Global ETD Search

51	La diversité des toxines de scorpions et leur intérêt dans la recherche biologique et pharmacologique : (purification et caractérisation chimique, pharmacologique et immunologique des toxines de scorpion présentant des problèmes de santé publique au Moyen Orient et leurs implications pharmacologiques) / Scorpion toxins diversity and their interest in biological an pharmacological research : purification and chemical, pharmacological and immunological characterization of toxins from scorpions involved in Public Health problems in Middle-East and their pharmacological applications Abbas, Najwa 10 December 2010 (has links) Les scorpions du genre Androctonus, comme Androctonus australis en Algérie et en Tunisieou Androctonus mauretanicus au Maroc, sont responsables d’environ 100.000 piqûres par ansur l’ensemble du Maghreb, suivies de 1 % de décès. Ils posent un réel problème de santépublique. Les toxines «alpha» modulant les canaux sodium voltage-activés (Nav) sontresponsables de 80 à 90% de l’activité létale des venins d’Androctonus australis etmauretanicus. Cependant, certaines petites molécules sont aussi capables de bloquer lefonctionnement d’autres types de canaux ioniques, en particulier des canaux potassiumvoltage-activés (Kv).Au cours de cette thèse, nous avons isolé et caractérisé les composants du venind’Androctonus amoreuxi, scorpion largement distribué en Afrique du Nord et au Moyen-Orient, mais qui n’avait jusqu’ici fait l’objet d’aucune etude rigoureuse. Nous avons identifiéles constituants impliqués dans la toxicité du venin et précisé leurs propriétéspharmacologiques et immunologiques, ainsi que l’effet qu’elles induisent enélectrophysiologie sur des canaux Nav et Kv clonés exprimés dans l’ovocyte de Xenope.Nous avons recherché de nouveaux membres d’une famille de toxines récemment isolées, lesBirtoxines-like, et interprété leur polymorphisme biologique par la modélisation de leursstructures 3D. Enfin, nous avons mené à bien un programme portant sur les effetsantinociceptifs des toxines de scorpion chez la souris. Cela nous a permis de proposer uneexplication qui fait intervenir le système opiacé et la « contre-irritation ». L’effet des toxinesreconnues « analgésiques » a ensuite été testé en électrophysiologie sur des neuronesnocicepteurs. / The North African scorpion Androctonus australis in Algeria and Tunisia, or Androctonusmauretanicus in Morocco, are responsible of about 100.000 stings each year in Maghreb,followed by 1% of death. Small toxins modulating voltage-gated sodium channels (Nav),named “alpha”, are responsible of 80 to 90% of the total lethal activity from the Androctonusaustralis and mauretanicus venoms. However, smaller molecules are also able to block thefunctioning of another type of ionic channels, in particular, the voltage-gated potassiumchannels (Kv).During this thesis, we have isolated and characterized the compounds of the venom fromAndroctonus amoreuxi, a scorpion widely found in North Africa and Middle East, but neverseriously studied so far. We have identified the constituents implicated in the toxicity anddefined their immunological and pharmacological properties, as well as theirelectrophysiological effects on cloned Nav and Kv channels expressed in Xenopus oocytes.We also have looked for recently characterized new molecules, the Birtoxins-like, and tried toexplain their large biological polymorphism by 3D structural models. At last, we haveevaluated the antinociceptifs effects of scorpion toxins in mice. We have proposed that theantalgic effects observed after administration of scorpion toxins are partly due to a counterirritation phenomenon, which implicates the activation of an endogenous opioid system. The“analgesic” toxins have been further tested in electrophysiology on DRG neurons. Toxines de scorpions Canaux sodium voltage-activés Canaux potassium voltage-activés Nocicepteurs Contre-irritation Scorpion toxins Nociception Dnic Electrophysiology on DRG neurons
52	Projevy a důsledky turistifikace v Teplicích / Effects and consequences of turistifacion in Teplice Čáslavová, Eva January 2015 (has links) This diploma thesis deals with effects and consequences of touristification in the spa town of Teplice. The aim of this work is the analysis of current state of Teplice's spa therapy and monitoring of functional changes in the town. The emphasis is placed on activities, relational links and the level of co- operation and attitudes of the main participants in the tourism in the town. An inseparable part is also an opinion poll (investigation) among local residents. The aim of this dissertation is, except for findings and an evaluation of effects of touristification in the area of interest, also the suggestion of steps leading to stabilization and improvement of the situation. Powered by TCPDF (www.tcpdf.org)
53	Modely pro podporu rozhodování managementu destinace cestovního ruchu / Models Supporting Decision Making of a Tourism Destination Management STUDENÝ, Zdeněk January 2019 (has links) This diploma thesis focuses on the application of system thinking and its methods to the issues of decision making within destination management and its organizations. The main aim of the thesis was to create a model to support decision making of destination management organization and to plan sustainable and responsible tourism development in the destination. A partial aim was to create a simplified model in which a simulation of the given system was performed. This aim has been applied to the destination of Cesky Krumlov. The contribution of the work is to find optimal decisions, policies and individual processes in order to assess the subsequent impacts and manage the development of tourism destination towards sustainability.
