a battery of biotests to detect the presence of hazardous chemicals in soils, sewage sludges, sediments and aquatic systems.

  3. 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 Chemica

  4. Köln-Timişoara Molecular Activity Combined Models toward Interspecies Toxicity Assessment

    Science.gov (United States)

    Chicu, Sergiu A.; Putz, Mihai V.

    2009-01-01

    Aiming to provide a unified picture of computed activity – quantitative structure activity relationships, the so called Köln (ESIP-ElementSpecificInfluenceParameter) model for activity and Timisoara (Spectral-SAR) formulation of QSAR were pooled in order to assess the toxicity modeling and inter-toxicity correlation maps for aquatic organisms against paradigmatic organic compounds. The Köln ESIP model for estimation of a compound toxicity is based on the experimental measurement expressing the direct action of chemicals on the organism Hydractinia echinata so that the structural influence parameters are reflected by the metamorphosis degree itself. As such, the calculation of the structural parameters is absolutely necessary for correct evaluation and interpretation of the evolution of M(easured) and the C(computed) values. On the other hand, the Timişoara Spectral-SAR analysis offers correlation models and paths for H.e. species as well as for four other different organisms with which the toxicity may be inter-changed by means of the same mechanism of action induced by certain common chemicals. PMID:20057956

  5. In silico prediction of toxicity of non-congeneric industrial chemicals using ensemble learning based modeling approaches

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Kunwar P., E-mail: kpsingh_52@yahoo.com; Gupta, Shikha

    2014-03-15

    Ensemble learning approach based decision treeboost (DTB) and decision tree forest (DTF) models are introduced in order to establish quantitative structure–toxicity relationship (QSTR) for the prediction of toxicity of 1450 diverse chemicals. Eight non-quantum mechanical molecular descriptors were derived. Structural diversity of the chemicals was evaluated using Tanimoto similarity index. Stochastic gradient boosting and bagging algorithms supplemented DTB and DTF models were constructed for classification and function optimization problems using the toxicity end-point in T. pyriformis. Special attention was drawn to prediction ability and robustness of the models, investigated both in external and 10-fold cross validation processes. In complete data, optimal DTB and DTF models rendered accuracies of 98.90%, 98.83% in two-category and 98.14%, 98.14% in four-category toxicity classifications. Both the models further yielded classification accuracies of 100% in external toxicity data of T. pyriformis. The constructed regression models (DTB and DTF) using five descriptors yielded correlation coefficients (R{sup 2}) of 0.945, 0.944 between the measured and predicted toxicities with mean squared errors (MSEs) of 0.059, and 0.064 in complete T. pyriformis data. The T. pyriformis regression models (DTB and DTF) applied to the external toxicity data sets yielded R{sup 2} and MSE values of 0.637, 0.655; 0.534, 0.507 (marine bacteria) and 0.741, 0.691; 0.155, 0.173 (algae). The results suggest for wide applicability of the inter-species models in predicting toxicity of new chemicals for regulatory purposes. These approaches provide useful strategy and robust tools in the screening of ecotoxicological risk or environmental hazard potential of chemicals. - Graphical abstract: Importance of input variables in DTB and DTF classification models for (a) two-category, and (b) four-category toxicity intervals in T. pyriformis data. Generalization and predictive abilities of the

  6. The potential role of respiratory motion management and image guidance in the reduction of severe toxicities following stereotactic ablative radiation therapy for patients with centrally located early stage non-small cell lung cancer or lung metastases

    Directory of Open Access Journals (Sweden)

    Alexander eChi

    2014-06-01

    Full Text Available Image guidance allows delivery of very high doses of radiation over a few fractions, known as stereotactic ablative radiotherapy (SABR. This treatment is associated with excellent outcome for early stage non-small cell lung cancer and metastases to the lungs. In the delivery of SABR, central location constantly poses a challenge due to the difficulty of adequately sparing critical thoracic structures that are immediately adjacent to the tumor if an ablative dose of radiation is to be delivered to the tumor target. As of current, various respiratory motion management and image guidance strategies can be used to ensure accurate tumor target localization prior and/ or during daily treatment, which allows for maximal and safe reduction of set up margins. The incorporation of both may lead to the most optimal normal tissue sparing and the most accurate SABR delivery. Here, the clinical outcome, treatment related toxicities, and the pertinent respiratory motion management/image guidance strategies reported in the current literature on SABR for central lung tumors are reviewed.

  7. 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.

  8. TEARHS - Modelling toxic impacts on the airway system from exposure to fluctuating concentrations

    DEFF Research Database (Denmark)

    Duijm, N.J.; Markert, Frank; Ott, Søren

    2000-01-01

    information on toxic effects and the relevant time scale for exposure. Concentration-time-fatality relations areobtained from experiments with rats down to 5 minutes of exposure. If the information from these relations is extrapolated down to 5 to 10 seconds using different assumptions, the predicted...... to be small, in the order of a few seconds. Considering the aspiration pattern, it is concluded that relevant time scale for absorption in the airways is 5 to 10seconds. In real atmospheric, toxic gas clouds, fluctuations at this time scale are large. There is still a large gap between the empirical...... mortality is quite different. This study indicates thatatmospheric dispersion models for acutely toxic substances need to provide information about concentration fluctuations of time scales of 5 to 10 sec. Final conclusions can only be drawn when it becomes clear how the gap betweenconcentration...

  9. 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.

  10. Developing a multi-component immune model for evaluating the risk of respiratory illness in athletes.

    Science.gov (United States)

    Gleeson, Maree; Pyne, David B; Elkington, Lisa J; Hall, Sharron T; Attia, John R; Oldmeadow, Christopher; Wood, Lisa G; Callister, Robin

    2017-01-01

    Clinical and laboratory identification of the underlying risk of respiratory illness in athletes has proved problematic. The aim of this study was to determine whether clinical data, combined with immune responses to standardised exercise protocols and genetic cytokine polymorphism status, could identify the risk of respiratory illness (symptoms) in a cohort of highly-trained athletes. Male endurance athletes (n=16; VO2max 66.5 ± 5.1 mL.kg-1.min-1) underwent a clinical evaluation of known risk factors by a physician and comprehensive laboratory analysis of immune responses both at rest and after two cycling ergometer tests: 60 min at 65% VO2max (LONG); and 6 x 3 min intervals at 90% VO2max (INTENSE). Blood tests were performed to determine Epstein Barr virus (EBV) status and DNA was genotyped for a panel of cytokine gene polymorphisms. Saliva was collected for measurement of IgA and detection of EBV DNA. Athletes were then followed for 9 months for self-reported episodes of respiratory illness, with confirmation of the underlying cause by a sports physician. There were no associations with risk of respiratory illness identified for any parameter assessed in the clinical evaluations. The laboratory parameters associated with an increased risk of respiratory illnesses in highly-trained athletes were cytokine gene polymorphisms for the high expression of IL-6 and IFN-ɣ; expression of EBV-DNA in saliva; and low levels of salivary IgA concentration. A genetic risk score was developed for the cumulative number of minor alleles for the cytokines evaluated. Athletes prone to recurrent respiratory illness were more likely to have immune disturbances that allow viral reactivation, and a genetic predisposition to pro-inflammatory cytokine responses to intense exercise.

  11. Using biotic ligand models to predict metal toxicity in mineralized systems

    Science.gov (United States)

    Smith, Kathleen S.; Balistrieri, Laurie S.; Todd, Andrew S.

    2015-01-01

    The biotic ligand model (BLM) is a numerical approach that couples chemical speciation calculations with toxicological information to predict the toxicity of aquatic metals. This approach was proposed as an alternative to expensive toxicological testing, and the U.S. Environmental Protection Agency incorporated the BLM into the 2007 revised aquatic life ambient freshwater quality criteria for Cu. Research BLMs for Ag, Ni, Pb, and Zn are also available, and many other BLMs are under development. Current BLMs are limited to ‘one metal, one organism’ considerations. Although the BLM generally is an improvement over previous approaches to determining water quality criteria, there are several challenges in implementing the BLM, particularly at mined and mineralized sites. These challenges include: (1) historically incomplete datasets for BLM input parameters, especially dissolved organic carbon (DOC), (2) several concerns about DOC, such as DOC fractionation in Fe- and Al-rich systems and differences in DOC quality that result in variations in metal-binding affinities, (3) water-quality parameters and resulting metal-toxicity predictions that are temporally and spatially dependent, (4) additional influences on metal bioavailability, such as multiple metal toxicity, dietary metal toxicity, and competition among organisms or metals, (5) potential importance of metal interactions with solid or gas phases and/or kinetically controlled reactions, and (6) tolerance to metal toxicity observed for aquatic organisms living in areas with elevated metal concentrations.

  12. Human intake fraction of toxic pollutants: a model comparison between caltox and uses-lca

    OpenAIRE

    Huijbregts, Mark A J; Geelen, Loes M.J.; Edgar G. Hertwich; McKone, Thomas E.; Meent, Dik van de

    2004-01-01

    In Life Cycle Assessment and Comparative Risk Assessment potential human exposure to toxic pollutants can be expressed as the human intake fraction (iF), representing the fraction of the quantity emitted that enters the human population. To assess model uncertainty in the human intake fraction, ingestion and inhalation iFs of 367 substances emitted to air and freshwater were calculated with two commonly applied multi-media fate and exposure models, CalTOX and USES-LCA. Comparison of the ...

  13. 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.

  14. 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

    2016-10-01

    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.

  15. 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.

  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. 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

    Mitochondrial function is thought to play a role in sepsis-induced multiple organ failure. However, the temporal and organ specific alterations in mitochondrial function has yet to be fully elucidated. Many studies show reduced phosphorylating capacity while others have indicated that mitochondrial...... respiration is enhanced. The objective of the study was to evaluate the temporal dynamics of brain and liver mitochondrial function in a mouse model of sepsis.Sepsis was induced by cecal ligation and puncture. Controls were sham operated. Using high-resolution respirometry, brain and liver homogenates from 31......-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...

  18. Public health and budget impact of probiotics on common respiratory tract infections: a modelling study.

    Directory of Open Access Journals (Sweden)

    Irene Lenoir-Wijnkoop

    Full Text Available Two recent meta-analyses by the York Health Economics Consortium (YHEC and Cochrane demonstrated probiotic efficacy in reducing the duration and number of common respiratory tract infections (CRTI and associated antibiotic prescriptions. A health-economic analysis was undertaken to estimate the public health and budget consequences of a generalized probiotic consumption in France.A virtual age- and gender-standardized population was generated using a Markov microsimulation model. CRTI risk factors incorporated into this model were age, active/passive smoking and living in a community setting. Incidence rates and resource utilization were based on the 2011-2012 flu season and retrieved from the French GPs Sentinelles network. Results of both meta-analyses were independently applied to the French population to estimate CRTI events, assuming a generalized probiotic use compared to no probiotics during winter months: -0.77 days/CRTI episode (YHEC scenario or odds-ratio 0.58 for ≥1 CRTI episode (Cochrane scenario with vs. without probiotics. Economic perspectives were National Health System (NHS, society, family. Outcomes included cost savings related to the reduced numbers of CRTI episodes, days of illness, number of antibiotic courses, sick leave days, medical and indirect costs.For France, generalized probiotic use would save 2.4 million CRTI-days, 291,000 antibiotic courses and 581,000 sick leave days, based on YHEC data. Applying the Cochrane data, reductions were 6.6 million CRTI days, 473,000 antibiotic courses and 1.5 million sick days. From the NHS perspective, probiotics' economic impact was about €14.6 million saved according to YHEC and €37.7 million according to Cochrane. Higher savings were observed in children, active smokers and people with more frequent human contacts.Public health and budget impact of probiotics are substantial, whether they reduce CRTI episodes frequency or duration. Noteworthy, the 2011-12 winter CRTI

  19. Public Health and Budget Impact of Probiotics on Common Respiratory Tract Infections: A Modelling Study

    Science.gov (United States)

    Lenoir-Wijnkoop, Irene; Gerlier, Laetitia; Bresson, Jean-Louis; Le Pen, Claude; Berdeaux, Gilles

    2015-01-01

    Objectives Two recent meta-analyses by the York Health Economics Consortium (YHEC) and Cochrane demonstrated probiotic efficacy in reducing the duration and number of common respiratory tract infections (CRTI) and associated antibiotic prescriptions. A health-economic analysis was undertaken to estimate the public health and budget consequences of a generalized probiotic consumption in France. Methods A virtual age- and gender-standardized population was generated using a Markov microsimulation model. CRTI risk factors incorporated into this model were age, active/passive smoking and living in a community setting. Incidence rates and resource utilization were based on the 2011-2012 flu season and retrieved from the French GPs Sentinelles network. Results of both meta-analyses were independently applied to the French population to estimate CRTI events, assuming a generalized probiotic use compared to no probiotics during winter months: -0.77 days/CRTI episode (YHEC scenario) or odds-ratio 0.58 for ≥1 CRTI episode (Cochrane scenario) with vs. without probiotics. Economic perspectives were National Health System (NHS), society, family. Outcomes included cost savings related to the reduced numbers of CRTI episodes, days of illness, number of antibiotic courses, sick leave days, medical and indirect costs. Results For France, generalized probiotic use would save 2.4 million CRTI-days, 291,000 antibiotic courses and 581,000 sick leave days, based on YHEC data. Applying the Cochrane data, reductions were 6.6 million CRTI days, 473,000 antibiotic courses and 1.5 million sick days. From the NHS perspective, probiotics’ economic impact was about €14.6 million saved according to YHEC and €37.7 million according to Cochrane. Higher savings were observed in children, active smokers and people with more frequent human contacts. Conclusions Public health and budget impact of probiotics are substantial, whether they reduce CRTI episodes frequency or duration. Noteworthy

  20. Predictive modeling of respiratory tumor motion for real-time prediction of baseline shifts

    Science.gov (United States)

    Balasubramanian, A.; Shamsuddin, R.; Prabhakaran, B.; Sawant, A.

    2017-03-01

    Baseline shifts in respiratory patterns can result in significant spatiotemporal changes in patient anatomy (compared to that captured during simulation), in turn, causing geometric and dosimetric errors in the administration of thoracic and abdominal radiotherapy. We propose predictive modeling of the tumor motion trajectories for predicting a baseline shift ahead of its occurrence. The key idea is to use the features of the tumor motion trajectory over a 1 min window, and predict the occurrence of a baseline shift in the 5 s that immediately follow (lookahead window). In this study, we explored a preliminary trend-based analysis with multi-class annotations as well as a more focused binary classification analysis. In both analyses, a number of different inter-fraction and intra-fraction training strategies were studied, both offline as well as online, along with data sufficiency and skew compensation for class imbalances. The performance of different training strategies were compared across multiple machine learning classification algorithms, including nearest neighbor, Naïve Bayes, linear discriminant and ensemble Adaboost. The prediction performance is evaluated using metrics such as accuracy, precision, recall and the area under the curve (AUC) for repeater operating characteristics curve. The key results of the trend-based analysis indicate that (i) intra-fraction training strategies achieve highest prediction accuracies (90.5-91.4%) (ii) the predictive modeling yields lowest accuracies (50-60%) when the training data does not include any information from the test patient; (iii) the prediction latencies are as low as a few hundred milliseconds, and thus conducive for real-time prediction. The binary classification performance is promising, indicated by high AUCs (0.96-0.98). It also confirms the utility of prior data from previous patients, and also the necessity of training the classifier on some initial data from the new patient for reasonable

  1. 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.

    2013-01-01

    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…

  2. 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 ...

  3. Feasibility of a 3D human airway epithelial model to study respiratory absorption

    NARCIS (Netherlands)

    Reus, A.A.; Maas, W.J.M.; Jansen, H.T.; Constant, S.; Staal, Y.C.M.; Triel, J.J. van; Kuper, C.F.

    2014-01-01

    The respiratory route is an important portal for human exposure to a large variety of substances. Consequently, there is an urgent need for realistic in vitro strategies for evaluation of the absorption of airborne substances with regard to safety and efficacy assessment. The present study investiga

  4. Respiratory alkalosis.

    Science.gov (United States)

    Foster, G T; Vaziri, N D; Sassoon, C S

    2001-04-01

    Respiratory alkalosis is an extremely common and complicated problem affecting virtually every organ system in the body. This article reviews the various facets of this interesting problem. Respiratory alkalosis produces multiple metabolic abnormalities, from changes in potassium, phosphate, and calcium, to the development of a mild lactic acidosis. Renal handling of the above ions is also affected. The etiologies may be related to pulmonary or extrapulmonary disorders. Hyperventilation syndrome is a common etiology of respiratory alkalosis in the emergency department setting and is a diagnosis by exclusion. There are many cardiac effects of respiratory alkalosis, such as tachycardia, ventricular and atrial arrhythmias, and ischemic and nonischemic chest pain. In the lungs, vasodilation occurs, and in the gastrointestinal system there are changes in perfusion, motility, and electrolyte handling. Therapeutically, respiratory alkalosis is used for treatment of elevated intracranial pressure. Correction of a respiratory alkalosis is best performed by correcting the underlying etiology.

  5. 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

    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......, 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...... 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...

  6. Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation

    Institute of Scientific and Technical Information of China (English)

    Zhu Shi; Xiu-Ling Liang; Bing-Xun Lu; Su-Yue Pan; Xi Chen; Qi-Qiang Tang; Ying Wang; Fan Huang

    2005-01-01

    AIM: To observe the therapeutic effect of intrasplenic transplantation with embryonic hepatocytes on amelioration of hereditary copper accumulation in toxic milk (TX) mouse modeling Wilson disease. METHODS: Donor hepatocytes were harvested from 14-d fetal liver of a pregnant homogeneous DL mouse. These cells were successively cultured, labeled with fluorescein dye Hoechst 33342 for 24 h, and sequentially infused into the spleen parenchyma of the recipient TX mice. No host immunosuppression measures were taken. Two and four weeks after transplantation, the recipients were killed for routine histologic investigation and immunohistochemistry study up to 4 wk after transplantation. The serum copper and ceruloplasmin concentrations of the recipient mice were determined by graphite furnace atomic absorption spectroscopy.RESULTS: In the following 2nd and 4th wk after transplantation, the donor hepatocytes could be visualized in the livers of 47.3% recipients. The serum ceruloplasmin and copper concentrations increased by 1.6-fold after 2 wk and 2.0-fold times after 4 wk respectively, which ultimately rose from about 30% of the normal level to nearly 60%(P<0.01). The hepatic copper concentration decreased 7.2%, 4 wk after transplantation. Pathologic examination showed that there were many actively proliferative hepatocyte precursor cells with specific embryonic hepatocyte marker AFP migrated into hepatic sinusoidsof the recipients. A large number of cells carrying hepatocytes marker and albumin were observed in the recipient spleen tissues.CONCLUSION: Embryonic hepatocytes are capable of differentiating into mature hepatocytes in vivo. After transplantation, the hereditary abnormalities of copper metabolism in TX mice could be corrected partially by intrasplenic transplantation of homogeneous embryonic hepatocytes.

  7. 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.

  8. Reproductive toxicity and gender differences induced by cadmium telluride quantum dots in an invertebrate model organism

    Science.gov (United States)

    Yan, Si-Qi; Xing, Rui; Zhou, Yan-Feng; Li, Kai-Le; Su, Yuan-Yuan; Qiu, Jian-Feng; Zhang, Yun-Hu; Zhang, Ke-Qin; He, Yao; Lu, Xiao-Ping; Xu, Shi-Qing

    2016-09-01

    Sexual glands are key sites affected by nanotoxicity, but there is no sensitive assay for measuring reproductive toxicity in animals. The aim of this study was to investigate the toxic effects of cadmium telluride quantum dots (CdTe-QDs) on gonads in a model organism, Bombyx mori. After dorsal vein injection of 0.32 nmol of CdTe-QDs per individual, the QDs passed through the outer membranes of gonads via the generation of ROS in the membranes of spermatocysts and ovarioles, as well as internal germ cells, thereby inducing early germ cell death or malformations via complex mechanisms related to apoptosis and autophagy through mitochondrial and lysosomal pathways. Histological observations of the gonads and quantitative analyses of germ cell development showed that the reproductive toxicity was characterized by obvious male sensitivity. Exposure to QDs in the early stage of males had severe adverse effects on the quantity and quality of sperm, which was the main reason for the occurrence of unfertilized eggs. Ala- or Gly-conjugated QDs could reduce the nanotoxicity of CdTe-QDs during germ cell development and fertilization of their offspring. The results demonstrate that males are preferable models for evaluating the reproductive toxicity of QDs in combined in vivo/in vitro investigations.

