These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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However, there are hormonal, kidney related, gastrointestinal and neuromuscular factors among other, that can be involved in the etiopathogenesis of the disease. In the other hand, for osteoporosis prevention there are many lifestyle conditions that are very important, as dietary habits, physical activity, drugs and caffeine intake, smoking, associated diseases, etc. Based on the above, treatment and prevention of osteoporosis have to be addressed in a multidisciplinary and integral approach. \nThe knowledge about bone metabolism and the related disorders represents an extensive field that is currently increasing through many investigations conducted in the world. The purpose of this book is to show several reviews and original investigations related with osteoporosis.",isbn:null,printIsbn:"978-953-51-1066-8",pdfIsbn:"978-953-51-7145-4",doi:"10.5772/50259",price:119,priceEur:129,priceUsd:155,slug:"topics-in-osteoporosis",numberOfPages:290,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"1f49a9a4e5116c7ddf3398cab80470a4",bookSignature:"Margarita Valdes Flores",publishedDate:"May 15th 2013",coverURL:"https://cdn.intechopen.com/books/images_new/3516.jpg",numberOfDownloads:26754,numberOfWosCitations:52,numberOfCrossrefCitations:21,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:62,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:135,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 29th 2012",dateEndSecondStepPublish:"June 19th 2012",dateEndThirdStepPublish:"September 23rd 2012",dateEndFourthStepPublish:"December 22nd 2012",dateEndFifthStepPublish:"January 21st 2013",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"76697",title:"Dr.",name:"Margarita",middleName:null,surname:"Valdés-Flores",slug:"margarita-valdes-flores",fullName:"Margarita Valdés-Flores",profilePictureURL:"https://mts.intechopen.com/storage/users/76697/images/3776_n.jpg",biography:"Dr. Margarita Valdés graduated as M.D. at Autonomous University of Coahuila in 1989; as a Genetic specialist at National Autonomous University of Mexico in 1995, as a M.S. in 1999 and as a Ph.D. in 2002 at the same University. From 1998, she has been working at National Rehabilitation Institute as Genetics specialist and Researcher. She is professor in the Program of Masters and PhD in Medical Sciences and in the Genetics Specialty of Medicine Faculty at National Autonomous University of Mexico. Actually she is member of the National System of Researchers, of the Mexican Academy of Sciences and of the Mexican Academy of Surgery.\r\nBetween her lines of research highlights the investigation of the genetic component of Mexican population in relation to osteoporosis. Most of her published articles are related with this investigations.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"MedStar National Rehabilitation Hospital",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1044",title:"Osteoimmunology",slug:"osteoimmunology"}],chapters:[{id:"44505",title:"Molecular Aspects of Bone Remodeling",doi:"10.5772/54905",slug:"molecular-aspects-of-bone-remodeling",totalDownloads:3779,totalCrossrefCites:7,totalDimensionsCites:21,hasAltmetrics:0,abstract:null,signatures:"Alma Y. 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1. Introduction
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Although numerous medications have been developed for anxiety disorders and related neuropsychiatric conditions including phobias, these diseases still represent a large unmet medical need. This may be because despite the concerted research and drug development efforts by pharmaceutical research companies and academic laboratories alike, the mechanisms of these disorders still remain to be fully elucidated. Animal models have been proposed to accelerate research in this area. The current chapter focuses on a somewhat novel and underutilized laboratory organism, the zebrafish, which may have great utility in anxiety research.
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Zebrafish have been successfully utilized in developmental biology, a discipline that often employs molecular biology and genetic methods. As a result of the past three decades of intensive investigation with zebrafish, this species has become one of the favourite model organisms of geneticists. The accumulated genetic knowledge about, and the genetic methods specifically developed for the zebrafish now make this species particularly attractive for several research fields other than developmental biology. One of these fields is behavioural neuroscience. Indeed, the number of zebrafish publications in the latter field has started to exponentially increase. This may be because zebrafish strikes an optimal compromise between system complexity and practical simplicity. On the one hand it is a complex organism with brain anatomy, neurophysiology, and molecular characteristics (e.g. nucleotide sequence of its genes) highly similar to those of other vertebrates including mammals. On the other hand, it is small, easy and cheap to maintain in the laboratory and has been highly amenable to high-throughput screening (e.g. forward genetic or drug screens). The latter is particularly noteworthy for the purposes of unravelling of the genetic (and in general the biological) mechanisms of complex brain functions and the disorders of these functions. High-throughput screens may have the ability to identify a good proportion of the potentially large number of molecular players involved in these functions.