54	A tutela jurídica da água como acoplamento entre o direito ambiental e sanitário Cardoso Neto, Nicolau 13 December 2016 (has links) Submitted by JOSIANE SANTOS DE OLIVEIRA (josianeso) on 2017-07-10T13:21:23Z No. of bitstreams: 1 Nicolau Cardoso Neto_.pdf: 4708309 bytes, checksum: 1dd8c22aad711af3486a701ea6beea21 (MD5) / Made available in DSpace on 2017-07-10T13:21:23Z (GMT). No. of bitstreams: 1 Nicolau Cardoso Neto_.pdf: 4708309 bytes, checksum: 1dd8c22aad711af3486a701ea6beea21 (MD5) Previous issue date: 2016-12-13 / Nenhuma / A presente Tese apresenta uma abordagem acerca da identificação da ocorrência de acoplamento estrutural entre as operações dos Subsistemas Jurídico Ambiental e Jurídico de Saúde do Sistema Jurídico Brasileiro. Para tanto, utilizou-se a água com qualidade e potável para o consumo humano como operação para compreender se ocorrem irritações entre as estruturas dos referidos subsistemas. Emprega-se como teoria de base os Sistemas Sociais de Niklas Luhmann, em especial O Direito da Sociedade, para a realização de autodescrição dos subsistemas para então aplicar a comparação e a identificação das irritações entre as estruturas que provocam o acoplamento estrutural. É empregado o método de abordagem Sistêmico, com a intenção de realizar comparação entre os subsistemas por meio da realização de autorreferência de vinte e quatro normas. Também foram empregados os métodos de Procedimento Comparativo e Funcionalista, e as técnicas de pesquisa Bibliográfica e Legislativa com o intuito de verificar as semelhanças e/ou divergências e sua funcionalidade, de forma a possibilitar a identificação das operações e estruturas de cada um dos subsistemas. Os resultados demonstraram a ocorrência de acoplamento estrutural entre os Subsistemas quanto à operacionalização da proteção do meio ambiente e da execução de ações de saúde no que se refere ao tema água com qualidade ao identificar-se a irritação das operações. Evidenciou-se que as estruturas acopladas realizam operações apoiadas em objetivos, princípios, diretrizes e sistemas de fiscalização e controle sobre o mesmo objeto, quanto à intenção de ofertar qualidade de vida para a população, por meio de processos e condições que procuram garantir qualidade para a água; seja no espaço natural sobre a utilização dos recursos naturais ou mesmo sobre aqueles de prestação de serviço de acesso a água que visam proteger os recursos hídricos de forma a disporem sobre maneiras de gestão e proteção desta para que possua qualidade para diferentes usos, e, consequentemente, segurança para ser servida como potável para o consumo realizado pela população. Dessa forma, foi confirmada a hipótese principal desse estudo, qual seja, a ocorrência de acoplamento de operações das estruturas do Subsistema Jurídico Ambiental, relacionadas à qualidade de vida da população brasileira por meio da proteção do meio ambiente, e do Subsistema Jurídico de Saúde, quanto à prática de prevenção e controle dos fatores de risco à saúde decorrentes do meio ambiente que possam prejudicar a qualidade de vida da população. / The present thesis presents an approach on identifying the occurrence of structural coupling between operations of the Legal Environmental Subsystems and Legal Health of the Brazilian Legal System. Therefore, it was used quality water, safe for human consumption as an operation to understand if there are irritations between the structures of these subsystems. The Social Systems of Niklas Luhmann's are used as the base theory, in particular the Law as a Social System, for self-description of the subsystems in order to apply the comparison and identification of the irritations between the structures that cause the structural coupling. The method of systemic approach was used, intending as a comparison between the subsystems by performing twenty-four rules of self-referencing. Methods of Comparative and Functionalist Procedure and the techniques of Bibliographic and Legislative research were also used in order to verify the similarities and/or divergences and their functionality, allowing the identification of the operations and structures of each subsystem. The results demonstrated the occurrence of structural coupling between subsystems on the implementation of environmental protection and the implementation of health actions on the theme quality of water, by identifying the irritation of operations. It was evidenced that the coupled structures perform operations