  9. Reproductive toxicity and gender differences induced by cadmium telluride quantum dots in an invertebrate model organism

    Science.gov (United States)

    Yan, Si-Qi; Xing, Rui; Zhou, Yan-Feng; Li, Kai-Le; Su, Yuan-Yuan; Qiu, Jian-Feng; Zhang, Yun-Hu; Zhang, Ke-Qin; He, Yao; Lu, Xiao-Ping; Xu, Shi-Qing

    2016-01-01

    Sexual glands are key sites affected by nanotoxicity, but there is no sensitive assay for measuring reproductive toxicity in animals. The aim of this study was to investigate the toxic effects of cadmium telluride quantum dots (CdTe-QDs) on gonads in a model organism, Bombyx mori. After dorsal vein injection of 0.32 nmol of CdTe-QDs per individual, the QDs passed through the outer membranes of gonads via the generation of ROS in the membranes of spermatocysts and ovarioles, as well as internal germ cells, thereby inducing early germ cell death or malformations via complex mechanisms related to apoptosis and autophagy through mitochondrial and lysosomal pathways. Histological observations of the gonads and quantitative analyses of germ cell development showed that the reproductive toxicity was characterized by obvious male sensitivity. Exposure to QDs in the early stage of males had severe adverse effects on the quantity and quality of sperm, which was the main reason for the occurrence of unfertilized eggs. Ala- or Gly-conjugated QDs could reduce the nanotoxicity of CdTe-QDs during germ cell development and fertilization of their offspring. The results demonstrate that males are preferable models for evaluating the reproductive toxicity of QDs in combined in vivo/in vitro investigations. PMID:27669995

  10. RESPIRATORY SYSTEM

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    10.1 Respiratory failure2003068 Evaluation of non-invasive ventilation in a-cute respiratory failure with chronic obstructive pulmonary disease. GU Jianyong(顾俭勇), et al. Dept E-mergen, Zhongshan Hosp, Fudan Univ, Shanghai 200032. Shanghai J Med 2002; 25 (12): 741 - 743.Objective:To observe the effect of non-invasive venti-lation(NIV) in acute respiratory failure with chronic

  11. Mathematical model of the growth of a mollusk affected by a toxicant and by temperature fluctuations

    Energy Technology Data Exchange (ETDEWEB)

    Kurchenko, T.S.; Burtnaya, I.L.

    1979-01-01

    An attempt is made to model the effect of a gamma isomer of hexachloran (lindane) and of temperature fluctuations on the growth of bivalves. The model is based on an experimental study of the effect of the toxicant on Radix ovata and Viviparus viviparus, and also on the Putter-Bertalanffy-Vinberg models and the model of Zotin. Quite good agreements has been obtained between calculated and experimental data, and growth curves have been constructed for the weight increase of the animals when exposed to lindane concentrations not tested in the experiment.

  12. Dechlorination kinetics of TCE at toxic TCE concentrations: Assessment of different models.

    Science.gov (United States)

    Haest, P J; Springael, D; Smolders, E

    2010-01-01

    The reductive dechlorination of trichloroethene (TCE) in a TCE source zone can be self-inhibited by TCE toxicity. A study was set up to examine the toxicity of TCE in terms of species specific degradation kinetics and microbial growth and to evaluate models that describe this self-inhibition. A batch experiment was performed using the TCE dechlorinating KB-1 culture at initial TCE concentrations ranging from 0.04mM to saturation (8.4mM). Biodegradation activity was highest at 0.3mM TCE and no activity was found at concentrations from 4 to 8mM. Species specific TCE and cis-DCE (cis-dichloroethene) degradation rates and Dehalococcoides numbers were modeled with Monod kinetics combined with either Haldane inhibition or a log-logistic dose-response inhibition on these rates. The log-logistic toxicity model appeared the most appropriate model and predicts that the species specific degradation activities are reduced by a factor 2 at about 1mM TCE, respectively cis-DCE. However, the model showed that the inhibitive effects on the time for TCE to ethene degradation are a complex function of degradation kinetics and the initial cell densities of the dechlorinating species. Our analysis suggests that the self-inhibition on biodegradation cannot be predicted by a single concentration threshold without information on the cell densities.

  13. Web-Based Toxic Gas Dispersion Model for Shuttle Launch Operations

    Science.gov (United States)

    Bardina, Jorge; Thirumalainambi, Rajkumar

    2004-01-01

    During the launch of the Space Shuttle vehicle, the burning of liquid hydrogen fuel with liquid oxygen at extreme high temperatures inside the three space shuttle main engines, and the burning of the solid propellant mixture of ammonium perchlorate oxidizer, aluminum fuel, iron oxide catalyst, polymer binder, and epoxy curing agent in the two solid rocket boosters result in the formation of a large cloud of hot, buoyant toxic exhaust gases near the ground level which subsequently rises and entrains into ambient air until the temperature and density of the cloud reaches an approximate equilibrium with ambient conditions. In this paper, toxic gas dispersion for various gases are simulated over the web for varying environmental conditions which is provided by rawinsonde data. The model simulates chemical concentration at ground level up to 10 miles (1 KM grids) in downrange up to an hour after launch. The ambient concentration of the gas dispersion and the deposition of toxic particles are used as inputs for a human health risk assessment model. The advantage of the present model is the accessibility and dissemination of model results to other NASA centers over the web. The model can be remotely operated and various scenarios can be analyzed.

  14. alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress.

    Science.gov (United States)

    Sharma, Nijee; Brandis, Katrina A; Herrera, Sara K; Johnson, Brandon E; Vaidya, Tulaza; Shrestha, Ruja; Debburman, Shubhik K

    2006-01-01

    Parkinson's disease (PD) is a common neurodegenerative disorder that results from the selective loss of midbrain dopaminergic neurons. Misfolding and aggregation of the protein alpha-synuclein, oxidative damage, and proteasomal impairment are all hypotheses for the molecular cause of this selective neurotoxicity. Here, we describe a Saccharomyces cerevisiae model to evaluate the misfolding, aggregation, and toxicity-inducing ability of wild-type alpha-synuclein and three mutants (A30P, A53T, and A30P/A53T), and we compare regulation of these properties by dysfunctional proteasomes and by oxidative stress. We found prominent localization of wild-type and A53T alpha-synuclein near the plasma membrane, supporting known in vitro lipid-binding ability. In contrast, A30P was mostly cytoplasmic, whereas A30P/A53T displayed both types of fluorescence. Surprisingly, alpha-synuclein was not toxic to several yeast strains tested. When yeast mutants for the proteasomal barrel (doa3-1) were evaluated, delayed alpha-synuclein synthesis and membrane association were observed; yeast mutant for the proteasomal cap (sen3-1) exhibited increased accumulation and aggregation of alpha-synuclein. Both sen3-1and doa3-1 mutants exhibited synthetic lethality with alpha-synuclein. When yeasts were challenged with an oxidant (hydrogen peroxide), alpha-synuclein was extremely lethal to cells that lacked manganese superoxide dismutase Mn-SOD (sod2Delta) but not to cells that lacked copper, zinc superoxide dismutase Cu,Zn-SOD (sod1Delta). Despite the toxicity, sod2Delta cells never displayed intracellular aggregates of alpha-synuclein. We suggest that the toxic alpha-synuclein species in yeast are smaller than the visible aggregates, and toxicity might involve alpha-synuclein membrane association. Thus, yeasts have emerged effective organisms for characterizing factors and mechanisms that regulate alpha-synuclein toxicity.

  15. A numerical model of the respiratory modulation of pulmonary shunt and PaO2 oscillations for acute lung injury.

    Science.gov (United States)

    Beda, Alessandro; Jandre, Frederico C; Giannella-Neto, Antonio

    2010-03-01

    It is an accepted hypothesis that the amplitude of the respiratory-related oscillations of arterial partial pressure of oxygen (DeltaPaO2) is primarily modulated by fluctuations of pulmonary shunt (Deltas), the latter generated mainly by cyclic alveolar collapse/reopening, when present. A better understanding of the relationship between DeltaPaO2, Deltas, and cyclic alveolar collapse/reopening can have clinical relevance for minimizing the severe lung damage that the latter can cause, for example during mechanical ventilation (MV) of patients with acute lung injury (ALI). To this aim, we numerically simulated the effect of such a relationship on an animal model of ALI under MV, using a combination of a model of lung gas exchange during tidal ventilation with a model of time dependence of shunt on alveolar collapse/opening. The results showed that: (a) the model could adequately replicate published experimental results regarding the complex dependence of DeltaPaO2 on respiratory frequency, driving pressure (DeltaP), and positive end-expiratory pressure (PEEP), while simpler models could not; (b) such a replication strongly depends on the value of the model parameters, especially of the speed of alveolar collapse/reopening; (c) the relationship between DeltaPaO2 and Deltas was overall markedly nonlinear, but approximately linear for PEEP>or=6 cmH2O, with very large DeltaPaO2 associated with relatively small Deltas.

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

    Science.gov (United States)

    Wegener Sleeswijk, Anneke; Heijungs, Reinout

    2010-06-15

    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 the calculation of LCA characterisation factors for human toxicity and ecotoxicity. The model is differentiated on the level of 239 countries/territories and 50 seas/oceans. Each region has its own set of homogeneous compartments, and the regions are interconnected by atmospheric and aquatic flows. Multimedia transport and degradation calculations are largely based on the EUSES 2.0 multimedia model, and are supplemented by specific equations to account for the advective air and water transport between different countries and/or seas. Metal-specific equations are added to account for speciation in fresh and marine surface water. Distribution parameters for multimedia transport equations are differentiated per country or sea with respect to geographic features, hydrology, and climate. The model has been tested with nitrobenzene as a test chemical, for emissions to all countries in the world. Spatially differentiated characterisation factors turn out to show wide ranges of variation between countries, especially for releases to inland water and soil compartments. Geographic position, distribution of lakes and rivers and variations in environmental temperature and rain rate are decisive parameters for a number of different characterisation factors. Population density and dietary intake play central roles in the variation of characterisation factors for human toxicity. Among the countries that show substantial deviations from average values of the characterisation factors are not only small and remote islands, but also countries with a significant economic production rate, as indicated by their GDPs. It is concluded that spatial differentiation between countries is an important

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

    Science.gov (United States)

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

    2008-09-01

    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

  18. 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

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

    OpenAIRE

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

    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 variet...

  20. A QICAR Model for Metal Ion Toxicity Established via PLS Method

    Institute of Scientific and Technical Information of China (English)

    LI Yu; JIANG Long; LI Xiao-li; HU Yan; WEN Jing-ya

    2013-01-01

    The partial least squares(PLS) method was employed to establish a quantitative ion characteristics-activity relationship(QICAR) model for metal ion toxicity(EC50 of 15 metal ions).The ion characteristics included AN(the atomic number),AIP(the change in ionization potential,eV),Xm(the electronegativity,eV),AW(the atomic weight),Xm2r(the covalent index),△E0(the absolute difference between electrochemical potential of the ion and that of its first stable reduced state,eV),│lgKoH│(the absolute value of the lg of the first hydrolysis constant),AR(the atomic radius,nm),AR/AW(the ratio between atomic radius and atomic weight) and σp(the softness index) selected based on relative correlation analysis.The simulated and tested(with the other four metals) efficiency coefficients of the model are 0.88 and 0.96,respectively.The information revealed from the QICAR model indicates that the value of the metal ion toxicity was positively correlated with variables AN,△IP,Xm,AW and Xm2r; negatively correlated with variables △E0,│lgKoH│,AR/AW,AR and σp,and ion characteristics AE0,Xm,σp and Xm2r were found to contribute more to the toxicity of metal ions via the accurate analysis method provided by PLS.The model could be used to predict the toxicity of the target metals and preliminary to assess combined pollution and environmental risk for heavy metals in the environments.

  1. Toxicity Mechanisms of the Food Contaminant Citrinin: Application of a Quantitative Yeast Model

    OpenAIRE

    Amparo Pascual-Ahuir; Elena Vanacloig-Pedros; Markus Proft

    2014-01-01

    Mycotoxins are important food contaminants and a serious threat for human nutrition. However, in many cases the mechanisms of toxicity for this diverse group of metabolites are poorly understood. Here we apply live cell gene expression reporters in yeast as a quantitative model to unravel the cellular defense mechanisms in response to the mycotoxin citrinin. We find that citrinin triggers a fast and dose dependent activation of stress responsive promoters such as GRE2 or SOD2. More specifical...

  2. A model for the evaluation of respiratory therapy program admissions criteria.

    Science.gov (United States)

    Flanigan, K S

    1985-05-01

    Attrition in respiratory therapy programs is a waste of both human and economic resources and may be one cause of the current shortage of qualified personnel. Poor academic performance has been shown to be the leading cause of program attrition. The purposes of this study were to establish the predictive abilities of aptitude and performance measures for classroom and laboratory performance in a respiratory therapy program and to describe a methodology for the development of academic admissions criteria. The preprogram college cumulative grade point average (pPGPA), the preprogram science-mathematics grade point average (S-M GPA), the American College Test (ACT) composite, and four ACT subtest scores of 39 graduates of The Ohio State University Respiratory Therapy Division were compared to their program grade point average (PGPA). We applied a multiple regression analysis and derived regression equations. Multiple regression analysis demonstrated that the S-M GPA is the most significant predictor of program academic performance (P less than or equal to 0.05). The derived regression equation was applied to calculate the minimum S-M GPA for admission by using the standard error of the estimate (SEE) of the regression equation and the mean minimum acceptable PGPA at a 95% confidence interval. For those students who have met the minimum S-M GPA, we have experienced no academic attrition. Multiple regression analysis of student data and the derived regression equations may be used to determine program-specific admissions criteria.

  3. Comprehensive toxicity study of safrole using a medium-term animal model with gpt delta rats.

    Science.gov (United States)

    Jin, M; Kijima, A; Suzuki, Y; Hibi, D; Inoue, T; Ishii, Y; Nohmi, T; Nishikawa, A; Ogawa, K; Umemura, T

    2011-12-18

    In order to investigate a medium-term animal model using reporter gene transgenic rodents in which general toxicity, genotoxicity and carcinogenicity are evaluated, F344 gpt delta rats were given a diet containing 0.1% and 0.5% (a carcinogenic dose) safrole for 13 weeks. Serum biochemistry and histopathological examinations revealed overt hepatotoxicity of safrole, in line with previous reports. In the current study, safrole treatment possibly resulted in renal toxicity in male rats. In the in vivo mutation assays, an increase or a tendency to increase of the gpt mutant frequencies (MFs) was observed in both sexes at the carcinogenic dose. The number and area of foci of glutathione S-transferase placental form (GST-P) positive hepatocytes, ratio of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and 8-hydroxydeoxyguanosine (8-OHdG) levels in liver DNA were significantly increased in both sexes of the 0.5% group. The overall data suggested that the present model might be a promising candidate for investigating comprehensive toxicities of the agents. In addition, data demonstrating the base modification and cell proliferation due to exposure to safrole could contribute to understanding safrole-induced hepatocarcinogenesis, which imply expanding in application of this model.

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

    Science.gov (United States)

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

    2015-09-22

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

  5. Off-site toxic consequence assessment: a simplified modeling procedure and case study.

    Science.gov (United States)

    Guarnaccia, Joe; Hoppe, Tom

    2008-11-15

    An assessment of off-site exposure from spills/releases of toxic chemicals can be conducted by compiling site-specific operational, geographic, demographic, and meteorological data and by using screening-level public-domain modeling tools (e.g., RMP Comp, ALOHA and DEGADIS). In general, the analysis is confined to the following: event-based simulations (allow for the use of known, constant, atmospheric conditions), known receptor distances (on the order of miles or less), short time scale for the distances considered (order of 10's of minutes or less), gently sloping rough terrain, dense and neutrally buoyant gas dispersion, known chemical inventory and infrastructure (used to define source-term), and known toxic endpoint (defines significance). While screening-level models are relatively simple to use, care must be taken to ensure that the results are meaningful. This approach allows one to assess risk from catastrophic release (e.g., via terrorism), or plausible release scenarios (related to standard operating procedures and industry standards). In addition, given receptor distance and toxic endpoint, the model can be used to predict the critical spill volume to realize significant off-site risk. This information can then be used to assess site storage and operation parameters and to determine the most economical and effective risk reduction measures to be applied.

  6. The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man.

    NARCIS (Netherlands)

    Louisse, J.; de Jong, E.; van de Sandt, J.J.M.; Blaauboer, B.J.; Woutersen, R.A.; Piersma, A.H.; Rietjens, I.M.C.M.; Verwei, M.

    2010-01-01

    At present, regulatory assessment of systemic toxicity is almost solely performed using animal models. The EU REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for

  7. The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man

    NARCIS (Netherlands)

    Louisse, J.; Jong, E. de; Sandt, J.J.M. van de; Blaauboer, B.J.; Woutersen, R.A.; Piersma, A.H.; Rietjens, I.M.C.M.; Verwei, M.

    2010-01-01

    At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration

  8. The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-respomse curves for in vivo developmental toxicity of glycol ethers in rat and man

    NARCIS (Netherlands)

    Louisse, J.; Jong, de E.; Sandt, van de J.J.M.; Blaauboer, B.J.; Woutersen, R.A.; Piersma, A.H.; Rietjens, I.; Verwei, M.

    2010-01-01

    At present, regulatory assessment of systemic toxicity is almost solely performed using animal models. The EU REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for

  9. Numerical simulation of micro-particle deposition in a realistic human upper respiratory tract model during transient breathing cycle

    Institute of Scientific and Technical Information of China (English)

    Jian hua Huang; Lian zhong Zhang

    2011-01-01

    An more reliable human upper respiratory tract model that consisted of an oropharynx and four generations of asymmetric tracheo-bronchial (TB) airways has been constructed to investigate the micro-particle deposition pattern and mass distribution in five lobes under steady inspiratory condition in former work by Huang and Zhang (2011 ).In the present work,transient airflow patterns and particle deposition during both inspiratory and expiratory processes were numerically simulated in the realistic human upper respiratory tract model with 14 cartilaginous rings (CRs) in the tracheal tube.The present model was validated under steady inspiratory flow rates by comparing current results with the theoretical models and published experimental data.The transient deposition fraction was found to strongly depend on breathing flow rate and particle diameter but slightly on turbulence intensity.Particles were mainly distributed in the high axial speed zones and traveled basically following the secondary flow.“Hot spots” of deposition were found in the lower portion of mouth cavity and posterior wall of pharynx/larynx during inspiration,but transferred to upper portion of mouth and interior wall of pharynx/larynx during expiration.The deposition fraction in the trachea during expiration was found to be much higher than that during inspiration because of the stronger secondary flow.

  10. Effects of pesticides on soil invertebrates in model ecosystem and field studies: a review and comparison with laboratory toxicity data

    NARCIS (Netherlands)

    Jänsch, S.; Frampton, G.K.; Römbke, J.; Brink, van den P.J.; Scott-Fordsmand, J.J.

    2006-01-01

    A systematic review was carried out to investigate the extent to which higher-tier (terrestrial model ecosystem [TME] and field) data regarding pesticide effects can be compared with laboratory toxicity data for soil invertebrates. Data in the public domain yielded 970 toxicity endpoint data sets, r

  11. Development of a biotic ligand model to predict the acute toxicity of cadmium to Daphnia pulex.

    Science.gov (United States)

    Clifford, Matthew; McGeer, James C

    2010-06-01

    The goal of this study was to develop a biotic ligand model (BLM) to predict the acute toxicity of cadmium to Daphnia pulex. Organisms were cultured in moderately soft water and standard 48h acute toxicity tests were used to determine EC50s in various water chemistries where the effects of Ca(2+), Na(+), Mg(2+), Cl(-), K(+), pH, and two sources of natural organic matter (Suwannee River and Nordic Reservoir) were evaluated. Overall, toxicity responses were consistent with the free-ion activity model and the principles inherent in the BLM. Increases in Ca(2+) resulted in higher EC50s, indicating that Cd(2+) competes with Ca(2+) for uptake at the biotic ligand. Similar cation competition effects were observed when Mg(2+) was varied but with a less pronounced protective effect relative to Ca(2+). Changes in Na(+) and K(+) concentrations had no significant effect on Cd toxicity. EC50 values did not change significantly when pH was adjusted over a range from 8.0 to 6.1. Additions of natural organic matter resulted in elevated dissolved organic carbon (DOC) concentrations that significantly reduced Cd bioavailability via complexation of Cd(2+). An existing biotic ligand model (HydroQual BLM ver 2.2.3) was tested for its ability to predict acute Cd toxicity to D. pulex. Once the BLM was adjusted for the relatively sensitivity of D. pulex the protective effects of Ca and DOC could be predicted reasonably well but other test chemistries did not match with measured EC50s. Binding constants derived from the test results (logK(CaBL) of 4.1, logK(MgBL) of 3.7, logK(HBL) of 6.1 and logK(CdBL) of 7.0) were used to develop a modified BLM for the effects of Cd on D. pulex that accounted for the moderating effect of Ca and Mg on acute toxicity but overestimated the protective effect of DOC. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  12. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs

    Science.gov (United States)

    Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty

    2016-01-01

    in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs. PMID:28127503

  13. 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

  14. Computational modeling as part of alternative testing strategies in the respiratory and cardiovascular systems: inhaled nanoparticle dose modeling based on representative aerosol measurements and corresponding toxicological analysis.

    Science.gov (United States)

    Pilou, Marika; Mavrofrydi, Olga; Housiadas, Christos; Eleftheriadis, Kostas; Papazafiri, Panagiota

    2015-05-01

    The objectives of modeling in this work were (a) the integration of two existing numerical models in order to connect external exposure to nanoparticles (NPs) with internal dose through inhalation, and (b) to use computational fluid-particle dynamics (CFPD) to analyze the behavior of NPs in the respiratory and the cardiovascular system. Regarding the first objective, a lung transport and deposition model was combined with a lung clearance/retention model to estimate NPs dose in the different regions of the human respiratory tract and some adjacent tissues. On the other hand, CFPD was used to estimate particle transport and deposition of particles in a physiologically based bifurcation created by the third and fourth lung generations (respiratory system), as well as to predict the fate of super-paramagnetic particles suspended in a liquid under the influence of an external magnetic field (cardiovascular system). All the above studies showed that, with proper refinement, the developed computational models and methodologies may serve as an alternative testing strategy, replacing transport/deposition experiments that are expensive both in time and resources and contribute to risk assessment.