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The chapter discusses how the zebrafish may be utilized in the modeling of human anxiety disorders and in the analysis of the mechanisms of these disorders. Admittedly, the zebrafish is rather novel in this research and does not have a proven track record. The chapter is focussed on behavioural test paradigms that may have the capacity to induce anxiety related behavioural responses. The chapter argues that the foundation of research into the mechanisms of anxiety disorders is such behavioural paradigms as they will allow the quantification of functional changes in the brain induced by mutations or drugs and thus will facilitate the discovery of underlying mechanisms and drug targets. The chapter also argues that the most successful behavioural test paradigms will be those that represent ethological validity, i.e. consider the species-specific characteristics and the ecology and evolutionary history of the zebrafish. The chapter reviews several such recently developed test paradigms and presents data, for example, on the behavioural effects of the natural and synthetic alarm substances, a chemical that is released from the skin of injured fish, as well as on other test methods that utilize visual stimuli, including computer animated (moving) images of sympatric predators of zebrafish. The chapter also provides a detailed description of the behavioural responses these stimuli induce and makes recommendations for further development of these methods and how they may be employed in forward genetic screening for mutations involved in anxiety related phenotypes. The chapter concludes that, although the zebrafish is rather novel in anxiety research, the increasing number of publications with this species suggests a successful future.
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2. Human anxiety remains a major unmet medical need despite decades of preclinical and clinical research
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First let us define some basic terms. I use “fear” to describe the behaviour or internal state of the subject (human or non-human animal) that is elicited by aversive stimuli that can potentially harm the subject and/or signal such harm or forms of danger. For the sake of simplicity, I define anxiety as an abnormally prolonged, exaggerated, or misdirected form of fear. Please note that these definitions do not assume the presence or the absence of consciousness, awareness, or understanding of fear or of the stimuli that induce it and thus are employed equally to human and non-human animals.
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Human anxiety is one of the most prevalent neuropsychiatric conditions. Approximately 5% of people living in westernized countries will suffer from general anxiety disorder during their life time and, for example, just in the United States as many as 10 million patients suffer from this disease at any given time point (Weisberg, 2009). The numbers are likely larger for other parts of the world and certainly even more staggering if one considers other types of anxiety disorders such as panic disorders, post-traumatic stress disorders (PTSD), phobias, or less severe forms of anxiety (Garakani et al., 2006; Choy et al., 2007; Klein, 1996). Despite decades of research, the quality of life of individuals suffering from anxiety related disorders is still significantly reduced even in patients with mild forms of the disease (for a review see Mendlowicz & Stein, 2000) because the treatment options, including pharmacological approaches, have been limited, variable or ineffective.
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Most agree that the key to the development of appropriate treatment methods is the understanding of the mechanisms of the disease. Unfortunately, the mechanisms of anxiety related disorders have not been fully understood (Matthew et al., 2008). This is not to say that we do not know anything. Clearly a lot of knowledge has been accumulated already. For example, neuroanatomical and neuroimaging studies have confirmed that the amygdala and its reciprocal connections with the prefrontal cortex play a central role (for review see Matthew et al., 2008) but other brain regions, e.g. the periaqueductal gray (Misslin, 2003; Takahashi et al., 2008), have also been implicated in fear responses and anxiety related abnormalities. Progress has been made at levels of investigation other than neuroanatomy too. Numerous neurotransmitter systems, neurochemicals and hormones have been shown to be significantly altered in anxiety disorders (for review see Matthew et al., 2008). For example, the concentration of Corticotropin-Releasing Factor (CRF) has been shown to be elevated in some anxiety disorders, pharmacological blockade of glucocorticoids and noradrenaline has been proposed for trauma-related anxiety, and the glutamatergic system has been implicated in other forms of anxiety (for review see Matthew et al., 2008). The role the serotoninergic system may play in anxiety disorders has also been extensively studied (e.g. Leonardo & Hen, 2006). The involvement of neuropeptides substance P, neuropeptide Y, oxytocin, orexin, and galanin have also been demonstrated in anxiety (e.g. Matthew et al., 2008). While many of the above mechanisms represent potentially good pharmacological targets allowing the eventual development of drug therapies, the complexity of these disorders and the limited understanding of the mechanisms behind them warrants further detailed inquiries into the neurobiology of the disease.