based on objectives, principles, guidelines and monitoring systems and control over the same object, about the intention of offering quality of life for the population, by means of processes and conditions that seek to guarantee quality of water; be it, in natural environment when of the use of natural resources or even on those providing water access services which aim to protect the water resources in order to provide the ways of managing and protecting its quality for different uses, and, consequently, the security for it to be safely provided for population consumption. Thus, the main hypothesis of this study was confirmed, that is, the occurrence of coupling operations on the structures of the Legal Environmental Subsystem, related to the quality of life of the Brazilian population by means of protection of the environment, and, of the Legal Subsystem of Health, as for the practice of prevention and control of health risk factors resulting in an environment that could cause prejudice to the quality of life of the population. Acoplamento estrutural Água com qualidade Autodescrição Irritação sistêmica Structural coupling Water quality Self-description Irritation systemic
55	Evaluation of physico-chemical properties of biorefinery-derived amphiphilic molecules and their effects on multi-scale biological models / Evaluation des propriétés physico-chimiques de molécules amphiphiles dérivées de la bio-raffinerie et leurs effets sur des modèles biologiques multi-échelles Lu, Biao 16 October 2015 (has links) Aujourd'hui, un grand nombre de nouvelles molécules peuvent être synthétisées à partir de la biomasse. Les tensioactifs dérivés de sucre sont notamment considérés comme une alternative aux tensioactifs fossiles en raison de leur biodégradabilité et de leur biocompatibilité. Cependant, les études associant la caractérisation physico-chimique et les propriétés biologiques de ce type de tensio-actifs sont limitées. Il est ainsi difficile de prédire les propriétés d'un tensioactif à partir de sa structure chimique. L'établissement d'une méthodologie permettant de relier la structure des surfactants à leurs propriétés apparait pertinent. Dans ce travail, quatre surfactants dérivés de sucre ayant chacun une chaîne C8 liée à une tête glucose ou maltose par un groupe amide ont été caractérisés par leurs propriétés tensio-actives dans différentes solutions (eau et milieu biologique). Leurs interactions avec des protéines ont également été analysées. Concernant l'évaluation des propriétés biologiques, des tests de cytotoxicité/irritation ont été effectués sur trois modèles in-vitro : 1) modèle cellulaire 20 (cellules L929 cultivées en monocouche), Il) modèle cellulaire 30 (cellules L929 cultivées dans un gel de collagène), Ill) épiderme humain reconstitué. Les résultats indiquent que les quatre surfactants synthétisés présentent de bonnes propriétés tensio-actives et trois d'entre eux sont moins cytotoxiques que des tensioactifs de référence. Plusieurs hypothèses permettant de relier la structure chimique des molécules à leurs propriétés physico-chimiques et biologiques ont été proposées. Des travaux futurs permettront d'enrichir la base de données sur les relations structure-propriétés des tensioactifs issus de la biomasse, et de l'utiliser pour synthétiser des surfactants présentant des propriétés adaptées aux applications envisagées. / Nowadays, a wide variety of new molecules can derive from biomass. Among them, the family of sugar-based surfactants, which are considered as alternatives to fossil-based surfactants, due to their relatively high biodegradability and biocompatibility, exhibit interesting properties both in terms of their self-assembly and their ability to induce biological responses. In the study, for the purpose to analyse these properties, different methodologies have been established. In this work, physico-chemistry and cellular biology methodologies are associated to analyse the properties of pre-selected molecules characterized by gradua) structure modifications. Firstly, we have screened synthesized sugar-based surfactants according to their solubility and their ability to reduce surface tension of water. Four pre-selected molecules, with a C8 chain linked to a glucose or maltose head through an amide functional group, either under the form of carbamoyl (carbohydrate scaffold bearing the carbonyl) or alkylcarboxamide (the alkyl chain bearing the carbonyl), were then dissolved