  15. Dispersion modeling of accidental releases of toxic gases - utility for the fire brigades.

    Science.gov (United States)

    Stenzel, S.; Baumann-Stanzer, K.

    2009-09-01

    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. 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 Viennese fire brigade, OMV Refining & Marketing GmbH and Synex Ries & Greßlehner GmbH. RETOMOD was funded by the KIRAS safety research program of 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. For the purpose of our study the following models were tested and compared: ALOHA (Areal Location of Hazardous atmosphere, EPA), MEMPLEX (Keudel av-Technik GmbH), Trace (Safer System), Breeze (Trinity Consulting), SAM (Engineering office Lohmeyer). A set of reference scenarios for Chlorine, Ammoniac, Butane and Petrol were proceed, with the models above, in order to predict and estimate the human exposure during the event. Furthermore, the application of the observation-based analysis and forecasting system INCA, developed in the Central Institute for Meteorology and Geodynamics (ZAMG) in case of toxic release was

  16. 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

    Directory of Open Access Journals (Sweden)

    Yosra Baratli

    2014-01-01

    Full Text Available 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 (Vmax, complexes I, III, and IV activities, Vsucc (complexes II, III, and IV activities, and Vtmpd, (complex IV activity, together with mitochondrial coupling (Vmax/V0 were determined in controls conditions and after exposure to 250, 300, and 350 μg/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: Vmax (from 30 ± 1.6 to 17.9 ± 1.5; P<0.001, Vsucc (from 33.9 ± 1.7 to 24.3 ± 1.0; P<0.01, Vtmpd (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 μg/ml Fe3O4 in the form of Fe3+ 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.

  17. Toxic releases and risk disparity: a spatiotemporal model of industrial ecology and social empowerment.

    Science.gov (United States)

    Aoyagi, Hannah; Ogunseitan, Oladele A

    2015-06-02

    Information-based regulations (IBRs) are founded on the theoretical premise that public participation in accomplishing policy goals is empowered by open access to information. Since its inception in 1988, the Toxics Release Inventory (TRI) has provided the framework and regulatory impetus for the compilation and distribution of data on toxic releases associated with industrial development, following the tenets of IBR. As TRI emissions are reputed to disproportionately affect low-income communities, we investigated how demographic characteristics are related to change in TRI emissions and toxicity risks between 1989 and 2002, and we sought to identify factors that predict these changes. We used local indicators of spatial association (LISA) maps and spatial regression techniques to study risk disparity in the Los Angeles urban area. We also surveyed 203 individuals in eight communities in the same region to measure the levels of awareness of TRI, attitudes towards air pollution, and general environmental risk. We discovered, through spatial lag models, that changes in gross and toxic emissions are related to community ethnic composition, poverty level, home ownership, and base 1989 emissions (R-square=0.034-0.083). We generated a structural equation model to explain the determinants of social empowerment to act on the basis of environmental information. Hierarchical confirmatory factor analysis (HCFA) supports the theoretical model that individual empowerment is predicted by risk perception, worry, and awareness (Chi-square=63.315, p=0.022, df=42). This study provides strong evidence that spatiotemporal changes in regional-scale environmental risks are influenced by individual-scale empowerment mediated by IBRs.

  18. 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

  19. 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.

  20. General pharmacological properties of a new non-opiate antitussive: zipeprol (3024 CERM). I. Action on respiratory function and acute toxicity.

    Science.gov (United States)

    Rispat, G; Burgi, H; Cosnier, D; Duchêne-Marullaz, P; Streichenberger, G

    1976-04-01

    1-(2-Methoxy-2-phenyl)-ethyl-4-(2-hydroxy-3-methoxy-3-phenyl)-propyl-iperazine-dihydrochloride (zipeprol, Respilene) is a substance of non-phenanthrenic chemical structure. In the cat, it antagonised cough induced by stimulation of the superior laryngeal nerve or by direct mechanical excitation of the sensitive tracheo-bronchial receptors. The efficacy of zipeprol after enteral administration made it possible both to establish good intestinal absorption and to rank it favourably in relation to several major antitussive reference products; codeine, codethyline, dextromethorphan, diphenhydramine and pentoxyverine. The activity of zipeprol was superior or equal to that of all these substances, excdept codeine. The antitussive properties appeared to be due to a central action. Other properties have been demonstrated which suggest at least a supplementary mechanism in the inhibition of cough, in addition to the central action. These consisted of slight antihistamine and anticholinergic properties, marked local-anesthetic potency and bronchospasmolytic activity. This latter property was demonstrated by the inhibition of histamine and serotonin induced bronchospasm in the guinea-pig. In vitro, using human sputum, zipeprol had a mucolytic action, shown by a decrease in sputum vis viscosity and lysis of DNA and AMPS fibrils. In the dog, at high doses, zipeprol unlike codeine, did not inhibit central stimulation of respiration by hypercapnia, in addition no modification of ventilatory dynamics or blood gases was seen. On the basis of these results, zipeprol can be considered as possessing no respiratory depressant effect even in the upper ranges of its antitussive doses.

  1. Zebrafish Embryo Toxicity Microscale Model for Ichthyotoxicity Evaluation of Marine Natural Products.

    Science.gov (United States)

    Bai, Hong; Kong, Wen-Wen; Shao, Chang-Lun; Li, Yun; Liu, Yun-Zhang; Liu, Min; Guan, Fei-Fei; Wang, Chang-Yun

    2016-04-01

    Marine organisms often protect themselves against their predators by chemical defensive strategy. The second metabolites isolated from marine organisms and their symbiotic microbes have been proven to play a vital role in marine chemical ecology, such as ichthyotoxicity, allelopathy, and antifouling. It is well known that the microscale models for marine chemoecology assessment are urgently needed for trace quantity of marine natural products. Zebrafish model has been widely used as a microscale model in the fields of environment ecological evaluation and drug safety evaluation, but seldom reported for marine chemoecology assessment. In this work, zebrafish embryo toxicity microscale model was established for ichthyotoxicity evaluation of marine natural products by using 24-well microplate based on zebrafish embryo. Ichthyotoxicity was evaluated by observation of multiple toxicological endpoints, including coagulation egg, death, abnormal heartbeat, no spontaneous movement, delayed hatch, and malformation of the different organs during zebrafish embryogenesis periods at 24, 48, and 72 h post-fertilization (hpf). 3,4-Dichloroaniline was used as the positive control for method validation. Subsequently, the established model was applied to test the ichthyotoxic activity of the compounds isolated from corals and their symbiotic microbes and to isolate the bioactive secondary metabolites from the gorgonian Subergorgia mollis under bioassay guidance. It was suggested that zebrafish embryo toxicity microscale model is suitable for bioassay-guided isolation and preliminary bioactivity screening of marine natural products.

  2. Simple in vitro models can predict pulmonary toxicity of silver nanoparticles.

    Science.gov (United States)

    Braakhuis, Hedwig M; Giannakou, Christina; Peijnenburg, Willie J G M; Vermeulen, Jolanda; van Loveren, Henk; Park, Margriet V D Z

    2016-08-01

    To study the effects of nanomaterials after inhalation, a large number of in vitro lung models have been reported in literature. Although the in vitro models contribute to the reduction of animal studies, insufficient data exists to determine the predictive value of these in vitro models for the in vivo situation. The aim of this study was to determine the correlation between in vitro and in vivo data by comparing the dose metrics of silver nanoparticles in an in vitro lung model of increasing complexity to our previously published in vivo inhalation study. In vivo, the previously published study showed that the alveolar dose expressed as particle surface area is the most suitable dose metric to describe the toxicity of silver nanoparticles after inhalation. The results of the present study show that particle surface area is a suitable dose metric to describe the effects of silver nanoparticles when using a simple monolayer of lung epithelial cells. The dose metric shifted from particle surface area to particle mass when adding an increasing number of macrophages. In addition, a co-culture of endothelial cells, epithelial cells and macrophages on a Transwell® insert correlated less well to the in vivo results compared to the epithelial monolayer. We conclude that for studying the acute pulmonary toxicity of nanoparticles simple in vitro models using an epithelial monolayer better predict the in vivo response compared to complex co-culture models.

  3. 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.

  4. 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.

  5. 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.

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

    Science.gov (United States)

    Nardini, Stefano; Annesi-Maesano, Isabella; Del Donno, Mario; Delucchi, Maurizio; Bettoncelli, Germano; Lamberti, Vincenzo; Patera, Carlo; Polverino, Mario; Russo, Antonio; Santoriello, Carlo; Soverina, Patrizio

    2014-01-01

    to 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.

  7. Evaluation of Common Use Brominated Flame Retardant (BFR Toxicity Using a Zebrafish Embryo Model

    Directory of Open Access Journals (Sweden)

    Crystal Y. Usenko

    2016-09-01

    Full Text Available Brominated flame retardants (BFRs are used to reduce the flammability of plastics, textiles, and electronics. BFRs vary in their chemical properties and structures, and it is expected that these differences alter their biological interactions and toxicity. Zebrafish were used as the model organism for assessing the toxicity of nine structurally-diverse BFRs. In addition to monitoring for overt toxicity, the rate of spontaneous movement, and acetylcholinesterase and glutathione-S-transferase (GST activities were assessed following exposure. The toxicities of BFRs tested can be ranked by LC50 as tetrabromobisphenol A (TBBPA < 4,4′-isopropylidenebis[2-(2,6-dibromophenoxylethanol] (TBBPA-OHEE < Pentabromochlorocyclohexane (PBCH < 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (TBB < hexabromocyclododecane (HBCD < hexabromobenzene (HBB < Tetrabromophthalic anhydride (PHT4. No adverse effect was observed in di(2-ethylhexyl tetrabromophthalate (TBPH or dibromoneopentyl glycol (DBNPG-treated embryos. The rate of spontaneous movement was decreased in a concentration-dependent manner following exposure to four of the nine compounds. GST activity was elevated following treatment with PBCH, TBBPA, HBCD, and HBB. The results indicate that exposure to several BFRs may activate an antioxidant response and alter behavior during early development. Some of the BFRs, such as TBBPA and TBBPA-OHEE, induced adverse effects at concentrations lower than chemicals that are currently banned. These results suggest that zebrafish are sensitive to exposure to BFRs and can be used as a comparative screening model, as well as to determine alterations in behavior following exposure and probe mechanisms of action.

  8. Animal models of disease: feline hyperthyroidism: an animal model for toxic nodular goiter.

    Science.gov (United States)

    Peterson, Mark E

    2014-11-01

    Since first discovered just 35 years ago, the incidence of spontaneous feline hyperthyroidism has increased dramatically to the extent that it is now one of the most common disorders seen in middle-aged to senior domestic cats. Hyperthyroid cat goiters contain single or multiple autonomously (i.e. TSH-independent) functioning and growing thyroid nodules. Thus, hyperthyroidism in cats is clinically and histologically similar to toxic nodular goiter in humans. The disease in cats is mechanistically different from Graves' disease, because neither the hyperfunction nor growth of these nodules depends on extrathyroidal circulating stimulators. The basic lesion appears to be an excessive intrinsic growth capacity of some thyroid cells, but iodine deficiency, other nutritional goitrogens, or environmental disruptors may play a role in the disease pathogenesis. Clinical features of feline toxic nodular goiter include one or more palpable thyroid nodules, together with signs of hyperthyroidism (e.g. weight loss despite an increased appetite). Diagnosis of feline hyperthyroidism is confirmed by finding the increased serum concentrations of thyroxine and triiodothyronine, undetectable serum TSH concentrations, or increased thyroid uptake of radioiodine. Thyroid scintigraphy demonstrates a heterogeneous pattern of increased radionuclide uptake, most commonly into both thyroid lobes. Treatment options for toxic nodular goiter in cats are similar to that used in humans and include surgical thyroidectomy, radioiodine, and antithyroid drugs. Most authorities agree that ablative therapy with radioiodine is the treatment of choice for most cats with toxic nodular goiter, because the animals are older, and the disease will never go into remission.

  9. 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

  10. 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.

  11. 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.

  12. RESPIRATORY SYSTEM

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    2004494 Respiratory control in obstructive sleep apnea hypopnea syndrome. WANG Wei (王玮), et al. Instit Respir Dis, 1st Affili Hosp, China Med Limy, Shenyang 110001. Chin J Intern Med 2004; 43 (9): 647-650.

  13. 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.

  14. Evaluation of pulmonary dysfunctions and acid-base imbalances induced by Chlamydia psittaci in a bovine model of respiratory infection.

    Science.gov (United States)

    Ostermann, Carola; Linde, Susanna; Siegling-Vlitakis, Christiane; Reinhold, Petra

    2014-01-01

    Chlamydia psittaci (Cp) is a respiratory pathogen capable of inducing acute pulmonary zoonotic disease (psittacosis) or persistent infection. To elucidate the pathogenesis of this infection, a translational large animal model was recently introduced by our group. This study aims at quantifying and differentiating pulmonary dysfunction and acid-base imbalances induced by Cp. Forty-two calves were grouped in (i) animals inoculated with Cp (n = 21) and (ii) controls sham-inoculated with uninfected cell culture (n = 21). For pulmonary function testing, impulse oscillometry, capnography, and FRC (functional residual capacity) measurement were applied to spontaneously breathing animals. Variables of acid-base status were assessed in venous blood using both (i) traditional Henderson-Hasselbalch and (ii) strong ion approach. Both obstructive and restrictive pulmonary disorders were induced in calves experimentally inoculated with Cp. Although disorders in respiratory mechanics lasted for 8-11 days, the pattern of spontaneous breathing was mainly altered in the period of acute illness (until 4 days post inoculation, dpi). Expiration was more impaired than inspiration, resulting in elevated FRC. Ventilation was characterised by a reduction in tidal volume (-25%) combined with an increased percentage of dead space volume and a significant reduction of alveolar volume by 10%. Minute ventilation increased significantly (+50%) due to a compensatory doubling of respiratory rate. Hyperventilatory hypocapnia at 2-3 dpi resulted in slightly increased blood pH at 2 dpi. However, the acid-base equilibrium was additionally influenced by metabolic components, i.e. the systemic inflammatory response, all of which were detected with help of the strong ion theory. Decreased concentrations of albumin (2-10 dpi), a negative acute-phase marker, resulted in a decrease in the sum of non-volatile weak acids (Atot), revealing an alkalotic effect. This was counterbalanced by acidic effects

  15. Respiratory and oral vaccination improves protection conferred by the live vaccine strain against pneumonic tularemia in the rabbit model.

    Science.gov (United States)

    Stinson, Elizabeth; Smith, Le'Kneitah P; Cole, Kelly Stefano; Barry, Eileen M; Reed, Douglas S

    2016-10-01

    Tularemia is a severe, zoonotic disease caused by a gram-negative bacterium, Francisella tularensis We have previously shown that rabbits are a good model of human pneumonic tularemia when exposed to aerosols containing a virulent, type A strain, SCHU S4. We further demonstrated that the live vaccine strain (LVS), an attenuated type B strain, extended time to death when given by scarification. Oral or aerosol vaccination has been previously shown in humans to offer superior protection to parenteral vaccination against respiratory tularemia challenge. Both oral and aerosol vaccination with LVS were well tolerated in the rabbit with only minimal fever and no weight loss after inoculation. Plasma antibody titers against F. tularensis were higher in rabbits that were vaccinated by either oral or aerosol routes compared to scarification. Thirty days after vaccination, all rabbits were challenged with aerosolized SCHU S4. LVS given by scarification extended time to death compared to mock-vaccinated controls. One orally vaccinated rabbit did survive aerosol challenge, however, only aerosol vaccination extended time to death significantly compared to scarification. These results further demonstrate the utility of the rabbit model of pneumonic tularemia in replicating what has been reported in humans and macaques as well as demonstrating the utility of vaccination by oral and respiratory routes against an aerosol tularemia challenge.

  16. Muscle weakness in respiratory and peripheral skeletal muscles in a mouse model for nebulin-based nemaline myopathy.

    Science.gov (United States)

    Joureau, Barbara; de Winter, Josine M; Stam, Kelly; Granzier, Henk; Ottenheijm, Coen A C

    2017-01-01

    Nemaline myopathy is among the most common non-dystrophic congenital myopathies, and is characterized by the presence of nemaline rods in skeletal muscles fibers, general muscle weakness, and hypotonia. Although respiratory failure is the main cause of death in nemaline myopathy, only little is known regarding the contractile strength of the diaphragm, the main muscle of inspiration. To investigate diaphragm contractility, in the present study we took advantage of a mouse model for nebulin-based nemaline myopathy that we recently developed. In this mouse model, exon 55 of Neb is deleted (Neb(ΔExon55)), a mutation frequently found in patients. Diaphragm contractility was determined in permeabilized muscle fibers and was compared to the contractility of permeabilized fibers from three peripheral skeletal muscles: soleus, extensor digitorum longus, and gastrocnemius. The force generating capacity of diaphragm muscle fibers of Neb(ΔExon55) mice was reduced to 25% of wildtype levels, indicating severe contractile weakness. The contractile weakness of diaphragm fibers was more pronounced than that observed in soleus muscle, but not more pronounced than that observed in extensor digitorum longus and gastrocnemius muscles. The reduced muscle contractility was at least partly caused by changes in cross-bridge cycling kinetics which reduced the number of bound cross-bridges. The severe diaphragm weakness likely contributes to the development of respiratory failure in Neb(ΔExon55) mice and might explain their early, postnatal death. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Searching for animal models and potential target species for emerging pathogens: Experience gained from Middle East respiratory syndrome (MERS coronavirus

    Directory of Open Access Journals (Sweden)

    Júlia Vergara-Alert

    2017-06-01

    Full Text Available Emerging and re-emerging pathogens represent a substantial threat to public health, as demonstrated with numerous outbreaks over the past years, including the 2013–2016 outbreak of Ebola virus in western Africa. Coronaviruses are also a threat for humans, as evidenced in 2002/2003 with infection by the severe acute respiratory syndrome coronavirus (SARS-CoV, which caused more than 8000 human infections with 10% fatality rate in 37 countries. Ten years later, a novel human coronavirus (Middle East respiratory syndrome coronavirus, MERS-CoV, associated with severe pneumonia, arose in the Kingdom of Saudi Arabia. Until December 2016, MERS has accounted for more than 1800 cases and 35% fatality rate. Finding an animal model of disease is key to develop vaccines or antivirals against such emerging pathogens and to understand its pathogenesis. Knowledge of the potential role of domestic livestock and other animal species in the transmission of pathogens is of importance to understand the epidemiology of the disease. Little is known about MERS-CoV animal host range. In this paper, experimental data on potential hosts for MERS-CoV is reviewed. Advantages and limitations of different animal models are evaluated in relation to viral pathogenesis and transmission studies. Finally, the relevance of potential new target species is discussed.

  18. SU-E-J-73: Generation of Volumetric Images with a Respiratory Motion Model Based On An External Surrogate Signal

    Energy Technology Data Exchange (ETDEWEB)

    Hurwitz, M; Williams, C; Mishra, P; Dhou, S; Lewis, J [Brigham and Women' s Hospital, Dana-Farber Cancer Center, Harvard Medical School, Boston, MA, Boston, MA (United States)

    2014-06-01

    Purpose: Respiratory motion during radiotherapy treatment can differ significantly from motion observed during imaging for treatment planning. Our goal is to use an initial 4DCT scan and the trace of an external surrogate marker to generate 3D images of patient anatomy during treatment. Methods: Deformable image registration is performed on images from an initial 4DCT scan. The deformation vectors are used to develop a patient-specific linear relationship between the motion of each voxel and the trajectory of an external surrogate signal. Correlations in motion are taken into account with principal component analysis, reducing the number of free parameters. This model is tested with digital phantoms reproducing the breathing patterns of ten measured patient tumor trajectories, using five seconds of data to develop the model and the subsequent thirty seconds to test its predictions. The model is also tested with a breathing physical anthropomorphic phantom programmed to reproduce a patient breathing pattern. Results: The error (mean absolute, 95th percentile) over 30 seconds in the predicted tumor centroid position ranged from (0.8, 1.3) mm to (2.2, 4.3) mm for the ten patient breathing patterns. The model reproduced changes in both phase and amplitude of the breathing pattern. Agreement between prediction and truth over the entire image was confirmed by assessing the global voxel intensity RMS error. In the physical phantom, the error in the tumor centroid position was less than 1 mm for all images. Conclusion: We are able to reconstruct 3D images of patient anatomy with a model correlating internal respiratory motion with motion of an external surrogate marker, reproducing the expected tumor centroid position with an average accuracy of 1.4 mm. The images generated by this model could be used to improve dose calculations for treatment planning and delivered dose estimates. This work was partially funded by a research grant from Varian Medical Systems.

  19. [Respiratory distress].

    Science.gov (United States)

    Galili, D; Garfunkel, A; Elad, S; Zusman, S P; Malamed, S F; Findler, M; Kaufman, E

    2002-01-01

    Dental treatment is usually conducted in the oral cavity and in very close proximity to the upper respiratory airway. The possibility of unintentionally compromising this airway is high in the dental environment. The accumulation of fluid (water or blood) near to the upper respiratory airway or the loosening of teeth fragmentations and fallen dental instruments can occur. Also, some of the drugs prescribed in the dental practice are central nervous system depressants and some are direct respiratory drive depressors. For this reason, awareness of the respiratory status of the dental patient is of paramount importance. This article focuses on several of the more common causes of respiratory distress, including airway obstruction, hyperventilation, asthma, bronchospasm, pulmonary edema, pulmonary embolism and cardiac insufficiency. The common denominator to all these conditions described here is that in most instances the patient is conscious. Therefore, on the one hand, valuable information can be retrieved from the patient making diagnosis easier than when the patient is unconscious. On the other hand, the conscious patient is under extreme apprehension and stress under such situations. Respiratory depression which occurs during conscious sedation or following narcotic analgesic medication will not be dealt with in this article. Advanced pain and anxiety control techniques such as conscious sedation and general anesthesia should be confined only to operators who undergo special extended training.

  20. alpha-Synuclein fission yeast model: concentration-dependent aggregation without plasma membrane localization or toxicity.

    Science.gov (United States)

    Brandis, Katrina A; Holmes, Isaac F; England, Samantha J; Sharma, Nijee; Kukreja, Lokesh; DebBurman, Shubhik K

    2006-01-01

    Despite fission yeast's history of modeling salient cellular processes, it has not yet been used to model human neurodegeneration-linked protein misfolding. Because alpha-synuclein misfolding and aggregation are linked to Parkinson's disease (PD), here, we report a fission yeast (Schizosaccharomyces pombe) model that evaluates alpha-synuclein misfolding, aggregation, and toxicity and compare these properties with those recently characterized in budding yeast (Saccharomyces cerevisiae). Wild-type alpha-synuclein and three mutants (A30P, A53T, and A30P/A53T) were expressed with thiamine-repressible promoters (using vectors of increasing promoter strength: pNMT81, pNMT41, and pNMT1) to test directly in living cells the nucleation polymerization hypothesis for alpha-synuclein misfolding and aggregation. In support of the hypothesis, wild-type and A53T alpha-synuclein formed prominent intracellular cytoplasmic inclusions within fission yeast cells in a concentration- and time-dependent manner, whereas A30P and A30P/A53T remained diffuse throughout the cytoplasm. A53T alpha-synuclein formed aggregates faster than wild-type alpha-synuclein and at a lower alpha-synuclein concentration. Unexpectedly, unlike in budding yeast, wild-type and A53T alpha-synuclein did not target to the plasma membrane in fission yeast, not even at low alpha-synuclein concentrations or as a precursor step to forming aggregates. Despite alpha-synuclein's extensive aggregation, it was surprisingly nontoxic to fission yeast. Future genetic dissection might yield molecular insight into this protection against toxicity. We speculate that alpha-synuclein toxicity might be linked to its membrane binding capacity. To conclude, S. pombe and S. cerevisiae model similar yet distinct aspects of alpha-synuclein biology, and both organisms shed insight into alpha-synuclein's role in PD pathogenesis.

  1. Towards elucidation of the toxic mechanism of copper on the model green alga Chlamydomonas reinhardtii.

    Science.gov (United States)

    Jiang, Yongguang; Zhu, Yanli; Hu, Zhangli; Lei, Anping; Wang, Jiangxin

    2016-09-01

    Toxic effects of copper on aquatic organisms in polluted water bodies have garnered particular attention in recent years. Microalgae play an important role in aquatic ecosystems, and they are sensitive to heavy metal pollution. Thus, it is important to clarify the mechanism of copper toxicity first for ecotoxicology studies. In this study, the physiological, biochemical and gene expression characteristics of a model green microalga, Chlamydomonas reinhardtii, with 0, 50, 150 and 250 μM copper treatments were investigated. The response of C. reinhardtii to copper stress was significantly shown at a dose dependent manner. Inhibition of cell growth and variation of total chlorophyll content were observed with copper treatments. The maximum photochemical efficiency of PSII, actual photochemical efficiency of PSII and photochemical quenching value decreased in the 250 μM copper treatment with minimum values equal to 28, 24 and 60 % of the control values respectively. The content of lipid peroxidation biomarker malondialdehyde with copper treatments increased with a maximum value sevenfold higher than the control value. Inhibition of cell growth and photosynthesis was ascribed to peroxidation of membrane lipids. The glutathione content and activities of antioxidant enzymes, glutathione S-transferase, glutathione peroxidase, superoxide dismutase and peroxidase were induced by copper. Interestingly, the expression of antioxidant genes and the photosynthetic gene decreased in most copper treatments. In conclusion, oxidative stress caused by production of excess reactive oxidative species might be the major mechanism of copper toxicity on C. reinhardtii.

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

    Science.gov (United States)

    Santoyo-Sánchez, Mitzi; Thévenod, Frank; Barbier, Olivier

    2017-01-01

    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). PMID:28737682

  3. 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.

  4. 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.

  5. An alternative antidote therapy in amitriptyline-induced rat toxicity model: theophylline.

    Science.gov (United States)

    Oransay, Kubilay; Kalkan, Sule; Hocaoglu, Nil; Arici, Aylin; Tuncok, Yesim

    2011-01-01

    We planned this study in order to investigate the effects of theophylline on cardiovascular parameters in an anaesthetized rat model of amitriptyline toxicity. In the preliminary study, we tested theophylline as 1 mg/kg of bolus, followed by a 0.5-mg/kg infusion. Toxicity was induced by the infusion of 0.94 mg/kg/min of amitriptyline up to the point of a 40-45% inhibition of mean arterial pressure (MAP). The rats were randomized to two groups: a group of 5% dextrose bolus followed by 5% dextrose infusion, and another group with theophylline bolus followed by infusion. Amitriptyline caused a significant decrease in MAP and prolongation in QRS; however, it did not alter heart rate (HR). When compared to the dextrose group, theophylline administration increased MAP, shortened prolonged QRS duration, and increased HR (P  0.05). Bolus doses followed by a continuous infusion of theophylline were found to be effective in reversing the hypotension and QRS prolongation seen in amitriptyline toxicity. One of the possible explanations of this beneficial effect is nonselective adenosine antagonism of theophylline. Further studies are needed to reveal the exact mechanism of the observed effect.

  6. Linking in Vitro Effects and Detected Organic Micropollutants in Surface Water Using Mixture-Toxicity Modeling.

    Science.gov (United States)

    Neale, Peta A; Ait-Aissa, Selim; Brack, Werner; Creusot, Nicolas; Denison, Michael S; Deutschmann, Björn; Hilscherová, Klára; Hollert, Henner; Krauss, Martin; Novák, Jiří; Schulze, Tobias; Seiler, Thomas-Benjamin; Serra, Helene; Shao, Ying; Escher, Beate I

    2015-12-15

    Surface water can contain countless organic micropollutants, and targeted chemical analysis alone may only detect a small fraction of the chemicals present. Consequently, bioanalytical tools can be applied complementary to chemical analysis to detect the effects of complex chemical mixtures. In this study, bioassays indicative of activation of the aryl hydrocarbon receptor (AhR), activation of the pregnane X receptor (PXR), activation of the estrogen receptor (ER), adaptive stress responses to oxidative stress (Nrf2), genotoxicity (p53) and inflammation (NF-κB) and the fish embryo toxicity test were applied along with chemical analysis to water extracts from the Danube River. Mixture-toxicity modeling was applied to determine the contribution of detected chemicals to the biological effect. Effect concentrations for between 0 to 13 detected chemicals could be found in the literature for the different bioassays. Detected chemicals explained less than 0.2% of the biological effect in the PXR activation, adaptive stress response, and fish embryo toxicity assays, while five chemicals explained up to 80% of ER activation, and three chemicals explained up to 71% of AhR activation. This study highlights the importance of fingerprinting the effects of detected chemicals.

  7. Modeling physiological processes that relate toxicant exposure and bacterial population dynamics.

    Directory of Open Access Journals (Sweden)

    Tin Klanjscek

    Full Text Available Quantifying effects of toxicant exposure on metabolic processes is crucial to predicting microbial growth patterns in different environments. Mechanistic models, such as those based on Dynamic Energy Budget (DEB theory, can link physiological processes to microbial growth.Here we expand the DEB framework to include explicit consideration of the role of reactive oxygen species (ROS. Extensions considered are: (i additional terms in the equation for the "hazard rate" that quantifies mortality risk; (ii a variable representing environmental degradation; (iii a mechanistic description of toxic effects linked to increase in ROS production and aging acceleration, and to non-competitive inhibition of transport channels; (iv a new representation of the "lag time" based on energy required for acclimation. We estimate model parameters using calibrated Pseudomonas aeruginosa optical density growth data for seven levels of cadmium exposure. The model reproduces growth patterns for all treatments with a single common parameter set, and bacterial growth for treatments of up to 150 mg(Cd/L can be predicted reasonably well using parameters estimated from cadmium treatments of 20 mg(Cd/L and lower. Our approach is an important step towards connecting levels of biological organization in ecotoxicology. The presented model reveals possible connections between processes that are not obvious from purely empirical considerations, enables validation and hypothesis testing by creating testable predictions, and identifies research required to further develop the theory.

  8. Human Umbilical Cord Blood-Derived Neural Stem Cell Line as a Screening Model for Toxicity.

    Science.gov (United States)

    Patnaik, Rajashree; Padhy, Rabindra Nath

    2017-04-01

    The aim was to investigate whether a human neural stem cell (NSC) line derived from human umbilical cord blood (hUCB) can be used for toxicity study. Toxicity of both neurotoxic environmental xenobiotics, methyl mercury chloride (CH3HgCl), lead acetate (CH3COOPb), and chlorpyrifos (CP), and non-neurotoxic insecticide, dichlorvos, as well as non-neurotoxic drugs, theophylline and acetaminophen were assessed. Additionally, differentiation of neuronal and glial cell lines derived from hUCB was elucidated. It was observed that CH3HgCl was more toxic to human NSCs in comparison to CH3COOPb and CP. The minimum inhibitory concentration (MIC) value against NSCs was 3, 10, and 300 mg/L, in each staining process, acridine orange/ethidium bromide (AO/EB) staining, 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay, and Hoechst staining, for CH3HgCl, CP, and CH3COOPb, respectively. CH3HgCl had the LC25 value as 10.0, 14.4, and 12.7 mg/L, by staining method mentioned in succession. CP had the LC25 value as 21.9, 23.7, and 18.4 mg/L; similarly, CH3COOPb had LC25 values, successively as 616.9, 719.2, and 890.3 mg/L. LC50 values ranged from 18.2 to 21.7 mg/L for CH3HgCl, 56.4 to 60.2 mg/L for CP, and 1000 to 1460.1 for CH3COOPb. Theophylline, acetaminophen, and dichlorvos had no impact on the viability of NSCs. This work justified that hUCB-NSC model can be used for toxicity study.

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Ntie-Kang F

    2016-07-01

    Full Text Available Fidele Ntie-Kang,1,2,* Conrad Veranso Simoben,1,2,* Berin Karaman,1 Valery Fuh Ngwa,3 Philip Neville Judson,4 Wolfgang Sippl,1 Luc Meva’a Mbaze5 1Department of Pharmaceutical Chemistry, Martin-Luther University of Halle-Wittenberg, Halle (Saale, Germany; 2Department of Chemistry, University of Buea, Buea, Cameroon; 3Interuniversity Institute For Biostatistics and Statistical Bioinformatics (I-BioStat, University of Hasselt, Hasselt, Belgium; 4Chemical Bioactivity Information Centre, Harrogate, UK; 5Department of Chemistry, Faculty of Science, University of Douala, Douala, Cameroon *These authors contributed equally to this work Abstract: 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

  11. QSTR with extended topochemical atom (ETA) indices. 14. QSAR modeling of toxicity of aromatic aldehydes to Tetrahymena pyriformis

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Kunal, E-mail: kunalroy_in@yahoo.com [Drug Theoretics and Cheminformatics Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032 (India); Das, Rudra Narayan [Drug Theoretics and Cheminformatics Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032 (India)

    2010-11-15

    Aldehydes are a toxic class of chemicals causing severe health hazards. In this background, quantitative structure-toxicity relationship (QSTR) models have been developed in the present study using Extended Topochemical Atom (ETA) indices for a large group of 77 aromatic aldehydes for their acute toxicity against the protozoan ciliate Tetrahymena pyriformis. The ETA models have been compared with those developed using various non-ETA topological indices. Attempt was also made to include the n-octanol/water partition coefficient (log K{sub o/w}) as an additional descriptor considering the importance of hydrophobicity in toxicity prediction. Thirty different models were developed using different chemometric tools. All the models have been validated using internal validation and external validation techniques. The statistical quality of the ETA models was found to be comparable to that of the non-ETA models. The ETA models have shown the important effects of steric bulk, lipophilicity, presence of electronegative atom containing substituents and functionality of the aldehydic oxygen to the toxicity of the aldehydes. The best ETA model (without using log K{sub o/w}) shows encouraging statistical quality (Q{sub int}{sup 2}=0.709,Q{sub ext}{sup 2}=0.744). It is interesting to note that some of the topological models reported here are better in statistical quality than previously reported models using quantum chemical descriptors.

  12. 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).

  13. Integrating (Q)SAR models, expert systems and read-across approaches for the prediction of developmental toxicity.

    Science.gov (United States)

    Hewitt, M; Ellison, C M; Enoch, S J; Madden, J C; Cronin, M T D

    2010-08-01

    It has been estimated that reproductive and developmental toxicity tests will account for a significant proportion of the testing costs associated with REACH compliance. Consequently, the use of alternative methods to predict developmental toxicity is an attractive prospect. The present study evaluates a number of computational models and tools which can be used to aid assessment of developmental toxicity potential. The performance and limitations of traditional (quantitative) structure-activity relationship ((Q)SARs) modelling, structural alert-based expert system prediction and chemical profiling approaches are discussed. In addition, the use of category formation and read-across is also addressed. This study demonstrates the limited success of current modelling methods when used in isolation. However, the study also indicates that when used in combination, in a weight-of-evidence approach, better use may be made of the limited toxicity data available and predictivity improved. Recommendations are provided as to how this area could be further developed in the future.

  14. In vivo toxicity of enoxaparin encapsulated in mucoadhesive nanoparticles: Topical application in a wound healing model

    Science.gov (United States)

    Huber, S. C.; Marcato, P. D.; Barbosa, R. M.; Duran, N.; Annichino-Bizzacchi, J. M.

    2013-04-01

    Wound healing comprises four distinct phases and involves many cell events and biologic markers. The use of nanoparticles for topical application has gaining attention due to its deeper penetration in the skin and the retention capacity of the drug in the site of application. In this study the effect and toxicity of mucoadhesive polymeric nanoparticles loaded with enoxaparin was evaluated in in vivo model of skin ulcer. Our results showed an interesting formulation based on mucoadhesive nanoparticles with enoxaparin that improved wound healing without cytotoxicity in vitro in all endpoint evaluated. Then, this semi-solid formulation is a promising option for skin ulcer treatment.

  15. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling.

    Science.gov (United States)

    Louisse, Jochem; Bosgra, Sieto; Blaauboer, Bas J; Rietjens, Ivonne M C M; Verwei, Miriam

    2015-07-01

    The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity data obtained from in vitro assays for risk assessment, in vitro concentration-response data need to be translated into in vivo dose-response data that are needed to obtain points of departure for risk assessment, like a benchmark dose (BMD). In the present study, we translated in vitro concentration-response data of the retinoid all-trans-retinoic acid (ATRA), obtained in the differentiation assay of the embryonic stem cell test, into in vivo dose-response data using a physiologically based kinetic model for rat and human that is mainly based on kinetic model parameter values derived using in vitro techniques. The predicted in vivo dose-response data were used for BMD modeling, and the obtained BMDL10 values [lower limit of the 95 % confidence interval on the BMD at which a benchmark response equivalent to a 10 % effect size (BMR10) is reached (BMD10)] for rat were compared with BMDL10 values derived from in vivo developmental toxicity data in rats reported in the literature. The results show that the BMDL10 values from predicted dose-response data differ about sixfold from the BMDL10 values obtained from in vivo data, pointing at the feasibility of using a combined in vitro-in silico approach for defining a point of departure for toxicological risk assessment.

  16. Respiratory-like rhythmic activity can be produced by an excitatory network of non-pacemaker neuron models.

    Science.gov (United States)

    Kosmidis, Efstratios K; Pierrefiche, Olivier; Vibert, Jean-François

    2004-08-01

    It is still unclear whether the respiratory-like rhythm observed in slice preparations containing the pre-Bötzinger complex is of pacemaker or network origin. The rhythm persists in the absence of inhibition, but blocking pacemaker activity did not always result in rhythm abolition. We developed a computational model of the slice to show that respiratory-like rhythm can emerge as a network property without pacemakers or synaptic inhibition. The key currents of our model cell are the low- and high-threshold calcium currents and the calcium-dependent potassium current. Depolarization of a single unit by current steps or by raising the external potassium concentration can induce periodic bursting activity. Gaussian stimulation increased the excitability of the model without evoking oscillatory activity, as indicated by autocorrelation analysis. In response to hyperpolarizing pulses, the model produces prolonged relative refractory periods. At the network level, an increase of external potassium concentration triggers rhythmic activity that can be attributed to cellular periodic bursting, network properties, or both, depending on different parameters. Gaussian stimulation also induces rhythmic activity that depends solely on network properties. In all cases, the calcium-dependent potassium current has a central role in burst termination and interburst duration. However, when periodic inhibition is considered, the activation of this current is responsible for the characteristic amplification ramp of the emerged rhythm. Our results may explain controversial results from studies blocking pacemakers in vitro and show a shift in the role of the calcium-dependent potassium current in the presence of network inhibition.

  17. 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.

  18. Particle deposition in a child respiratory tract model: in vivo regional deposition of fine and ultrafine aerosols in baboons.

    Science.gov (United States)

    Albuquerque-Silva, Iolanda; Vecellio, Laurent; Durand, Marc; Avet, John; Le Pennec, Déborah; de Monte, Michèle; Montharu, Jérôme; Diot, Patrice; Cottier, Michèle; Dubois, Francis; Pourchez, Jérémie

    2014-01-01

    To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols ([d16-d84], equal to [0.15 µm-0.5 µm], [0.25 µm-1 µm], or [1 µm-9 µm]). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the [1 µm-9 µm] aerosol (72% ± 17%). The [0.15 µm-0.5 µm] aerosol was associated almost exclusively with thoracic region deposition (84% ± 4%). Airborne particles in the range of [0.25 µm-1 µm] showed an intermediate deposition pattern, with 49% ± 8% in the extrathoracic region and 51% ± 8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the [1 µm-9 µm] aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.

  19. Particle deposition in a child respiratory tract model: in vivo regional deposition of fine and ultrafine aerosols in baboons.

    Directory of Open Access Journals (Sweden)

    Iolanda Albuquerque-Silva

    Full Text Available To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region of radioactive polydisperse aerosols ([d16-d84], equal to [0.15 µm-0.5 µm], [0.25 µm-1 µm], or [1 µm-9 µm]. Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the [1 µm-9 µm] aerosol (72% ± 17%. The [0.15 µm-0.5 µm] aerosol was associated almost exclusively with thoracic region deposition (84% ± 4%. Airborne particles in the range of [0.25 µm-1 µm] showed an intermediate deposition pattern, with 49% ± 8% in the extrathoracic region and 51% ± 8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the [1 µm-9 µm] aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.

  20. 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.)

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

    Energy Technology Data Exchange (ETDEWEB)

    Wennberg, Berit M.; Baumann, Pia; Gagliardi, Giovanna (Dept. of Medical Physics, Karolinska Univ. Hospital and the Karolinska Inst., Stockholm (Sweden)), e-mail: berit.wennberg@karolinska.se (and others)

    2011-05-15

    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 alpha/beta = 3 Gy was used and the USC parameters used were: alpha/beta = 3 Gy, D{sub 0} = 1.0 Gy, n = 10, alpha 0.206 Gy-1 and d{sub 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{sub 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

  2. 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...

  3. 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.

  4. Electrical circuit models of the human respiratory system reflect small airway impairment measured by impulse oscillation (IOS).

    Science.gov (United States)

    Goldman, Michael D; Nazeran, Homer; Ramos, Carlos; Toon, Emily; Oates, Katrina; Bilton, Diana; Meraz, Erika; Hafezi, Nazila; Diong, Bill

    2010-01-01

    The use of the forced oscillatory input impedance parameter, frequency-dependence of Resistance (fdR), to assess small airway impairment (SAI) has not been widely accepted due to concern about the effects of "upper airway shunt" on oscillometric resistance and low frequency reactance. On the other hand, recent medical studies suggest that low frequency reactance is a very sensitive index of treatment intervention directed at small airways. The present study was undertaken to analyze and compare Impulse Oscillometry (IOS) resistance and reactance data with model-derived indices of small airway function from two models of the respiratory impedance, one with, and the other without an element for upper airway shunt capacitance. Fifty six patients with stable chronic obstructive lung disease of varying severity due to Cystic Fibrosis (CF) and 21 patients with asthma were evaluated by IOS testing. IOS data were input into the augmented RIC (aRIC) model with an upper airway shunt capacitance, and the extended RIC (eRIC) model, without a shunt capacitance element. Model-derived indices were compared between the two models for CF patients separately from asthma patients. We conclude that IOS indices of SAI are modeled equally well with or without upper airway shunt capacitance, and do not seem to be dependent on upper airway shunt capacitance.