in water/ cell culture media for surface tension measurements. Their behaviors in solutions were characterized by Krafft points, Critical Micellar Concentrations or self-assembling properties through different methods. To evaluate the cytotoxic/ irritant effects of these molecules on cells and tissues, 3 in-vitro models were established: I) 2D cell culture mode! (L929 cell monolayer) II) 3D ce!! culture mode! (L929 cells embedded in collagen gel) and III) Reconstituted human epidermis (differentiated human keratinocytes). Corresponding experiments were carried out on these models with increasing complexity. Results show that the synthesized sugar-based surfactants, GlulamideC8, Glu6amideC8, Glu6amideC8' and MallamideC8 can reduce the surface tension of water solution to the came level as standard surfactants (Tween 20 and Hecameg). In the meantime, GlulamideC8, Glu6amideC8' and MallamideC8 present Iess cytotoxicity effects on L929 cells both in the monolayer model and the 3D mode! than Tween 20 and Hecameg. All synthesized and standard surfactants (GlulamideC8, Glu6amideC8, Gu6amideC8', MallamideC8, Tween 20 and Hecameg) have no significant cytotoxic/ irritant effects on reconstituted human epidermis at 1000 ig/mL after 48 h of topical application. Discussions have been made according to the results of experiments to establish possible structures/ physico-chemical properties - cytotoxicity relationships of these surfactants. Molécules amphiphiles Tensioactifs Biodégradabilité Cytotoxicité Bio-raffinerie Sugar-based surfactant Krafft point Surface-active properties 2D/3D cell models Cytotoxicity evaluation Reconstituted human epidermis Skin irritation Structure-properties relationships
56	Waiting for the Cows to Come Home: A Political Ethnography of Security in a Complex World. Explorations in the Magyar Borderlands of Contemporary Ukraine Simonyi, André 16 September 2013 (has links) This dissertation explores the ways in which the everyday (in)securities of people in southwestern Ukraine can illuminate our understanding of contemporary political life. Rather than using traditional units of analysis or given categories—the state, the individual, identity—the dissertation focuses on relations between people in and connected to a single village to develop a novel framework for analyzing politics and the political. The dissertation opens with an interrogation of the practical and theoretical challenges associated with current conceptualizations of security; our understanding of the political; and the role of ethnography in theorization and presents a research design meant to address those challenges. Drawing upon extensive participant-observation and other immersion-based research in a post-Soviet borderland wedged between Ukraine and Slovakia, and using an analytical tool I call “togetherness,” the thesis presents an ethnographic account of social interactions, economy, and authority in this largely Hungarian-speaking rural area. The third part of the dissertation applies the idea of an ontological shift and draws on complex systems and structuration theory (Luhmann and Giddens, respectively) to rethink the ethnographic analysis and to highlight relationships between structural and existential realms of political life. Here, the concept of security becomes central to the theorization, and the overall argument illuminates the intimate relationship between the idea of security and the political. Ultimately, this approach allows us to expand the scope of political ethnography: theorizing beyond thick description; integrating broader perspectives without losing the texture of the local; and developing an approach to research that can be replicated in other settings. political ethnography security complex systems community structuration ontological shift togetherness systems theory border borderlands modern systems theory Luhmann Giddens post-foundational principae naturae ratio status Ukraine Hungary magyar Slovakia Europe Zakarpattia Palágy-Komoróc Kisszelmenc Roms existential contradiction structural contradiction world society International Relations globalization Ungvár Beregszász perspectivism interpretivism post-communism transnational identity citizenship differentiation relation identity-territory security-network irritation global ethnography Roma