  5. Population based external validation of a European predictive model for respiratory syncytial virus hospitalization of premature infants born 33 to 35 weeks of gestational age

    DEFF Research Database (Denmark)

    Stensballe, Lone G; Fullarton, John R; Carbonell-Estrany, Xavier

    2010-01-01

    Prospectively collected population-based data on 2529 Danish infants born at 33 to 35 weeks of gestation were used to validate an European predictive model of respiratory syncytial virus (RSV) hospitalization. The model was found to be robust with a diagnostic accuracy of 65.9% to distinguish bet...

  6. Identification of Chemical Vascular Disruptors During Development Using An Integrative Predictive Toxicity Model and Zebrafish and in Vitro Functional Angiogenesis Assays.

    Science.gov (United States)

    Identification of chemical vascular disruptors during development using an integrative predictive toxicity model and zebrafish and in vitro functional angiogenesis assays Chemically-induced vascular toxicity during embryonic development can result in a wide range of adverse pre...

  7. Identification of Chemical Vascular Disruptors During Development Using An Integrative Predictive Toxicity Model and Zebrafish and in Vitro Functional Angiogenesis Assays.

    Science.gov (United States)

    Identification of chemical vascular disruptors during development using an integrative predictive toxicity model and zebrafish and in vitro functional angiogenesis assays Chemically-induced vascular toxicity during embryonic development can result in a wide range of adverse pre...

  8. 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

  9. Modeling dispersion from toxic gas released after a train collision in Graniteville, SC.

    Science.gov (United States)

    Buckley, Robert L; Hunter, Charles H; Addis, Robert P; Parker, Matthew J

    2007-03-01

    The Savannah River National Laboratory (SRNL) Weather Information and Display System was used to provide meteorological and atmospheric modeling/consequence assessment support to state and local agencies after the collision of two Norfolk Southern freight trains on the morning of January 6, 2005. This collision resulted in the release of several toxic chemicals to the environment, including chlorine. The dense and highly toxic cloud of chlorine gas that formed in the vicinity of the accident was responsible for 9 fatalities and caused injuries to more than 500 others. Transport model results depicting the forecast path of the ongoing release were made available to emergency managers in the county's Unified Command Center shortly after SRNL received a request for assistance. Support continued over the ensuing 2 days of the active response. The SRNL also provided weather briefings and transport/consequence assessment model results to responders from the South Carolina Department of Health and Environmental Control, the Savannah River Site (SRS) Emergency Operations Center, Department of Energy headquarters, and hazard material teams dispatched from the SRS. Operational model-generated forecast winds used in consequence assessments conducted during the incident were provided at 2-km horizontal grid spacing during the accident response. High-resolution Regional Atmospheric Modeling System (RAMS, version 4.3.0) simulation was later performed to examine potential influences of local topography on plume migration in greater detail. The detailed RAMS simulation was used to determine meteorology using multiple grids with an innermost grid spacing of 125 m. Results from the two simulations are shown to generally agree with meteorological observations at the time; consequently, local topography did not significantly affect wind in the area. Use of a dense gas dispersion model to simulate localized plume behavior using the higher-resolution winds indicated agreement with

  10. 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

  11. The embryonic stem cell test combined with toxicogenomics as an alternative testing model for the assessment of developmental toxicity.

    Science.gov (United States)

    van Dartel, Dorien A M; Piersma, Aldert H

    2011-09-01

    One of the most studied in vitro alternative testing methods for identification of developmental toxicity is the embryonic stem cell test (EST). Although the EST has been formally validated, the applicability domain as well as the predictability of the model needs further study to allow successful implementation of the EST as an alternative testing method in regulatory toxicity testing. Genomics technologies have already provided a proof of principle of their value in identification of toxicants such as carcinogenic compounds. Also within the EST, gene expression profiling has shown its value in the identification of developmental toxicity and in the evaluation of factors critical for risk assessment, such as dose and time responses. It is expected that the implementation of genomics into the EST will provide a more detailed end point evaluation as compared to the classical morphological scoring of differentiation cultures. Therefore, genomics may contribute to improvement of the EST, both in terms of definition of its applicability domain as well as its predictive capacity. In the present review, we present the progress that has been made with regard to the prediction of developmental toxicity using the EST combined with transcriptomics. Furthermore, we discuss the developments of additional aspects required for further optimization of the EST, including kinetics, the use of human embryonic stem cells (ESC) and computational toxicology. Finally, the current and future use of the EST model for prediction of developmental toxicity in testing strategies and in regulatory toxicity evaluations is discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. A stochastic model to determine the economic value of changing diagnostic test characteristics for identification of cattle for treatment of bovine respiratory disease.

    Science.gov (United States)

    Theurer, M E; White, B J; Larson, R L; Schroeder, T C

    2015-03-01

    Bovine respiratory disease is an economically important syndrome in the beef industry, and diagnostic accuracy is important for optimal disease management. The objective of this study was to determine whether improving diagnostic sensitivity or specificity was of greater economic value at varied levels of respiratory disease prevalence by using Monte Carlo simulation. Existing literature was used to populate model distributions of published sensitivity, specificity, and performance (ADG, carcass weight, yield grade, quality grade, and mortality risk) differences among calves based on clinical respiratory disease status. Data from multiple cattle feeding operations were used to generate true ranges of respiratory disease prevalence and associated mortality. Input variables were combined into a single model that calculated estimated net returns for animals by diagnostic category (true positive, false positive, false negative, and true negative) based on the prevalence, sensitivity, and specificity for each iteration. Net returns for each diagnostic category were multiplied by the proportion of animals in each diagnostic category to determine group profitability. Apparent prevalence was categorized into low (diagnostic specificity, perhaps through a confirmatory test interpreted in series or pen-level diagnostics, can increase diagnostic value more than improving sensitivity. Mortality risk was the primary driver for net returns. The results from this study are important for determining future research priorities to analyze diagnostic techniques for bovine respiratory disease and provide a novel way for modeling diagnostic tests.

  13. Prospective validation of a prognostic model for respiratory syncytial virus bronchiolitis in late preterm infants: a multicenter birth cohort study.

    Directory of Open Access Journals (Sweden)

    Maarten O Blanken

    Full Text Available OBJECTIVES: This study aimed to update and validate a prediction rule for respiratory syncytial virus (RSV hospitalization in preterm infants 33-35 weeks gestational age (WGA. STUDY DESIGN: The RISK study consisted of 2 multicenter prospective birth cohorts in 41 hospitals. Risk factors were assessed at birth among healthy preterm infants 33-35 WGA. All hospitalizations for respiratory tract infection were screened for proven RSV infection by immunofluorescence or polymerase chain reaction. Multivariate logistic regression analysis was used to update an existing prediction model in the derivation cohort (n = 1,227. In the validation cohort (n = 1,194, predicted versus actual RSV hospitalization rates were compared to determine validity of the model. RESULTS: RSV hospitalization risk in both cohorts was comparable (5.7% versus 4.9%. In the derivation cohort, a prediction rule to determine probability of RSV hospitalization was developed using 4 predictors: family atopy (OR 1.9; 95%CI, 1.1-3.2, birth period (OR 2.6; 1.6-4.2, breastfeeding (OR 1.7; 1.0-2.7 and siblings or daycare attendance (OR 4.7; 1.7-13.1. The model showed good discrimination (c-statistic 0.703; 0.64-0.76, 0.702 after bootstrapping. External validation showed good discrimination and calibration (c-statistic 0.678; 0.61-0.74. CONCLUSIONS: Our prospectively validated prediction rule identifies infants at increased RSV hospitalization risk, who may benefit from targeted preventive interventions. This prediction rule can facilitate country-specific, cost-effective use of RSV prophylaxis in late preterm infants.

  14. 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.

  15. 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

    2017-02-14

    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.

  16. Toxicity of different forms of graphene in a chicken embryo model.

    Science.gov (United States)

    Szmidt, Maciej; Sawosz, Ewa; Urbańska, Kaja; Jaworski, Sławomir; Kutwin, Marta; Hotowy, Anna; Wierzbicki, Mateusz; Grodzik, Marta; Lipińska, Ludwika; Chwalibog, André

    2016-10-01

    In the present work, the toxicity of three forms of graphene: pristine graphene (pG), graphene oxide (GO), and reduced graphene oxide (rGO) was investigated using a chicken embryo model. Fertilized chicken eggs were divided into the control group and groups administered with pG, GO, and rGO, in concentrations of 50, 500, and 5000 μg/ml. The experimental solutions were injected in ovo into the eggs, and at day 18 of incubation, the embryo survival, body and organ weights, the ultrastructure of liver samples, and the concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the livers were measured. Survival of embryos decreased significantly after treatment with all types of graphene, but not in a dose-dependent manner. The body weights were only slightly affected by the highest doses of graphene, while the organ weights were not different among treatment groups. In all experimental groups, atypical hepatocyte ultrastructure and mitochondrial damage were observed. The concentration of the marker of DNA damage 8-OHdG in the liver significantly decreased after pG and rGO treatments. Further in vivo studies with different animal models are necessary to clarify the level of toxicity of different types of graphene and to estimate the concentrations appropriate to evaluate their biomedical applications and environmental hazard.

  17. Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity.

    Science.gov (United States)

    Deshpande, Laxmikant S; Phillips, Kristin; Huang, Beverly; DeLorenzo, Robert J

    2014-09-01

    Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment.

  18. Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.

    Science.gov (United States)

    Minami, S Sakura; Min, Sang-Won; Krabbe, Grietje; Wang, Chao; Zhou, Yungui; Asgarov, Rustam; Li, Yaqiao; Martens, Lauren H; Elia, Lisa P; Ward, Michael E; Mucke, Lennart; Farese, Robert V; Gan, Li

    2014-10-01

    Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

  19. Re-evaluation of metal bioaccumulation and chronic toxicity in Hyalella azteca using saturation curves and the biotic ligand model

    Energy Technology Data Exchange (ETDEWEB)

    Borgmann, U.; Norwood, W.P.; Dixon, D.G

    2004-10-01

    Bioaccumulation by Hyalella of all metals studied so far in our laboratory was re-evaluated to determine if the data could be explained satisfactorily using saturation models. Saturation kinetics are predicted by the biotic ligand model (BLM), now widely used in modelling acute toxicity, and are a pre-requisite if the BLM is to be applied to chronic toxicity. Saturation models provided a good fit to all the data. Since these are mechanistically based, they provide additional insights into metal accumulation mechanisms not immediately apparent when using allometric models. For example, maximum Cd accumulation is dependent on the hardness of the water to which Hyalella are acclimated. The BLM may need to be modified when applied to chronic toxicity. Use of saturation models for bioaccumulation, however, also necessitates the need for using saturation models for dose-response relationships in order to produce unambiguous estimates of LC50 values based on water and body concentrations. This affects predictions of toxicity at very low metal concentrations and results in lower predicted toxicity of mixtures when many metals are present at low concentrations.

  20. Silicone Modeling of the Interior Spaces of Hollow Organs: Use in Dog and Manatee Respiratory Tract and in a Beef Heart

    Directory of Open Access Journals (Sweden)

    Charles J. Grossman

    2011-01-01

    Full Text Available Problem statement: The mechanism, by which the Florida manatee (Trichechus manatus latirostris vocalizes, remains unknown because the manatee larynx does not contain true vocal cords. Since sound can be generated when air passes through a narrow respiratory structure we needed to visualize the internal anatomy of manatee respiratory tract to locate any candidate regions for study. Approach: To visualize the internal anatomy of upper and lower manatee respiratory tract we have developed a rapid but accurate method of modeling these structures using liquid silicone. We first tested this technique on the respiratory structure of a cadaver dog and then applied it to two small manatees which had died through natural causes. Incisions were made in the trachea of both dog and manatees and commercially available liquid silicone was then forced into the upper and lower respiratory tracts used a slightly modified common automobile grease gun. The animals were then refrigerated overnight and the silicone was allowed to cure for a period of 24 h. Results: In dog, we removed cured silicone model by applying mild force to it after surgically opening the nasal cavity. In the manatees some dissection was necessary for release of mold from the upper nasal cavity, but only mild force was necessary with no dissection to release silicone model from the lower tract. Because the models created exhibited great accuracy and fine structure, including presence of tertiary bronchi in the manatee respiratory tract, we realized that the technique was applicable for use in other hollow organs. We applied this method to the visualization of internal structure of a fresh beef heart and were pleased with the accuracy and detail of model produced. Conclusion: We suggest that this technique can be adopted for three-dimensional visualization of the internal structure and volume estimation of many hollow organs in a wide variety of organisms with both minimal

  1. Genetic and chemical modifiers of a CUG toxicity model in Drosophila.

    Directory of Open Access Journals (Sweden)

    Amparo Garcia-Lopez

    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.

  2. 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.

  3. Respiratory failure

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970318 A study on evoked potentials in cor pul-monale patients with chronic respiratory failure.QIAO Hui(乔慧), et al. Beijing Neurosurg Instit,Beijing, 100050. Chin J Geriatr 1997; 16(1): 43-45. Objective: Evoked protential was used to detect thechange of brain function in cor pulmonale patients with

  4. RESPIRATORY SYSTEM

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    6.1 Upper respiratory tract disease and bronchial asthma2004073 A study on the heterogenous apoptosis of lymphocytes, eosinophils, and neutrophils from peripheral blood of asthmatic patients. LIU Chuntao (刘春涛), et al. West China Hosp, Sichuan Univ, Chengdu 610041. Chin J Tuberc Respir Dis 2003; 26(10):610 - 614.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. Otophylloside B Protects Against Aβ Toxicity in Caenorhabditis elegans Models of Alzheimer's Disease.

    Science.gov (United States)

    Yang, Jie; Huang, Xiao-Bing; Wan, Qin-Li; Ding, Ai-Jun; Yang, Zhong-Lin; Qiu, Ming-Hua; Sun, Hua-Ying; Qi, Shu-Hua; Luo, Huai-Rong

    2017-02-13

    Alzheimer's disease (AD) is a major public health concern worldwide and the few drugs currently available only treat the symptoms. Hence, there is a strong need to find more effective anti-AD agents. Cynanchum otophyllum is a traditional Chinese medicine for treating epilepsy, and otophylloside B (Ot B), isolated from C. otophyllum, is the essential active component. Having previously identified anti-aging effects of Ot B, we evaluated Ot B for AD prevention in C. elegans models of AD and found that Ot B extended lifespan, increased heat stress-resistance, delayed body paralysis, and increased the chemotaxis response. Collectively, these results indicated that Ot B protects against Aβ toxicity. Further mechanistic studies revealed that Ot B decreased Aβ deposition by decreasing the expression of Aβ at the mRNA level. Genetic analyses showed that Ot B mediated its effects by increasing the activity of heat shock transcription factor (HSF) by upregulating the expression of hsf-1 and its target genes, hsp-12.6, hsp-16.2 and hsp-70. Ot B also increased the expression of sod-3 by partially activating DAF-16, while SKN-1 was not essential in Ot B-mediated protection against Aβ toxicity.

  10. Hepatoprotective Effect of ψ-Glutathione in a Murine Model of Acetaminophen-Induced Liver Toxicity.

    Science.gov (United States)

    More, Swati S; Nugent, Jaime; Vartak, Ashish P; Nye, Steffan M; Vince, Robert

    2017-03-20

    Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios. While both agents appear to be equally efficacious when timely administered, ψ-GSH partly retains its efficacy even in the face of substantial delay in administration. Thus, implied is the ability of ψ-GSH to intercept secondary toxicology following APAP insult. Oral availability and complete lack of toxicity as evaluated by liver function tests and survival analysis underscored ψ-GSH as a safer and more efficacious alternative to NAC. Finally, the pharmacodynamic mimicry of GSH by ψ-GSH is illustrated through the isolation and chemical characterization of an entity that can arise only through direct encounter of ψ-GSH with N-acetyl-p-benzoquinoneimine, the primary toxic metabolite of APAP.

  11. Toxicity and metabolism of layered double hydroxide intercalated with levodopa in a Parkinson's disease model.

    Science.gov (United States)

    Kura, Aminu Umar; Ain, Nooraini Mohd; Hussein, Mohd Zobir; Fakurazi, Sharida; Hussein-Al-Ali, Samer Hasan

    2014-04-09

    Layered hydroxide nanoparticles are generally biocompatible, and less toxic than most inorganic nanoparticles, making them an acceptable alternative drug delivery system. Due to growing concern over animal welfare and the expense of in vivo experiments both the public and the government are interested to find alternatives to animal testing. The toxicity potential of zinc aluminum layered hydroxide (ZAL) nanocomposite containing anti-Parkinsonian agent may be determined using a PC 12 cell model. ZAL nanocomposite demonstrated a decreased cytotoxic effect when compared to levodopa on PC12 cells with more than 80% cell viability at 100 µg/mL compared to less than 20% cell viability in a direct levodopa exposure. Neither levodopa-loaded nanocomposite nor the un-intercalated nanocomposite disturbed the cytoskeletal structure of the neurogenic cells at their IC50 concentration. Levodopa metabolite (HVA) released from the nanocomposite demonstrated the slow sustained and controlled release character of layered hydroxide nanoparticles unlike the burst uptake and release system shown with pure levodopa treatment.

  12. Toxicity mechanisms of the food contaminant citrinin: application of a quantitative yeast model.

    Science.gov (United States)

    Pascual-Ahuir, Amparo; Vanacloig-Pedros, Elena; Proft, Markus

    2014-05-22

    Mycotoxins are important food contaminants and a serious threat for human nutrition. However, in many cases the mechanisms of toxicity for this diverse group of metabolites are poorly understood. Here we apply live cell gene expression reporters in yeast as a quantitative model to unravel the cellular defense mechanisms in response to the mycotoxin citrinin. We find that citrinin triggers a fast and dose dependent activation of stress responsive promoters such as GRE2 or SOD2. More specifically, oxidative stress responsive pathways via the transcription factors Yap1 and Skn7 are critically implied in the response to citrinin. Additionally, genes in various multidrug resistance transport systems are functionally involved in the resistance to citrinin. Our study identifies the antioxidant defense as a major physiological response in the case of citrinin. In general, our results show that the use of live cell gene expression reporters in yeast are a powerful tool to identify toxicity targets and detoxification mechanisms of a broad range of food contaminants relevant for human nutrition.

  13. Toxicity Mechanisms of the Food Contaminant Citrinin: Application of a Quantitative Yeast Model

    Directory of Open Access Journals (Sweden)

    Amparo Pascual-Ahuir

    2014-05-01

    Full Text Available Mycotoxins are important food contaminants and a serious threat for human nutrition. However, in many cases the mechanisms of toxicity for this diverse group of metabolites are poorly understood. Here we apply live cell gene expression reporters in yeast as a quantitative model to unravel the cellular defense mechanisms in response to the mycotoxin citrinin. We find that citrinin triggers a fast and dose dependent activation of stress responsive promoters such as GRE2 or SOD2. More specifically, oxidative stress responsive pathways via the transcription factors Yap1 and Skn7 are critically implied in the response to citrinin. Additionally, genes in various multidrug resistance transport systems are functionally involved in the resistance to citrinin. Our study identifies the antioxidant defense as a major physiological response in the case of citrinin. In general, our results show that the use of live cell gene expression reporters in yeast are a powerful tool to identify toxicity targets and detoxification mechanisms of a broad range of food contaminants relevant for human nutrition.

  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. 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.

  16. Critical analysis of 3-D organoid in vitro cell culture models for high-throughput drug candidate toxicity assessments.

    Science.gov (United States)

    Astashkina, Anna; Grainger, David W

    2014-04-01

    Drug failure due to toxicity indicators remains among the primary reasons for staggering drug attrition rates during clinical studies and post-marketing surveillance. Broader validation and use of next-generation 3-D improved cell culture models are expected to improve predictive power and effectiveness of drug toxicological predictions. However, after decades of promising research significant gaps remain in our collective ability to extract quality human toxicity information from in vitro data using 3-D cell and tissue models. Issues, challenges and future directions for the field to improve drug assay predictive power and reliability of 3-D models are reviewed. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Pulmonary Toxicity of Cholinesterase Inhibitors

    Science.gov (United States)

    2006-01-01

    discusses respiratory and pulmonary toxicity through direct venomous and was synthesized at Porton Down, England, inhalation of AChEIs and indirect...effects on all aspects of res- in 1952. piration through systemic toxicity. Due to their high toxicity in mammals and volatile OP nerve agents can be... produc - century with the development of the present-day vesicants tion facility late in the war and moved it back to Russia, and AChEIs (or OP class

  18. 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

    , representing the performance of an individual model relative to the average dataset performance. Prediction models by van Vugt et al. and Heckerling et al. demonstrated the highest pooled AUC of 0.79 (95% CI 0.74-0.85) and 0.72 (0.68-0.76), respectively. Other models by Diehr et al., Singal et al., Melbye et...

  19. Human intake fraction of toxic pollutants: a model comparison between caltox and uses-lca

    Energy Technology Data Exchange (ETDEWEB)

    Huijbregts, Mark A.J.; Geelen, Loes M.J.; Hertwich, Edgar G.; McKone, Thomas E.; van de Meent, Dik

    2004-01-06

    In Life Cycle Assessment and Comparative Risk Assessment potential human exposure to toxic pollutants can be expressed as the human intake fraction (iF), representing the fraction of the quantity emitted that enters the human population. To assess model uncertainty in the human intake fraction, ingestion and inhalation iFs of 367 substances emitted to air and freshwater were calculated with two commonly applied multi-media fate and exposure models, CalTOX and USES-LCA. Comparison of the model outcomes reveal that uncertainty in the ingestion iFs was up to a factor of 70. The uncertainty in the inhalation iFs was up to a factor of 865,000. The comparison showed that relatively few model differences account for the uncertainties found. An optimal model structure in the calculation of human intake fractions can be achieved by including (1) rain and no-rain scenarios, (2) a continental sea water compartment, (3) drinking water purification, (4) pH-correction of chemical properties, and (5) aerosol-associated deposition on plants. Finally, vertical stratification of the soil compartment combined with a chemical-dependent soil depth may be considered in future intake fraction calculations.

  20. 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.

  1. Preparation and analysis of active rat model of rheumatoid arthritis with features of TCM toxic heat-stasis painful obstruction

    Directory of Open Access Journals (Sweden)

    Yanan Wang

    2015-07-01

    Conclusion: The CIA model established in this study presents both active RA pathologic features and characteristics of the symptoms of toxic heat-stasis painful obstruction 12 weeks after successful establishment of an animal model. In addition, this study may be a valuable reference for development of animal studies with combined Eastern and Western medicines in dialectics and identification of diseases.

  2. Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy.

    Science.gov (United States)

    Renier, Kayla J; Troxell-Smith, Sandra M; Johansen, Jamie A; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Chua, Jason P; Sun Kim, Hong; Lieberman, Andrew P; Breedlove, S Marc; Jordan, Cynthia L

    2014-07-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.

  3. 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.

  4. 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

  5. Bayesian inference of the lung alveolar spatial model for the identification of alveolar mechanics associated with acute respiratory distress syndrome

    Science.gov (United States)

    Christley, Scott; Emr, Bryanna; Ghosh, Auyon; Satalin, Josh; Gatto, Louis; Vodovotz, Yoram; Nieman, Gary F.; An, Gary

    2013-06-01

    Acute respiratory distress syndrome (ARDS) is acute lung failure secondary to severe systemic inflammation, resulting in a derangement of alveolar mechanics (i.e. the dynamic change in alveolar size and shape during tidal ventilation), leading to alveolar instability that can cause further damage to the pulmonary parenchyma. Mechanical ventilation is a mainstay in the treatment of ARDS, but may induce mechano-physical stresses on unstable alveoli, which can paradoxically propagate the cellular and molecular processes exacerbating ARDS pathology. This phenomenon is called ventilator induced lung injury (VILI), and plays a significant role in morbidity and mortality associated with ARDS. In order to identify optimal ventilation strategies to limit VILI and treat ARDS, it is necessary to understand the complex interplay between biological and physical mechanisms of VILI, first at the alveolar level, and then in aggregate at the whole-lung level. Since there is no current consensus about the underlying dynamics of alveolar mechanics, as an initial step we investigate the ventilatory dynamics of an alveolar sac (AS) with the lung alveolar spatial model (LASM), a 3D spatial biomechanical representation of the AS and its interaction with airflow pressure and the surface tension effects of pulmonary surfactant. We use the LASM to identify the mechanical ramifications of alveolar dynamics associated with ARDS. Using graphical processing unit parallel algorithms, we perform Bayesian inference on the model parameters using experimental data from rat lung under control and Tween-induced ARDS conditions. Our results provide two plausible models that recapitulate two fundamental hypotheses about volume change at the alveolar level: (1) increase in alveolar size through isotropic volume change, or (2) minimal change in AS radius with primary expansion of the mouth of the AS, with the implication that the majority of change in lung volume during the respiratory cycle occurs in the

  6. Mouse Models of Acute Respiratory Distress Syndrome: A Review of Analytical Approaches, Pathologic Features, and Common Measurements.

    Science.gov (United States)

    Aeffner, Famke; Bolon, Brad; Davis, Ian C

    2015-12-01

    Acute respiratory distress syndrome (ARDS) is a severe pulmonary reaction requiring hospitalization, which is incited by many causes, including bacterial and viral pneumonia as well as near drowning, aspiration of gastric contents, pancreatitis, intravenous drug use, and abdominal trauma. In humans, ARDS is very well defined by a list of clinical parameters. However, until recently no consensus was available regarding the criteria of ARDS that should be evident in an experimental animal model. This lack was rectified by a 2011 workshop report by the American Thoracic Society, which defined the main features proposed to delineate the presence of ARDS in laboratory animals. These should include histological changes in parenchymal tissue, altered integrity of the alveolar capillary barrier, inflammation, and abnormal pulmonary function. Murine ARDS models typically are defined by such features as pulmonary edema and leukocyte infiltration in cytological preparations of bronchoalveolar lavage fluid and/or lung sections. Common pathophysiological indicators of ARDS in mice include impaired pulmonary gas exchange and histological evidence of inflammatory infiltrates into the lung. Thus, morphological endpoints remain a vital component of data sets assembled from animal ARDS models.

  7. Dual hit lipopolysaccharide & oleic acid combination induced rat model of acute lung injury/acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    T N Hagawane

    2016-01-01

    Results: It was noted that the respiratory rate, and tumour necrosis factor-α (TNF-α levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6 levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals group. IL-1β levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. Interpretation & conclusions: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury.

  8. Predictive Modelling of Toxicity Resulting from Radiotherapy Treatments of Head and Neck Cancer

    CERN Document Server

    Dean, Jamie A; Harrington, Kevin J; Nutting, Christopher M; Gulliford, Sarah L

    2014-01-01

    In radiotherapy for head and neck cancer, the radiation dose delivered to the pharyngeal mucosa (mucosal lining of the throat) is thought to be a major contributing factor to dysphagia (swallowing dysfunction), the most commonly reported severe toxicity. There is a variation in the severity of dysphagia experienced by patients. Understanding the role of the dose distribution in dysphagia would allow improvements in the radiotherapy technique to be explored. The 3D dose distributions delivered to the pharyngeal mucosa of 249 patients treated as part of clinical trials were reconstructed. Pydicom was used to extract DICOM (digital imaging and communications in medicine) data (the standard file formats for medical imaging and radiotherapy data). NumPy and SciPy were used to manipulate the data to generate 3D maps of the dose distribution delivered to the pharyngeal mucosa and calculate metrics describing the dose distribution. Multivariate predictive modelling of severe dysphagia, including descriptions of the d...

  9. Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function

    Directory of Open Access Journals (Sweden)

    Magda Dubińska-Magiera

    2016-11-01

    Full Text Available The rapid progress in medicine, agriculture, and allied sciences has enabled the development of a large amount of potentially useful bioactive compounds, such as drugs and pesticides. However, there is another side of this phenomenon, which includes side effects and environmental pollution. To avoid or minimize the uncontrollable consequences of using the newly developed compounds, researchers seek a quick and effective means of their evaluation. In achieving this goal, the zebrafish (Danio rerio has proven to be a highly useful tool, mostly because of its fast growth and development, as well as the ability to absorb the molecules diluted in water through its skin and gills. In this review, we focus on the reports concerning the application of zebrafish as a model for assessing the impact of toxicants on skeletal muscles, which share many structural and functional similarities among vertebrates, including zebrafish and humans.

  10. Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function

    Science.gov (United States)

    Dubińska-Magiera, Magda; Daczewska, Małgorzata; Lewicka, Anna; Migocka-Patrzałek, Marta; Niedbalska-Tarnowska, Joanna; Jagla, Krzysztof

    2016-01-01

    The rapid progress in medicine, agriculture, and allied sciences has enabled the development of a large amount of potentially useful bioactive compounds, such as drugs and pesticides. However, there is another side of this phenomenon, which includes side effects and environmental pollution. To avoid or minimize the uncontrollable consequences of using the newly developed compounds, researchers seek a quick and effective means of their evaluation. In achieving this goal, the zebrafish (Danio rerio) has proven to be a highly useful tool, mostly because of its fast growth and development, as well as the ability to absorb the molecules diluted in water through its skin and gills. In this review, we focus on the reports concerning the application of zebrafish as a model for assessing the impact of toxicants on skeletal muscles, which share many structural and functional similarities among vertebrates, including zebrafish and humans. PMID:27869769

  11. Improved building up a model of toxicity towards Pimephales promelas by the Monte Carlo method.

    Science.gov (United States)

    Toropova, Alla P; Toropov, Andrey A; Raskova, Maria; Raska, Ivan

    2016-12-01

    By optimization of so-called correlation weights of attributes of simplified molecular input-line entry system (SMILES) quantitative structure - activity relationships (QSAR) for toxicity towards Pimephales promelas are established. A new SMILES attribute has been utilized in this work. This attribute is a molecular descriptor, which reflects (i) presence of different kinds of bonds (double, triple, and stereo chemical bonds); (ii) presence of nitrogen, oxygen, sulphur, and phosphorus atoms; and (iii) presence of fluorine, chlorine, bromine, and iodine atoms. The statistical characteristics of the best model are the following: n=226, r(2)=0.7630, RMSE=0.654 (training set); n=114, r(2)=0.7024, RMSE=0.766 (calibration set); n=226, r(2)=0.6292, RMSE=0.870 (validation set). A new criterion to select a preferable split into the training and validation sets are suggested and discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. QSAR modelling of the toxicity to Tetrahymena pyriformis by balance of correlations.

    Science.gov (United States)

    Toropov, A A; Toropova, A P; Benfenati, E; Manganaro, A

    2010-11-01

    Balance of correlations is an approach to build up quantitative structure-property/activity relationships (QSPR/QSAR). This approach is based on a split into the subtraining, calibration and test sets instead of classic split into training and test sets. The function of the calibration set is the preliminary check up of the model. In other words, the calibration set is like a preliminary test set. Computational experiments (with the Monte Carlo method) have shown that the statistical characteristics of the prediction for the toxicity to Tetrahymena pyriformis (the 50% growth inhibition concentration, IGC(50)) based on the balance of correlations are better than the statistical characteristics of the prediction based on the classic scheme.

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

    DEFF Research Database (Denmark)

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

    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 model...... highly controlled experimental infections and to study changes of symptoms, viral titer, and expression of microRNAs/mRNAs as the influenza infection progresses in time, generating information that would be difficult to obtain from human patients....

  14. Metal toxicity and the respiratory tract.

    Science.gov (United States)

    Nemery, B

    1990-02-01

    The type of lung disease caused by metal compounds depends on the nature of the offending agent, its physicochemical form, the dose, exposure conditions and host factors. The fumes or gaseous forms of several metals, e.g. cadmium (Cd), manganese (Mn), mercury (Hg), nickel carbonyl (Nl(CO)4, zinc chloride (ZnCl2), vanadium pentoxide (V2O5), may lead to acute chemical pneumonitis and pulmonary oedema or to acute tracheobronchitis. Metal fume fever, which may follow the inhalation of metal fumes e.g. zinc (Zn), copper (Cu) and many others, is a poorly understood influenza-like reaction, accompanied by an acute self-limiting neutrophil alveolitis. Chronic obstructive lung disease may result from occupational exposure to mineral dusts, including probably some metallic dusts, or from jobs involving the working of metal compounds, such as welding. Exposure to cadmium may lead to emphysema. Bronchial asthma may be caused by complex platinum salts, nickel, chromium or cobalt, presumably on the basis of allergic sensitization. The cause of asthma in aluminium workers is unknown. It is remarkable that asthma induced by nickel (Ni) or chromium (Cr) is apparently infrequent, considering their potency and frequent involvement as dermal sensitizers. Metallic dusts deposited in the lung may give rise to pulmonary fibrosis and functional impairment, depending on the fibrogenic potential of the agent and on poorly understood host factors. Inhalation of iron compounds causes siderosis, a pneumoconiosis with little or no fibrosis. Hard metal lung disease is a fibrosis characterized by desquamative and giant cell interstitial pneumonitis and is probably caused by cobalt, since a similar disease has been observed in workers exposed to cobalt in the absence of tungsten carbide. Chronic beryllium disease is a fibrosis with sarcoid-like epitheloid granulomas and is presumably due to a cell-mediated immune response to beryllium. Such a mechanism may be responsible for the pulmonary fibrosis occasionally found in subjects exposed to other metals e.g. aluminium (Al), titanium (Ti), rare earths. The proportion of lung cancer attributable to occupation is around 15%, with exposure to metals being frequently incriminated. Underground mining of e.g. uranium or iron is associated with a high incidence of lung cancer, as a result of exposure to radon. At least some forms of arsenic, chromium and nickel are well established lung carcinogens in humans. There is also evidence for increased lung cancer mortality in cadmium workers and in iron or steel workers.

  15. Respiratory Distress

    Science.gov (United States)

    1976-01-01

    The University of Miami School of Medicine asked the Research Triangle Institute for assistance in improvising the negative pressure technique to relieve respiratory distress in infants. Marshall Space Flight Center and Johnson Space Center engineers adapted this idea to the lower-body negative-pressure system seals used during the Skylab missions. Some 20,000 babies succumb to respiratory distress in the U.S. each year, a condition in which lungs progressively lose their ability to oxygenate blood. Both positive and negative pressure techniques have been used - the first to force air into lungs, the second to keep infant's lungs expanded. Negative pressure around chest helps the baby expand his lungs and maintain proper volume of air. If doctors can keep the infant alive for four days, the missing substance in the lungs will usually form in sufficient quantity to permit normal breathing. The Skylab chamber and its leakproof seals were adapted for medical use.

  16. Biology-based modeling to analyze uranium toxicity data on Daphnia magna in a multigeneration study.

    Science.gov (United States)

    Massarin, Sandrine; Beaudouin, Remy; Zeman, Florence; Floriani, Magali; Gilbin, Rodolphe; Alonzo, Frederic; Pery, Alexandre R R

    2011-05-01

    Recent studies have investigated chronic toxicity of waterborne depleted uranium on the life cycle and physiology of Daphnia magna. In particular, a reduction in food assimilation was observed. Our aims here were to examine whether this reduction could fully account for observed effects on both growth and reproduction, for three successive generations, and to investigate through microscope analyses whether this reduction resulted from direct damage to the intestinal epithelium. We analyzed data obtained by exposing Daphnia magna to uranium over three successive generations. We used energy-based models, which are both able to fit simultaneously growth and reproduction and are biologically relevant. Two possible modes of action were compared - decrease in food assimilation rate and increase in maintenance costs. In our models, effects were related either to internal concentration or to exposure concentration. The model that fitted the data best represented a decrease in food assimilation related to exposure concentration. Furthermore, observations of consequent histological damage to the intestinal epithelium, together with uranium precipitates in the epithelial cells, supported the assumption that uranium has direct effects on the digestive tract. We were able to model the data in all generations and showed that sensitivity increased from one generation to the next, in particular through a significant increase of the intensity of effect, once the threshold for appearance of effects was exceeded.

  17. QSAR modeling of toxicity of diverse organic chemicals to Daphnia magna using 2D and 3D descriptors

    Energy Technology Data Exchange (ETDEWEB)

    Kar, Supratik [Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032 (India); Roy, Kunal, E-mail: kunalroy_in@yahoo.com [Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032 (India)

    2010-05-15

    One of the major economic alternatives to experimental toxicity testing is the use of quantitative structure-activity relationships (QSARs) which are used in formulating regulatory decisions of environmental protection agencies. In this background, we have modeled a large diverse group of 297 chemicals for their toxicity to Daphnia magna using mechanistically interpretable descriptors. Three-dimensional (3D) (electronic and spatial) and two-dimensional (2D) (topological and information content indices) descriptors along with physicochemical parameter log K{sub o/w} (n-octanol/water partition coefficient) and structural descriptors were used as predictor variables. The QSAR models were developed by stepwise multiple linear regression (MLR), partial least squares (PLS), genetic function approximation (GFA), and genetic PLS (G/PLS). All the models were validated internally and externally. Among several models developed using different chemometric tools, the best model based on both internal and external validation characteristics was a PLS equation with 7 descriptors and three latent variables explaining 67.8% leave-one-out predicted variance and 74.1% external predicted variance. The PLS model suggests that higher lipophilicity and electrophilicity, less negative charge surface area and presence of ether linkage, hydrogen bond donor groups and acetylenic carbons are responsible for greater toxicity of chemicals. The developed model may be used for prediction of toxicity, safety and risk assessment of chemicals to achieve better ecotoxicological management and prevent adverse health consequences.

  18. 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

  19. RESPIRATORY SYSTEM

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    7.1 Upper respiratory tract disease and bronchial asthma2003306 Effects of vaccae on airway contraction and inflammation in asthmatic guinea pigs. ZHAO Xiao(赵晓燕), et al. Zhejiang Respir Drug Res Lab Med Sch, Zhejiang Univ, Hangzhou 310031. Chin J Tuberc Respir Dis 2003;26(4):218-222.Objective: To study the effects of Mycobacterium vaccae(M. vaccae)on the lung function, airway hyper-

  20. Optimizing predictive performance of CASE Ultra expert system models using the applicability domains of individual toxicity alerts.

    Science.gov (United States)

    Chakravarti, Suman K; Saiakhov, Roustem D; Klopman, Gilles

    2012-10-22

    Fragment based expert system models of toxicological end points are primarily comprised of a set of substructures that are statistically related to the toxic property in question. These special substructures are often referred to as toxicity alerts, toxicophores, or biophores. They are the main building blocks/classifying units of the model, and it is important to define the chemical structural space within which the alerts are expected to produce reliable predictions. Furthermore, defining an appropriate applicability domain is required as part of the OECD guidelines for the validation of quantitative structure-activity relationships (QSARs). In this respect, this paper describes a method to construct applicability domains for individual toxicity alerts that are part of the CASE Ultra expert system models. Defining applicability domain for individual alerts was necessary because each CASE Ultra model is comprised of multiple alerts, and different alerts of a model usually represent different toxicity mechanisms and cover different structural space; the use of an applicability domain for the overall model is often not adequate. The domain for each alert was constructed using a set of fragments that were found to be statistically related to the end point in question as opposed to using overall structural similarity or physicochemical properties. Use of the applicability domains in reducing false positive predictions is demonstrated. It is now possible to obtain ROC (receiver operating characteristic) profiles of CASE Ultra models by applying domain adherence cutoffs on the alerts identified in test chemicals. This helps in optimizing the performance of a model based on their true positive-false positive prediction trade-offs and reduce drastic effects on the predictive performance caused by the active/inactive ratio of the model's training set. None of the major currently available commercial expert systems for toxicity prediction offer the possibility to explore a

  1. 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

  2. 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.

  3. Mitigating Errors in External Respiratory Surrogate-Based Models of Tumor Position

    Energy Technology Data Exchange (ETDEWEB)

    Malinowski, Kathleen T. [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States); McAvoy, Thomas J. [Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States); Department of Chemical and Biomolecular Engineering and Institute of Systems Research, University of Maryland, College Park, MD (United States); George, Rohini [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Dieterich, Sonja [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); D' Souza, Warren D., E-mail: wdsou001@umaryland.edu [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States)

    2012-04-01

    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.

  4. 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.

  5. Evaluation of surveillance protocols for detecting porcine reproductive and respiratory syndrome virus infection in boar studs by simulation modeling.

    Science.gov (United States)

    Rovira, Albert; Reicks, Darwin; Muñoz-Zanzi, Claudia

    2007-09-01

    Because porcine reproductive and respiratory syndrome virus (PRRSV) can be transmitted through semen, PRRSV-free boar studs need to be routinely monitored to rapidly detect any potential PRRSV introduction. However, current protocols for monitoring PRRSV in boar studs are diverse, sometimes very costly, and their effectiveness has not been quantified. The objective of this study was to evaluate the ability of different monitoring protocols to detect PRRSV introduction into a negative boar stud by using a simulation modeling approach. A stochastic transmission model was constructed to simulate the spread of PRRSV in a typical negative boar stud in the USA (herd size of 200 boars, 60% annual replacement) and the performance of monitoring protocols by using different sample sizes (10, 30, and 60 samples), sampling frequency (3 times a week, weekly, and biweekly), and diagnostic procedures (PCR on semen, PCR on serum, ELISA on serum, and both PCR and ELISA on serum). The monitoring protocols were evaluated in terms of the time from PRRSV introduction into the boar stud to PRRSV detection. Protocols that used PCR on serum detected the PRRSV introduction earlier than protocols that used PCR on semen, and these were earlier than those that used ELISA on serum. The most intensive protocol evaluated (testing 60 boars 3 times a week by PCR on serum) would need 13 days to detect 95% of the PRRSV introductions. These results support field observations, suggesting that an intensive monitoring protocol needs to be in place in a boar stud to quickly detect a PRRSV introduction.