57	Waiting for the Cows to Come Home: A Political Ethnography of Security in a Complex World. Explorations in the Magyar Borderlands of Contemporary Ukraine Simonyi, André January 2013 (has links) This dissertation explores the ways in which the everyday (in)securities of people in southwestern Ukraine can illuminate our understanding of contemporary political life. Rather than using traditional units of analysis or given categories—the state, the individual, identity—the dissertation focuses on relations between people in and connected to a single village to develop a novel framework for analyzing politics and the political. The dissertation opens with an interrogation of the practical and theoretical challenges associated with current conceptualizations of security; our understanding of the political; and the role of ethnography in theorization and presents a research design meant to address those challenges. Drawing upon extensive participant-observation and other immersion-based research in a post-Soviet borderland wedged between Ukraine and Slovakia, and using an analytical tool I call “togetherness,” the thesis presents an ethnographic account of social interactions, economy, and authority in this largely Hungarian-speaking rural area. The third part of the dissertation applies the idea of an ontological shift and draws on complex systems and structuration theory (Luhmann and Giddens, respectively) to rethink the ethnographic analysis and to highlight relationships between structural and existential realms of political life. Here, the concept of security becomes central to the theorization, and the overall argument illuminates the intimate relationship between the idea of security and the political. Ultimately, this approach allows us to expand the scope of political ethnography: theorizing beyond thick description; integrating broader perspectives without losing the texture of the local; and developing an approach to research that can be replicated in other settings. political ethnography security complex systems community structuration ontological shift togetherness systems theory border borderlands modern systems theory Luhmann Giddens post-foundational principae naturae ratio status Ukraine Hungary magyar Slovakia Europe Zakarpattia Palágy-Komoróc Kisszelmenc Roms existential contradiction structural contradiction world society International Relations globalization Ungvár Beregszász perspectivism interpretivism post-communism transnational identity citizenship differentiation relation identity-territory security-network irritation global ethnography Roma
58	Development of Sensitive In Vitro Assays to Assess the Ocular Toxicity Potential of Chemicals and Ophthalmic Products McCanna, David January 2009 (has links) The utilization of in vitro tests with a tiered testing strategy for detection of mild ocular irritants can reduce the use of animals for testing, provide mechanistic data on toxic effects, and reduce the uncertainty associated with dose selection for clinical trials. The first section of this thesis describes how in vitro methods can be used to improve the prediction of the toxicity of chemicals and ophthalmic products. The proper utilization of in vitro methods can accurately predict toxic threshold levels and reduce animal use in product development. Sections two, three and four describe the development of new sensitive in vitro methods for predicting ocular toxicity. Maintaining the barrier function of the cornea is critical for the prevention of the penetration of infections microorganisms and irritating chemicals into the eye. Chapter 2 describes the development of a method for assessing the effects of chemicals on tight junctions using a human corneal epithelial and canine kidney epithelial cell line. In Chapter 3 a method that uses a primary organ culture for assessing single instillation and multiple instillation toxic effects is described. The ScanTox system was shown to be an ideal system to monitor the toxic effects over time as multiple readings can be taken of treated bovine lenses using the nondestructive method of assessing for the lens optical quality. Confirmations of toxic effects were made with the utilization of the viability dye alamarBlue. Chapter 4 describes the development of sensitive in vitro assays for detecting ocular toxicity by measuring the effects of chemicals on the mitochondrial integrity of bovine cornea, bovine lens epithelium and corneal epithelial cells, using fluorescent dyes. The goal of this research was to develop an in vitro test battery that can be used to accurately