  6. Timescale analysis of a mathematical model of acetaminophen metabolism and toxicity.

    Science.gov (United States)

    Reddyhoff, Dennis; Ward, John; Williams, Dominic; Regan, Sophie; Webb, Steven

    2015-12-01

    Acetaminophen is a widespread and commonly used painkiller all over the world. However, it can cause liver damage when taken in large doses or at repeated chronic doses. Current models of acetaminophen metabolism are complex, and limited to numerical investigation though provide results that represent clinical investigation well. We derive a mathematical model based on mass action laws aimed at capturing the main dynamics of acetaminophen metabolism, in particular the contrast between normal and overdose cases, whilst remaining simple enough for detailed mathematical analysis that can identify key parameters and quantify their role in liver toxicity. We use singular perturbation analysis to separate the different timescales describing the sequence of events in acetaminophen metabolism, systematically identifying which parameters dominate during each of the successive stages. Using this approach we determined, in terms of the model parameters, the critical dose between safe and overdose cases, timescales for exhaustion and regeneration of important cofactors for acetaminophen metabolism and total toxin accumulation as a fraction of initial dose.

  7. Cranberry extract supplementation exerts preventive effects through alleviating Aβ toxicity in Caenorhabditis elegans model of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    GUO Hong; DONG Yu-Qing; YE Bo-Ping

    2016-01-01

    Cranberry extract (CBE) rich in polyphenols are potent to delay paralysis induced by alleviating β-amyloid (Aβ) toxicity in C.elegans model of Alzheimer's disease (AD).In order to better apply CBE as an anti-AD agent efficiently,we sought to deterrmine whether preventive or therapeutic effect contributes more prominently toward CBE's anti-AD activity.As the level of Aβ toxicity and memory health are two major pathological parameters in AD,in the present study,we compared the effects of CBE on Aβ toxicity and memory health in the C.elegans AD model treated with preventive and therapeutic protocols.Our results revealed that CBE prominently showed the preventive efficacy,providing a basis for further investigation of these effects in mammals.

  8. Acute and Subacute Toxicity study of the Acetone Leaf extract of Centella asiatica in Experimental Animal Models

    Institute of Scientific and Technical Information of China (English)

    PK Chauhan; V Singh

    2012-01-01

    Objective: To evaluate acute and subacute toxicity of the acetone extract of Centella asiatica (Brahmi). Methods: Toxicity of Centella asiatica was evaluated in Swiss mice after ingestion of the extract during one day (acute model) and during 15 days (subacute model). The Biochemical parameters evaluated included creatinine, calcium, inorganic phosphorous, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed using commercial kits. Results: The results of the present investigation revealed that the LD50 of the extract is higher than 4000mg/kg and subacute treatment did not shows any change in corporal weight and hematological parameters. However, a change in liver weight but not in hepatic enzymes was observed. This suggested that the liver function is not altered by Centella asiatica. Some changes in the creatinine content were observed but could not be relative with the extract dose.Conclusions:The results suggest that the plant seems to be destitute of toxic effects in mice.

  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. 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.

  11. Arsenic-containing hydrocarbons are toxic in the in vivo model Drosophila melanogaster.

    Science.gov (United States)

    Meyer, S; Schulz, J; Jeibmann, A; Taleshi, M S; Ebert, F; Francesconi, K A; Schwerdtle, T

    2014-11-01

    Arsenic-containing hydrocarbons (AsHC) constitute one group of arsenolipids that have been identified in seafood. In this first in vivo toxicity study for AsHCs, we show that AsHCs exert toxic effects in Drosophila melanogaster in a concentration range similar to that of arsenite. In contrast to arsenite, however, AsHCs cause developmental toxicity in the late developmental stages of Drosophila melanogaster. This work illustrates the need for a full characterisation of the toxicity of AsHCs in experimental animals to finally assess the risk to human health related to the presence of arsenolipids in seafood.

  12. Repeat length and RNA expression level are not primary determinants in CUG expansion toxicity in Drosophila models.

    Directory of Open Access Journals (Sweden)

    Gwenn Le Mée

    Full Text Available Evidence for an RNA gain-of-function toxicity has now been provided for an increasing number of human pathologies. Myotonic dystrophies (DM belong to a class of RNA-dominant diseases that result from RNA repeat expansion toxicity. Specifically, DM of type 1 (DM1, is caused by an expansion of CUG repeats in the 3'UTR of the DMPK protein kinase mRNA, while DM of type 2 (DM2 is linked to an expansion of CCUG repeats in an intron of the ZNF9 transcript (ZNF9 encodes a zinc finger protein. In both pathologies the mutant RNA forms nuclear foci. The mechanisms that underlie the RNA pathogenicity seem to be rather complex and not yet completely understood. Here, we describe Drosophila models that might help unravelling the molecular mechanisms of DM1-associated CUG expansion toxicity. We generated transgenic flies that express inducible repeats of different type (CUG or CAG and length (16, 240, 480 repeats and then analyzed transgene localization, RNA expression and toxicity as assessed by induced lethality and eye neurodegeneration. The only line that expressed a toxic RNA has a (CTG(240 insertion. Moreover our analysis shows that its level of expression cannot account for its toxicity. In this line, (CTG(240.4, the expansion inserted in the first intron of CG9650, a zinc finger protein encoding gene. Interestingly, CG9650 and (CUG(240.4 expansion RNAs were found in the same nuclear foci. In conclusion, we suggest that the insertion context is the primary determinant for expansion toxicity in Drosophila models. This finding should contribute to the still open debate on the role of the expansions per se in Drosophila and in human pathogenesis of RNA-dominant diseases.

  13. Effect of water quality on mercury toxicity to Photobacterium phosphoreum: Model development and its application in natural waters.

    Science.gov (United States)

    Wang, Xinghao; Qu, Ruijuan; Wei, Zhongbo; Yang, Xi; Wang, Zunyao

    2014-06-01

    Mercury (Hg) compounds are widely distributed toxic environmental and industrial pollutants and they may bring danger to growth and development of aquatic organisms. The distribution of Hg species in the 3 percent NaCl solution was calculated using the chemical equilibrium model Visual MINTEQ, which demonstrated that Hg was mainly complexed by chlorides in the pH range 5.0-9.0 and the proportions of HgCl4(2-), HgCl3(-) and HgCl2(aq) reached to 95 percent of total Hg. Then the effects of cations (Ca(2+), Mg(2+), K(+) and H(+)), anions (HCO3(-), NO3(-), SO4(2-) and HPO4(2-)) and complexing agents (ethylene diamine tetraacetic acid (EDTA) and dissolved organic matter (DOM)) on Hg toxicity to Photobacterium phosphoreum were evaluated in standardized 15min acute toxicity tests. The significant increase of 6.3-fold in EC50 data with increasing pH was observed over the tested pH range of 5.0-8.0, which suggested the possible competition between hydroxyl and the negatively charged chloro-complex. By contrast, it was found that major cations (Ca(2+), Mg(2+) and K(+)) have little effect on Hg toxicity to P. phosphoreum. An interesting finding was that the addition of HPO4(2-) significantly increased Hg toxicity, which may imply that the addition of phosphate increased the soluble Hg-chloro complex species. Additions of complexing agents (EDTA and DOM) into the exposure water increased Hg bioavailability via complexation of Hg. Finally, a model which incorporated the effect of pH, HPO4(2-), HCO3(-), SO4(2-) and DOM on Hg toxicity was developed to predict acute Hg toxicity for P. phosphoreum, which may be a useful tool in setting realistic water quality criteria for different types of water.

  14. 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.

  15. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologycally based kinetic modeling

    NARCIS (Netherlands)

    Louisse, J.; Bosgra, S.; Blaauboer, B.J.; Rietjens, I.; Verwei, M.

    2015-01-01

    The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity d

  16. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

    NARCIS (Netherlands)

    Louisse, Jochem; Bosgra, Sieto; Blaauboer, Bas J.; Rietjens, Ivonne M. C. M.; Verwei, Miriam

    2015-01-01

    The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity d

  17. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

    NARCIS (Netherlands)

    Louisse, J.; Bosgra, S.; Blaauboer, B.J.; Rietjens, I.M.C.M.; Verwei, M.

    2015-01-01

    The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity

  18. Modeling Respiratory Gas Dynamics in the Aviator’s Breathing System. Volume 2. Appendices

    Science.gov (United States)

    1994-05-01

    Instruments & Life Support Division; 1984 August 7. 103. Dixon, GA; Krutz Jr, RW; Fischer , JR. Decompression Sickness and Bubble Formation in Females...1802-1814; 1986. 233. Linehan, JH; Haworth , ST; Nelin, LD; Krenz, GS; Dawson, CA. A Simple Distensible Vessel Model for Interpreting Pulmonary

  19. Secondary production of toxic nitropolycyclic aromatic hydrocarbon during the Asian dust event: approached by model simulation

    Science.gov (United States)

    Inomata, Y.; Kajino, M.; Sato, K.

    2016-12-01

    Nitrated polycyclic aromatic hydrocarbons (NPAHs) are one of toxic compounds in the atmospheric particles. NPAHs are emitted in the atmosphere through the combustion of fossil fuels such as coal and diesel. Furthermore, it is produced by heterogeneous reactions such as the surface on the mineral dust aerosols. 1-nitoropyrene (1-NP) is one of the most abundant NPAHs and considered as a probable carcinogen. It is found that the production of 1-NP occurred during the heavy Asian dust event in Beijing and Japan. In this study, we estimated production of 1-NP by heterogeneous reactions by using model simulations in Northeast Asia. The model was three dimensional chemical transport model, Regional Air Quality Model for POPs version. The model performance was investigated the comparison with the observations. We focused on heavy Asian dust event observed in Beijing on 18-20 March 2010. Several sensitivity calculations are conducted under the existence of Asian dust in order to investigate the effect of relative humidity and photolysis. On 18-20 March 2010, primary 1-NP concentrations are about 50 fg/m3. Under the existence of the Asian dust, secondary production of 1-NP is estimated to 7 times against the concentrations of primary emission. Horizontal distributions indicate that decrease of Pyr and increase of 1-NP is significant around Beijing in this Asian dust event. Secondary production of 1-NP was large in this area as well as the downwind region such as the East China Sea. It is found that secondary production of 1-NP is minor in dessert region because of lower concentrations of Pyrene (Pyr). Distribution of secondary produced 1-NP varied with concentrations of Pyr, transport of Asian dust. Secondary production of 1-NP in March 2010 was larger than the primary emission of 1-NP, whereas the secondary production was smaller than those of the primary emission in April and May, 2011.

  20. 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.

  1. Galleria mellonella as a novel in vivo model for assessment of the toxicity of 1-alkyl-3-methylimidazolium chloride ionic liquids.

    Science.gov (United States)

    Megaw, Julianne; Thompson, Thomas P; Lafferty, Ryan A; Gilmore, Brendan F

    2015-11-01

    The larval form of the Greater Wax Moth (Galleria mellonella) was evaluated as a model system for the study of the acute in vivo toxicity of 1-alkyl-3-methylimidazolium chloride ionic liquids. 24-h median lethal dose (LD50) values for nine of these ionic liquids bearing alkyl chain substituents ranging from 2 to 18 carbon atoms were determined. The in vivo toxicity of the ionic liquids was found to correlate directly with the length of the alkyl chain substituent, and the pattern of toxicity observed was in accordance with previous studies of ionic liquid toxicity in other living systems, including a characteristic toxicity 'cut-off' effect. However, G. mellonella appeared to be more susceptible to the toxic effects of the ionic liquids tested, possibly as a result of their high body fat content. The results obtained in this study indicate that G. mellonella represents a sensitive, reliable and robust in vivo model organism for the evaluation of ionic liquid toxicity.

  2. RESPIRATORY SYSTEM

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    7.1 Upper Respiratory Tract Diesase And Bronchial Asthma 2007072 Dysfunction of releasing adrenaline in asthmatic adrenaline medullary chromaffin cells due to functional redundancy primed by nerve growth factor. WANG Jun(汪俊), et al. Dept Resp Dis Xiangya Hosp Central South Univ, Changsha 410008. Chin J Tuberc Dis 2006;29(12):812-815. Objective To investigate the possible causes of the dysfunction of adrenaline release in asthma rats and to identify the role of nerve growth factor(NGF) in this process.

  3. Respiratory System

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    8.1 Respiratory failure2007204 Comparison of the effects of BiPAP ventilation combined with lung recruitment maneuvers and low tidal volume A/C ventilation in patients with acute respiratory distress syndrome. WANG Xiaozhi(王晓芝),et al. Dept Respir & Intensive Care Unit, Binzhou Med Coll, Binzhou 256603. Chin J Tuberc Respir Dis 2007;30(1):44-47. Objective To compare the effects of BiPAP ventilation combined with lung recruitment maneuvers(LRM) with low tidal volume A/C ventilation in patients with acute respiratory distress syndrome (ARDS). Methods A prospective, randomized comparison of BiPAP mechanical ventilation combined with lung recruitment maneuvers(test group) with low tidal volume A/C ventilation (control group) was conducted in 28 patients with ARDS. FiO2/PaO2 ratio, respiratory system compliance(Cs), central venous pressure (CVP), duration of ventilation support were recorded at 0 h, 48 h and 72 h separately. The ventilation associated lung injury and mortality at 28 d were also recorded. Results The FiO2/PaO2 ratio were (298±16) and (309±16) cm H2O, Cs were (38.4±2.2) and (42.0±1.3) ml/cm H2O, CVP were (13.8±0.8) and (11.6±0.7) cm H2O in the test group at 48 h and 72 h separately. In the control group, FiO2/PaO2 ratio were (212±12) and (246±17) cm H2O, Cs were (29.5±1.3) and (29.0±1.0) ml/cm H2O, CVP were 18.6±1.1 and (16.8±1.0) cm H2O. The results were better in the test group as compared with the control group (t=10.03-29. 68, all P<0.01). The duration of ventilation support in the test group was shorter than the control group [(14±3) d vs (19±3)d, t=4.80, P<0.01]. The mortality in 28 d and ventilation associated lung injury were similar in the two groups. Conclusion The results show that combination of LRM with BiPAP mode ventilation, as compared with the control group, contributes to the improved FiO2/PaO2 ratio, pulmonary compliance, stable homodynamic and shorter duration of ventilation support in patients with ARDs.

  4. Modeling chronic dietary cadmium bioaccumulation and toxicity from periphyton to Hyalella azteca.

    Science.gov (United States)

    Golding, Lisa A; Borgmann, Uwe; Dixon, D George

    2011-07-01

    A chronic (28-d) Cd saturation bioaccumulation model was developed to quantify the Cd contribution from a natural periphyton diet to Cd in the freshwater amphipod Hyalella azteca. Bioaccumulation was then linked to chronic toxic effects. Juvenile H. azteca were exposed to treatments of Cd in water (3.13-100 nmol/L nominal) and food (389-26,300 nmol/g ash-free dry mass). Cadmium bioaccumulation, survival, and growth were recorded. Dietary Cd was estimated to contribute 21 to 31, 59 to 94, and 40 to 55% to bioaccumulated Cd in H. azteca exposed to treatments of Cd primarily in water, food, and food + water, respectively. Survival as a function of Cd lethal body concentration (679 nmol/g; 95% confidence limits, 617-747) was the most robust endpoint. Body concentration integrated all exposure routes. Based on the lethal body concentration, dietary Cd was predicted to contribute markedly (26-90%) to Cd in H. azteca. Cadmium concentration and food nutritional quality (biomass, chlorophyll a, total lipid, fatty acids, total protein) had no effect on H. azteca nutritional quality (total lipid, fatty acids, total protein) but did influence H. azteca dry weight. This research highlighted the importance of including a dietary component when modeling chronic effects of Cd and when refining endpoints for use in ecological risk assessment and water quality guidelines.

  5. Systemic cytokine response in moribund mice of streptococcal toxic shock syndrome model.

    Science.gov (United States)

    Saito, Mitsumasa; Kajiwara, Hideko; Iida, Ken-ichiro; Hoshina, Takayuki; Kusuhara, Koichi; Hara, Toshiro; Yoshida, Shin-ichi

    2011-02-01

    Streptococcus pyogenes causes severe invasive disease in humans, including streptococcal toxic shock syndrome (STSS). We previously reported a mouse model that is similar to human STSS. When mice were infected intramuscularly with 10(7) CFU of S. pyogenes, all of them survived acute phase of infection. After 20 or more days of infection, a number of them died suddenly accompanied by S. pyogenes bacteremia. We call this phenomenon "delayed death". We analyzed the serum cytokine levels of mice with delayed death, and compared them with those of mice who died in the acute phase of intravenous S. pyogenes infection. The serum levels of TNF-α and IFN-γ in mice of delayed death were more than 100 times higher than those in acute death mice. IL-10 and IL-12, which were not detected in acute death, were also significantly higher in mice of delayed death. IL-6 and MCP-1 (CCL-2) were elevated in both groups of mice. It was noteworthy that not only pro-inflammatory cytokines but also anti-inflammatory cytokines were elevated in delayed death. We also found that intravenous TNF-α injection accelerated delayed death, suggesting that an increase of serum TNF-α induced S. pyogenes bacteremia in our mouse model.

  6. Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington’s disease model system

    Science.gov (United States)

    Xi, Wen; Wang, Xin; Laue, Thomas M.; Denis, Clyde L.

    2016-01-01

    Huntington’s disease (HD) results from expansions of polyglutamine stretches (polyQ) in the huntingtin protein (Htt) that promote protein aggregation, neurodegeneration, and death. Since the diversity and sizes of the soluble Htt-polyQ aggregates that have been linked to cytotoxicity are unknown, we investigated soluble Htt-polyQ aggregates using analytical ultracentrifugation. Soon after induction in a yeast HD model system, non-toxic Htt-25Q and cytotoxic Htt-103Q both formed soluble aggregates 29S to 200S in size. Because current models indicate that Htt-25Q does not form soluble aggregates, reevaluation of previous studies may be necessary. Only Htt-103Q aggregation behavior changed, however, with time. At 6 hr mid-sized aggregates (33S to 84S) and large aggregates (greater than 100S) became present while at 24 hr primarily only mid-sized aggregates (20S to 80S) existed. Multiple factors that decreased cytotoxicity of Htt-103Q (changing the length of or sequences adjacent to the polyQ, altering ploidy or chaperone dosage, or deleting anti-aging factors) altered the Htt-103Q aggregation pattern in which the suite of mid-sized aggregates at 6 hr were most correlative with cytotoxicity. Hence, the amelioration of HD and other neurodegenerative diseases may require increased attention to and discrimination of the dynamic alterations in soluble aggregation processes. PMID:27721444

  7. CORAL: quantitative structure-activity relationship models for estimating toxicity of organic compounds in rats.

    Science.gov (United States)

    Toropova, A P; Toropov, A A; Benfenati, E; Gini, G; Leszczynska, D; Leszczynski, J

    2011-09-01

    For six random splits, one-variable models of rat toxicity (minus decimal logarithm of the 50% lethal dose [pLD50], oral exposure) have been calculated with CORAL software (http://www.insilico.eu/coral/). The total number of considered compounds is 689. New additional global attributes of the simplified molecular input line entry system (SMILES) have been examined for improvement of the optimal SMILES-based descriptors. These global SMILES attributes are representing the presence of some chemical elements and different kinds of chemical bonds (double, triple, and stereochemical). The "classic" scheme of building up quantitative structure-property/activity relationships and the balance of correlations (BC) with the ideal slopes were compared. For all six random splits, best prediction takes place if the aforementioned BC along with the global SMILES attributes are included in the modeling process. The average statistical characteristics for the external test set are the following: n = 119 ± 6.4, R(2) = 0.7371 ± 0.013, and root mean square error = 0.360 ± 0.037. Copyright © 2011 Wiley Periodicals, Inc.

  8. 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. Precision

  9. Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data

    Science.gov (United States)

    EPA's ToxCast™ project is profiling the in vitro bioactivity of chemicals to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesized that developmental toxicity in guideline animal studies captured in the ToxRefDB database wou...

  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. Methoxyethylamino-numonafide Is an Efficacious and Minimally Toxic Amonafide Derivative in Murine Models of Human Cancer

    Directory of Open Access Journals (Sweden)

    Yanning Liu

    2011-05-01

    Full Text Available Amonafide is a DNA intercalator in clinical development for the treatment of cancer. The drug has a 5-position amine that is variably acetylated to form a toxic metabolite in humans, increasing adverse effects and complicating the dosing of amonafide. Numonafides, 6-amino derivatives of amonafide that avoid the toxic acetylation, also show in vitro anticancer activity, as we have previously described. Here, we report the in vitro and in vivo activities of two numonafides, 6-methoxyethylamino-numonafide (MEAN and 6-amino-numonafide (AN with comparisons to amonafide. The in vitro potencies and cellular anticancer mechanisms are similar for the two numonafides and amonafide. Results from several mouse models of human cancer demonstrate that AN and MEAN require slightly higher doses than amonafide for equal efficacy in short-term dosing models, but the same dose of all three compounds in long-term dosing models are equally efficacious. MEAN is tolerated much better than amonafide and AN at equally efficacious doses based on weight change, activity, stool consistency, and dose tolerance with survival as the end point. The studies presented here demonstrate that MEAN is much less toxic than amonafide or AN in mouse models of human liver and gastric cancers while being equally efficacious in vivo and inhibiting cancer cells through similar mechanisms. These findings demonstrate that numonafides can be less toxic than amonafide and support further preclinical development and novel anticancer agents or as replacements or amonafide.

  12. The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man.

    Science.gov (United States)

    Louisse, Jochem; de Jong, Esther; van de Sandt, Johannes J M; Blaauboer, Bas J; Woutersen, Ruud A; Piersma, Aldert H; Rietjens, Ivonne M C M; Verwei, Miriam

    2010-12-01

    At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices.

  13. A Markov computer simulation model of the economics of neuromuscular blockade in patients with acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Chow John L

    2006-03-01

    Full Text Available Abstract Background Management of acute respiratory distress syndrome (ARDS in the intensive care unit (ICU is clinically challenging and costly. Neuromuscular blocking agents may facilitate mechanical ventilation and improve oxygenation, but may result in prolonged recovery of neuromuscular function and acute quadriplegic myopathy syndrome (AQMS. The goal of this study was to address a hypothetical question via computer modeling: Would a reduction in intubation time of 6 hours and/or a reduction in the incidence of AQMS from 25% to 21%, provide enough benefit to justify a drug with an additional expenditure of $267 (the difference in acquisition cost between a generic and brand name neuromuscular blocker? Methods The base case was a 55 year-old man in the ICU with ARDS who receives neuromuscular blockade for 3.5 days. A Markov model was designed with hypothetical patients in 1 of 6 mutually exclusive health states: ICU-intubated, ICU-extubated, hospital ward, long-term care, home, or death, over a period of 6 months. The net monetary benefit was computed. Results Our computer simulation modeling predicted the mean cost for ARDS patients receiving standard care for 6 months to be $62,238 (5% – 95% percentiles $42,259 – $83,766, with an overall 6-month mortality of 39%. Assuming a ceiling ratio of $35,000, even if a drug (that cost $267 more hypothetically reduced AQMS from 25% to 21% and decreased intubation time by 6 hours, the net monetary benefit would only equal $137. Conclusion ARDS patients receiving a neuromuscular blocker have a high mortality, and unpredictable outcome, which results in large variability in costs per case. If a patient dies, there is no benefit to any drug that reduces ventilation time or AQMS incidence. A prospective, randomized pharmacoeconomic study of neuromuscular blockers in the ICU to asses AQMS or intubation times is impractical because of the highly variable clinical course of patients with ARDS.

  14. Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox - an animal model of smallpox.

    Science.gov (United States)

    Parker, Scott; Chen, Nanhai G; Foster, Scott; Hartzler, Hollyce; Hembrador, Ed; Hruby, Dennis; Jordan, Robert; Lanier, Randall; Painter, George; Painter, Wesley; Sagartz, John E; Schriewer, Jill; Mark Buller, R

    2012-04-01

    The human population is currently faced with the potential use of natural or recombinant variola and monkeypox viruses as biological weapons. Furthermore, the emergence of human monkeypox in Africa and its expanding environs poses a significant natural threat. Such occurrences would require therapeutic and prophylactic intervention with antivirals to minimize morbidity and mortality of exposed populations. Two orally-bioavailable antivirals are currently in clinical trials; namely CMX001, an ether-lipid analog of cidofovir with activity at the DNA replication stage and ST-246, a novel viral egress inhibitor. Both of these drugs have previously been evaluated in the ectromelia/mousepox system; however, the trigger for intervention was not linked to a disease biomarker or a specific marker of virus replication. In this study we used lethal, intranasal, ectromelia virus infections of C57BL/6 and hairless SKH1 mice to model human disease and evaluate exanthematous rash (rash) as an indicator to initiate antiviral treatment. We show that significant protection can be provided to C57BL/6 mice by CMX001 or ST-246 when therapy is initiated on day 6 post infection or earlier. We also show that significant protection can be provided to SKH1 mice treated with CMX001 at day 3 post infection or earlier, but this is four or more days before detection of rash (ST-246 not tested). Although in this model rash could not be used as a treatment trigger, viral DNA was detected in blood by day 4 post infection and in the oropharyngeal secretions (saliva) by day 2-3 post infection - thus providing robust and specific markers of virus replication for therapy initiation. These findings are discussed in the context of current respiratory challenge animal models in use for the evaluation of poxvirus antivirals. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using yeast models of OXPHOS deficiencies.

    Science.gov (United States)

    Fontanesi, Flavia; Diaz, Francisca; Barrientos, Antoni

    2009-10-01

    The oxidative phosphorylation (OXPHOS) system consists of five multimeric complexes embedded in the mitochondrial inner membrane. They work in concert to drive the aerobic synthesis of ATP. Mitochondrial and nuclear DNA mutations affecting the accumulation and function of these enzymes are the most common cause of mitochondrial diseases and have also been associated with neurodegeneration and aging. Several approaches for the assessment of the OXPHOS system enzymes have been developed. Based on the methods described elsewhere, this unit describes the creation and study of yeast models of mitochondrial OXPHOS deficiencies.

  16. 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.

  17. Respiratory failure

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930118 Facial or nasal mask pressure supportventilation in managing acute exacerbation ofchronic respiratory failure in COPD patients.CHEN Rongchang(陈荣昌),et al.GuangzhouInstit Respir Dis,Guangzhou 510120.Chin Tu-berc & Respir Dis 1992;15(5)285-287.Eleven COPD patients(age:65±9 yrs)withacute exacerbation of chronic respiratory failure(PaCO2 11.3±1.1kPa)were treated with maskpressure support ventilation,another 10 similarpatients(age:68±12yrs)served as controls.Bi-PAP ventilator was used with the followingmodifications:(1)Non-rehreathing valve set-in proximal to mask;(2)5 LPM oxygen flow de-livered into mask to reduce the dead space ef-fect.Mask ventilation was given 2-3 hours ev-ery time and 1-2 times daily for 7 days.Syn-

  18. Modeling of pharmaceuticals mixtures toxicity with deviation ratio and best-fit functions models.

    Science.gov (United States)

    Wieczerzak, Monika; Kudłak, Błażej; Yotova, Galina; Nedyalkova, Miroslava; Tsakovski, Stefan; Simeonov, Vasil; Namieśnik, Jacek

    2016-11-15

    The present study deals with assessment of ecotoxicological parameters of 9 drugs (diclofenac (sodium salt), oxytetracycline hydrochloride, fluoxetine hydrochloride, chloramphenicol, ketoprofen, progesterone, estrone, androstenedione and gemfibrozil), present in the environmental compartments at specific concentration levels, and their mutual combinations by couples against Microtox® and XenoScreen YES/YAS® bioassays. As the quantitative assessment of ecotoxicity of drug mixtures is an complex and sophisticated topic in the present study we have used two major approaches to gain specific information on the mutual impact of two separate drugs present in a mixture. The first approach is well documented in many toxicological studies and follows the procedure for assessing three types of models, namely concentration addition (CA), independent action (IA) and simple interaction (SI) by calculation of a model deviation ratio (MDR) for each one of the experiments carried out. The second approach used was based on the assumption that the mutual impact in each mixture of two drugs could be described by a best-fit model function with calculation of weight (regression coefficient or other model parameter) for each of the participants in the mixture or by correlation analysis. It was shown that the sign and the absolute value of the weight or the correlation coefficient could be a reliable measure for the impact of either drug A on drug B or, vice versa, of B on A. Results of studies justify the statement, that both of the approaches show similar assessment of the mode of mutual interaction of the drugs studied. It was found that most of the drug mixtures exhibit independent action and quite few of the mixtures show synergic or dependent action. Copyright © 2016. Published by Elsevier B.V.

  19. A foam model highlights the differences of the macro- and microrheology of respiratory horse mucus.

    Science.gov (United States)

    Gross, Andreas; Torge, Afra; Schaefer, Ulrich F; Schneider, Marc; Lehr, Claus-Michael; Wagner, Christian

    2017-07-01

    Native horse mucus is characterized with micro- and macrorheology and compared to hydroxyethylcellulose (HEC) gel as a model. Both systems show comparable viscoelastic properties on the microscale and for the HEC the macrorheology is in good agreement with the microrheology. For the mucus, the viscoelastic moduli on the macroscale are several orders of magnitude larger than on the microscale. Large amplitude oscillatory shear experiments show that the mucus responds nonlinearly at much smaller deformations than HEC. This behavior fosters the assumption that the mucus has a foam like structure on the microscale compared to the typical mesh like structure of the HEC, a model that is supported by cryogenic-scanning-electron-microscopy (CSEM) images. These images allow also to determine the relative amount of volume that is occupied by the pores and the scaffold. Consequently, we can estimate the elastic modulus of the scaffold. We conclude that this particular foam like microstructure should be considered as a key factor for the transport of particulate matter which plays a central role in mucus function with respect to particle penetration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Ana insect model for assessing arsenic toxicity: Arsenic elevated glutathione content in the musca domestica and trichoplusia ni

    Energy Technology Data Exchange (ETDEWEB)

    Zaman, K.; Pardini, R.S. [Univ. of Nevada, Reno, NV (United States)

    1995-12-01

    Throughout history, arsenic has acquired an unparalled reputation as a poison. Arsenic was used as a poison as early as 2000 B.C. The toxicity of arsenic (As) extends to mammals, fish, insects, plants and fungi. According to epidemiological evidence, inorganic arsenic compounds have been strongly suggested as human carcinogens. Human exposure to arsenic through various means is correlated with an increased incidence of skin, lung, and possibly liver cancers. Inorganic trivalent arsenic is systematically more poisonous than the pentavalent form and it is possible that pentavalent arsenic is reduced to the trivalent form before exerting any toxic effects. This study focuses on the potential to use two insect species, the housefly, Musca domestica and the cabbage looper moth, Trichoplusia ni, and a model for the study of arsenic toxicity. After 48 hours of exposure to Arsenic, a significant induction of Glutathione level and subsequent decrease in the level of GSSG in both species were observed. 21 refs., 2 figs., 1 tab.

  1. 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.

  2. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    This chapter reviews the human toxicological impacts of chemicals and how to assess these impacts in life cycle impact assessment (LCIA), in order to identify key processes and pollutants. The complete cause-effect pathway – from emissions of toxic substances up to damages on human health...... on characterisation factors means that results should by default be reported and interpreted in log scales when comparing scenarios or substance contribution! We conclude by outlining future trends in human toxicity modelling for LCIA, with promising developments for (a) better estimates of degradation halflives, (b......) the inclusion of ionization of chemicals in human exposure including bioaccumulation, (c) metal speciation, (d) spatialised models to differentiate the variability associated with spatialisation from the uncertainty, and (e) the assessment of chemical exposure via consumer products and occupational settings...

  3. Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models

    Directory of Open Access Journals (Sweden)

    Maggie Folkesson

    2016-07-01

    Full Text Available Tobacco use is strongly associated with cardiovascular disease and the only avoidable risk factor associated with development of aortic aneurysm. While smoking is the most common form of tobacco use, snuff and other oral tobacco products are gaining popularity, but research on potentially toxic effects of oral tobacco use has not kept pace with the increase in its use. Here, we demonstrate that cigarette smoke and snuff extracts are highly toxic to developing zebrafish embryos. Exposure to such extracts led to a palette of toxic effects including early embryonic mortality, developmental delay, cerebral hemorrhages, defects in lymphatics development and ventricular function, and aneurysm development. Both cigarette smoke and snuff were more toxic than pure nicotine, indicating that other compounds in these products are also associated with toxicity. While some toxicities were found following exposure to both types of tobacco product, other toxicities, including developmental delay and aneurysm development, were specifically observed in the snuff extract group, whereas cerebral hemorrhages were only found in the group exposed to cigarette smoke extract. These findings deepen our understanding of the pathogenic effects of cigarette smoking and snuff use on the cardiovascular system and illustrate the benefits of using zebrafish to study mechanisms involved in aneurysm development.

  4. Pharmacodynamic and pharmacokinetic profiling of delafloxacin in a murine lung model against community-acquired respiratory tract pathogens.

    Science.gov (United States)

    Thabit, Abrar K; Crandon, Jared L; Nicolau, David P

    2016-11-01

    Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S. aureus (MSSA), 2 MRSA and 2 Klebsiella pneumoniae isolates were studied. Delafloxacin doses varied from 0.5 mg/kg/day to 640 mg/kg/day and were given as once-daily to every 3 h regimens over the 24-h treatment period. Efficacy was measured as the change in log10 CFU at 24 h compared with 0-h controls. Plasma and bronchopulmonary pharmacokinetic studies were conducted. Delafloxacin demonstrated potent in vitro and in vivo activity. Delafloxacin demonstrated high penetration into the lung compartment, as epithelial lining fluid concentrations were substantially higher than free drug in plasma. The ratio of the area under the free drug concentration-time curve to the minimum inhibitory concentration of the infecting organism (fAUC/MIC) was the parameter that best correlated with the efficacy of the drug, and the magnitude required to achieve 1 log10 CFU reduction was 31.8, 24.7, 0.4 and 9.6 for S. pneumoniae, MRSA, MSSA and K. pneumoniae, respectively. The observed in vivo efficacy of delafloxacin was supported by the high pulmonary disposition of the compound. The results derived from this pre-clinical lung model support the continued investigation of delafloxacin for the treatment of community-acquired lower respiratory tract infections.

  5. EFFECTS OF AMANTADINE ON BEHAVIOR, RESPIRATORY CHAIN ENZYMES AND CREATINE KINASE IN AN ANIMAL MODEL OF SCHIZOPHRENIA

    Directory of Open Access Journals (Sweden)

    David de Lucena

    2013-03-01

    Full Text Available Introduction: Glutamate dysregulation may be involved in the pathophysiology of schizophrenia, and NMDA antagonists seem to be effective in its treatment. We evaluated the efficacy of amantadine (AMA in preventing ketamine (KET-induced effects in an animal model of schizophrenia. Methods: Adult Wistar rats received 10 mg/kg AMA for 10 days, followed by 7 days of 25 mg/kg KET ip. Thirty minutes after the last injection, rats were placed in an open-field apparatus for 60 minutes and killed by decapitation afterwards. Amygdala, hippocampus, prefrontal cortex and striatum were isolated and analyzed for creatine kinase (CK and respiratory chain enzyme activities. Results: KET increased crossings and reduced grooming, which was not prevented by AMA. KET also increased stereotypic movements, which was partially prevented by AMA. As for CK activity, KET increased it in the prefrontal cortex, striatum and amygdala, and AMA prevented it only in prefrontal cortex and striatum. The activity of complex I was not altered by KET, however, AMA+KET increased it in the striatum and amygdala. KET increased the activity of complex II in the striatum as well, whereas AMA+KET increased it in hippocampus, prefrontal cortex, and striatum. KET did not alter complex I-III activity, whereas AMA+KET increased it in hippocampus and amygdala. AMA+KET also increased complex IV activity in hippocampus and striatum, whereas KET had no effect on this activity. Conclusion: AMA did not prevent most of KET-induced alterations. New animal models should be employed in the study of AMA as a potential novel drug for schizophrenia.

  6. Use of the Biotic Ligand Model to predict metal toxicity to aquatic biota in areas of differing geology

    Science.gov (United States)

    Smith, Kathleen S.

    2005-01-01

    This work evaluates the use of the biotic ligand model (BLM), an aquatic toxicity model, to predict toxic effects of metals on aquatic biota in areas underlain by different rock types. The chemical composition of water, soil, and sediment is largely derived from the composition of the underlying rock. Geologic source materials control key attributes of water chemistry that affect metal toxicity to aquatic biota, including: 1) potentially toxic elements, 2) alkalinity, 3) total dissolved solids, and 4) soluble major elements, such as Ca and Mg, which contribute to water hardness. Miller (2002) compiled chemical data for water samples collected in watersheds underlain by ten different rock types, and in a mineralized area in western Colorado. He found that each rock type has a unique range of water chemistry. In this study, the ten rock types were grouped into two general categories, igneous and sedimentary. Water collected in watersheds underlain by sedimentary rock has higher mean pH, alkalinity, and calcium concentrations than water collected in watersheds underlain by igneous rock. Water collected in the mineralized area had elevated concentrations of calcium and sulfate in addition to other chemical constituents. Miller's water-chemistry data were used in the BLM (computer program) to determine copper and zinc toxicity to Daphnia magna. Modeling results show that waters from watersheds underlain by different rock types have characteristic ranges of predicted LC 50 values (a measurement of aquatic toxicity) for copper and zinc, with watersheds underlain by igneous rock having lower predicted LC 50 values than watersheds underlain by sedimentary rock. Lower predicted LC 50 values suggest that aquatic biota in watersheds underlain by igneous rock may be more vulnerable to copper and zinc inputs than aquatic biota in watersheds underlain by sedimentary rock. For both copper and zinc, there is a trend of increasing predicted LC 50 values with increasing dissolved

  7. 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.

  8. Insects as biological models to assay spider and scorpion venom toxicity

    Directory of Open Access Journals (Sweden)

    M. F. Manzoli-Palma

    2003-01-01

    Full Text Available This study was undertaken to develop an experimental protocol using insects as biological models to assay venom toxicity of the following spiders Loxosceles gaucho, Phoneutria nigriventer, Nephilengys cruentata and Tityus serrulatus scorpion. Three different insect species were bioassayed: Apis mellifera (Hymenoptera, Grillus assimilis (Orthoptera, and Diatraea saccharalis (Lepidoptera. Venoms were injected into the hemocele of insects with a microsyringe at concentrations that caused dose/weight-dependent effects; doses causing either paralysis (ED50 or death (LD50 were recorded for each venom and insect test-species. T. serrulatus and L. gaucho venoms were lethal to all tested species, while P. nigriventer venom caused paralysis and death, and N. cruentata venom caused only paralysis at the doses assayed. A comparison between the insect test species described above revealed that A. mellifera was highly sensitive to all venoms tested; even a tiny amount of N. cruentata non-lethal venom caused a change in the walking pattern leading to transient paralysis. D. saccharalis larvae were very resistant to all four venoms.

  9. Onset of streptococcal toxic shock syndrome is accelerated by bruising in a mouse model.

    Science.gov (United States)

    Seki, Masanori; Saito, Mitsumasa; Iida, Ken-Ichiro; Taniai, Hiroaki; Soejima, Takashi; Nakayama, Hiroaki; Yoshida, Shin-Ichi

    2008-04-01

    Streptococcal toxic shock syndrome (STSS) is the severest form of human infections caused by Streptococcus pyogenes. In our animal model of STSS [Saito M, Kajiwara H, Ishikawa T, et al. Delayed onset of systemic bacterial dissemination and subsequent death in mice injected intramuscularly with Streptococcus pyogenes. Microbiol Immunol 2001;45:777-86], mice inoculated intramuscularly with S. pyogenes strains initially suffer from a short illness, then recover and remain healthy for about 20 days, and finally become sick and incur a sudden death. Here we report that the death during the convalescent period was facilitated by artificially bruising an extremity remote from the site of the initial inoculation. Bacterial burden was found to be higher in the bruised site than in a non-bruised control extremity of each mouse examined. Bacteremia started to occur approximately 20 days after infection. These findings imply that a fresh bruise serves as a focus for bacterial multiplication in the presence of bacteremia, thereby facilitating the development of STSS.

  10. Biodistribution and acute toxicity of naked gold nanoparticles in a rabbit hepatic tumor model.

    Science.gov (United States)

    Glazer, Evan S; Zhu, Cihui; Hamir, Amir N; Borne, Agatha; Thompson, Catherine Shea; Curley, Steven A

    2011-12-01

    There is a paucity of data regarding the safety of administering solid gold nanoparticles (AuNPs) in large animal tumor models. We assessed the acute toxicity and biodistribution of 5 nm and 25 nm solid AuNPs in New Zealand White rabbits (n = 6 in each) with implanted liver Vx2 tumors 24 h after intravenous injection. Gold concentration was determined by inductively coupled plasma atomic emission spectrometry (ICP) and imaged with transmission electron microscopy (TEM). There was no clinico-pathologic evidence of renal, hepatic, pulmonary, or other organ dysfunction. After 25 nm AuNP administration, the concentration of white blood cells increased after treatment (p = 0.001). Most other blood studies were unchanged. AuNPs were distributed to the spleen, liver, and Vx2 tumors, but not to other tissues. The urinary excretion of AuNPs was bimodal as measured by ICP. 25 nm AuNPs were more evenly distributed throughout tissues and may be better tools for medical therapy.

  11. Genetic Mechanisms of Coffee Extract Protection in a Caenorhabditis elegans Model of β-Amyloid Peptide Toxicity

    OpenAIRE

    Dostal, Vishantie; Roberts, Christine M; Link, Christopher D

    2010-01-01

    Epidemiological studies have reported that coffee and/or caffeine consumption may reduce Alzheimer's disease (AD) risk. We found that coffee extracts can similarly protect against β-amyloid peptide (Aβ) toxicity in a transgenic Caenorhabditis elegans Alzheimer's disease model. The primary protective component(s) in this model is not caffeine, although caffeine by itself can show moderate protection. Coffee exposure did not decrease Aβ transgene expression and did not need to be present during...

  12. Weighted Feature Significance: A Simple, Interpretable Model of Compound Toxicity Based on the Statistical Enrichment of Structural Features

    OpenAIRE

    Huang, Ruili; Southall, Noel; Xia, Menghang; Cho, Ming-Hsuang; Jadhav, Ajit; Nguyen, Dac-Trung; Inglese, James; Tice, Raymond R.; Austin, Christopher P.

    2009-01-01

    In support of the U.S. Tox21 program, we have developed a simple and chemically intuitive model we call weighted feature significance (WFS) to predict the toxicological activity of compounds, based on the statistical enrichment of structural features in toxic compounds. We trained and tested the model on the following: (1) data from quantitative high–throughput screening cytotoxicity and caspase activation assays conducted at the National Institutes of Health Chemical Genomics Center, (2) dat...

  13. 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-