predict the ocular toxicity of new chemicals and ophthalmic formulations. By comparing the toxicity seen in vivo animals and humans with the toxicity response in these new in vitro methods, it was demonstrated that these in vitro methods can be utilized in a tiered testing strategy in the development of new chemicals and ophthalmic formulations. in vitro Alternative Methods alamarBlue rhodamine tight junctions bovine lens viability toxicity mitochondria mitochondria integrity benzalkonium chloride sodium dodecyl sulphate sodium lauryl sulfate scanning electron microscopy Draize Draize maximal average scores zonula occludens cosmetic directive PETA humane society animal league ICCVAM ECVAM JaCVAM BCOP bovine cornea ocular irritants ocular irritation ocular toxicity human corneal epithelial cells vitro confocal confocal microscopy metabolic activity optical quality reactive oxygen species contact lens contact lens care solutions barrier function microbial keratitis mulitipurpose solutions tight junction cell damage claudin ZO-1 occludin MDCK Madin Madin-Darby canine kidney cells cornea human cornea human corneal epithelium epithelial cell line human corneal epithelial cell line sodium fluorescein sodium fluorescein permeability fluorescein permeability ocular surface cell monolayer Araki-Sasaki cell physiology risk assessment safety assessment ScanTox scanning laser lens epithelium corneal cells in vitro model ophthalmic formulations multiple instillation back vertex animal testing rabbit testing alternatives to animal testing cultured bovine lens toxicity of chemicals irritation irritants laser scanner organ culture delayed toxicity toxins hydrogen peroxide cornea toxicity cornea toxicity models prediction of human toxicity no observable adverse effect level lowest observable adverse effect level NOAEL LOAEL toxicity thresholds safety factors cornea uncertainty factors preservatives disinfectants ophthalmic products preclinical preclinical testing epithelial barrier drug penetration clinical confocal microscopy animal rights rabbit cornea human cornea human clinical effects toxic animal rights activist sensitive measures toxic effect toxicity threshold agar overlay agar diffusion agar overlay method agar diffusion method cytochrome cytochrome c apoptosis necrotic apoptotic necrosis caspase rhodamine 123 resazuran resorufin cell death cell viability metabolic dye microsomal microsomal enzymes cytotoxicity cytotoxic cytotoxic effect MTT XTT WST-1 plasma membrane mitochondrial mitochondrial morphology ocular toxicity potential ocular toxicity human corneal epithelial cell line confocal analysis corneal epithelium cell fluorescence alamarBlue assay rhodamine dye animal welfare toxic injury degraded mitochondria epithelial monolayer disinfectants membrane integrity eye toxicity eye viability dye toxicity in humans human toxicity effects on the mitochondria mitochondrial toxicity in vitro battery in vitro test battery ophthalmic eye drop direct contact product safety cytotoxicity potential molecular molecular biology refine reduce replace sensitivity and relevance sensitivity relevance rabbit ocular irritation test product development cytotoxicity models cytotoxicity alternative methods replacements for animal testing three r's beagle tiered testing tiered testing strategy replacements animal testing mechanistic toxicity cornea mitochondria dose response threshold Vision Science and Biology
59	Development of Sensitive In Vitro Assays to Assess the Ocular Toxicity Potential of Chemicals and Ophthalmic Products McCanna, David January 2009 (has links) The utilization of in vitro tests with a tiered testing strategy for detection of mild ocular irritants can reduce the use of animals for testing, provide mechanistic data on toxic effects, and reduce the uncertainty associated with dose selection for clinical trials. The first section of this thesis describes how in vitro methods can be used to improve the prediction of the toxicity of chemicals and ophthalmic products. The proper utilization of in vitro methods can accurately predict toxic threshold levels and reduce animal use in product development. Sections two, three and four describe the development of new sensitive in vitro methods for predicting ocular toxicity. Maintaining the barrier function of the cornea is critical for the prevention of the penetration of infections microorganisms and irritating chemicals into the eye. Chapter 2 describes the development of a method for assessing the effects of chemicals on tight junctions using a human corneal epithelial and canine kidney epithelial cell line. In Chapter 3 a method that uses a primary organ culture for assessing single instillation and multiple instillation toxic effects is described. The ScanTox system was shown to be an ideal system to monitor the toxic effects over time as multiple readings can be taken of treated bovine lenses using the nondestructive method of assessing for the lens optical quality. Confirmations of toxic effects were made with the utilization of the viability dye alamarBlue. Chapter 4 describes the development of sensitive in vitro assays for detecting ocular toxicity by measuring the effects of chemicals on the mitochondrial integrity of bovine cornea, bovine lens epithelium and corneal epithelial cells, using fluorescent dyes. The goal of this research was to develop an in vitro test battery that can be used to accurately predict the ocular toxicity of new chemicals and ophthalmic formulations. By comparing the toxicity seen in vivo animals and humans with the toxicity response in these new in vitro methods, it was demonstrated that these in vitro methods can be utilized in a tiered testing strategy in the development of new chemicals and ophthalmic formulations. in vitro Alternative Methods alamarBlue rhodamine tight junctions bovine lens viability toxicity mitochondria mitochondria integrity benzalkonium chloride sodium dodecyl sulphate sodium lauryl sulfate scanning electron microscopy Draize Draize maximal average scores zonula occludens cosmetic directive PETA humane society animal league ICCVAM ECVAM JaCVAM BCOP bovine cornea ocular irritants ocular irritation ocular toxicity human corneal epithelial cells vitro confocal confocal microscopy metabolic activity optical quality reactive oxygen species contact lens contact lens care solutions barrier function microbial keratitis mulitipurpose solutions tight junction cell damage claudin ZO-1 occludin MDCK Madin Madin-Darby canine kidney cells cornea human cornea human corneal epithelium epithelial cell line human corneal epithelial cell line sodium fluorescein sodium fluorescein permeability fluorescein permeability ocular surface cell monolayer Araki-Sasaki cell physiology risk assessment safety assessment ScanTox scanning laser lens epithelium corneal cells in vitro model ophthalmic formulations multiple instillation back vertex animal testing rabbit testing alternatives to animal testing cultured bovine lens toxicity of chemicals irritation irritants laser scanner organ culture delayed toxicity toxins hydrogen peroxide cornea toxicity cornea toxicity models prediction of human toxicity no observable adverse effect level lowest observable adverse effect level NOAEL LOAEL toxicity thresholds safety factors cornea uncertainty factors preservatives disinfectants ophthalmic products preclinical preclinical testing epithelial barrier drug penetration clinical confocal microscopy animal rights rabbit cornea human cornea human clinical effects toxic animal rights activist sensitive measures toxic effect toxicity threshold agar overlay agar diffusion agar overlay method agar diffusion method cytochrome cytochrome c apoptosis necrotic apoptotic necrosis caspase rhodamine 123 resazuran resorufin cell death cell viability metabolic dye microsomal microsomal enzymes cytotoxicity cytotoxic cytotoxic effect MTT XTT WST-1 plasma membrane mitochondrial mitochondrial morphology ocular toxicity potential ocular toxicity human corneal epithelial cell line confocal analysis corneal epithelium cell fluorescence alamarBlue assay rhodamine dye animal welfare toxic injury degraded mitochondria epithelial monolayer disinfectants membrane integrity eye toxicity eye viability dye toxicity in humans human toxicity effects on the mitochondria mitochondrial toxicity in vitro battery in vitro test battery ophthalmic eye drop direct contact product safety cytotoxicity potential molecular molecular biology refine reduce replace sensitivity and relevance sensitivity relevance rabbit ocular irritation test product development cytotoxicity models cytotoxicity alternative methods replacements for animal testing three r's beagle tiered testing tiered testing strategy replacements animal testing mechanistic toxicity cornea mitochondria dose response threshold Vision Science and Biology

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