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3. Laboratory animals: Efficient tools of discovery
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Numerous human neuropsychiatric disorder have been successfully modelled or some of the mechanisms underlying these diseases investigated using laboratory animals (Flint & Shifman, 2008). Anxiety disorders are no exception to this (see e.g. Hohoff, 2009). This is not surprising given that at every level of biological organization, i.e. from behavioural traits to the nucleotide sequence of genes, evolutionary conservation of features has been repeatedly demonstrated. This is of course not to say that there are no species specific characteristics. But if one is interested in the fundamentally important questions, evolutionary conservation allows the experimenter to efficiently utilize model organisms especially if the laboratory species is closely related to human. Most anxiety related studies have been conducted with rats, a mammalian species that shows high DNA nucleotide sequence homologies to human. The interest in this species therefore is not surprising. For example, a medline (PubMed) literature search with keywords “anxiety” and “rat” returns close to 8 thousand publications. Another model organism, the house mouse, which is perhaps even more frequently used in biomedical research, is also well utilized in anxiety research. A medline search with this species also reveals close to 5 thousand published studies. In addition to the rodents utilized in the laboratory, other model organisms, including the dog (almost 5 hundred publications) or non-human primates (62 publications) have also been employed in the analysis of anxiety. Even such evolutionarily distant species to us as the fruit fly (Drosophila melanogaster) has been proposed as a research tool for the understanding of the mechanisms of human anxiety (Iliadi, 2009). The rich literature on anxiety research clearly demonstrates the major effort to utilize model organisms for the analysis and/or modeling of human anxiety.
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There are two principal reasons why one would like to use model organisms for the analysis of human disorders. First, is a practical consideration: laboratory organisms represent a compromise. These species can be kept and analyzed more cheaply than humans and they face fewer ethical roadblocks. Second, as argued above the evolutionary relatedness of laboratory organisms to us means that there may be numerous functional, e.g., neurobiological, physiological, biochemical and genetic homologies that the researcher can utilize in her/his quest for the understanding of the mechanisms of human anxiety (for examples see review by Denver (2009).
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4. Naturalistic (ethological) approaches should be employed when the question concerns the biological mechanisms of behaviour
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Many successful lines of investigation into the mechanisms of a broad range of behaviours have (e.g. Gerlai et al., 1999; Lu et al., 1997; Grant et al., 1992; Silva et al., 1992) utilized behavioural, electrophysiological, neuroanatomical and molecular genetics methods to investigate the mechanisms of brain function and how such mechanisms lead to the behavioral output. But when it comes to the method or approach of behavioural experimentation some controversies may need to be cleared. There may be many ways one can study animal and human behaviour. In the past and especially in North America classical psychologists argued that one has to be nature blind and ignore the unique species specific features of different organisms. This is the only way, went the argument, one could study the common, and thus most important, features of the phenomenon under investigation. This tenet led to an important controversy as to how to measure behaviour (Gerlai, 2001). It has been pointed out that, while not necessarily mutually exclusive, two fundamentally distinct approaches emerged, classical psychology and ethology. The classical psychology approach has emphasized the analysis of species invariant features that cut across multiple species, i.e. allow generalization of findings. The argument was that analysis of species independent features is expected to lead to easier translation from animal to human. On the other hand, the ethological approach has put more weight on naturalistic studies sensitive to species-specific features and the evolutionary and ecological relevance of the methods employed. Many, including I too, have argued that the ethological approach is more appropriate especially when one is interested in the question of biological mechanisms of behaviour (Crusio & Abeelen, 1986; Csányi & Gerlai, 1988; Gerlai & Clayton, 1999; Blanchard et al., 2003). There are two main reasons why this argument is made. One, alleles of genes that influence any trait under investigation have been selected by natural selection and the influence they exert on the phenotype is the result of evolution, the phylogenetic argument (Crusio, 1995). Two, analysis of the mechanisms underlying the phenotypical characteristics can only be conducted appropriately if the characteristics are not artificial constructs but are defined in a biologically meaningful manner. Although the question of what is biologically meaningful is not always easy to answer, in case of behaviour, the above argument translates to choosing methods that allow the quantification of natural, species-specific, responses that are the product of the studied organism and not of the experimenter’s subjective bias, the phenogenetic argument (Crusio, 1995). Briefly, one needs to design his/her experiments according to the natural behaviour of the studied species. Notably, results of nature-blind experiments may not be easier to generalize to the human clinic. As I put it previously, “offering a sizeable financial reward to a rat and giving tasty rat chow to humans might not represent ‘rigorous laboratory control\' of motivation: ignoring species-specific characteristics can lead to less obvious, but similar, mistakes in behavioural research” (\n\t\t\t\t\tGerlai & Clayton, 1999b).
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5. Antipredatory behaviour: An ethologically relevant method to study anxiety
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Naturalistic approaches thus may have an important place in research whose ultimate goal is to understand the biological mechanisms of abnormal fear responses in vertebrates including our own species (for discussion specific to fear/anxiety see Lister, 1990; Blanchard et al., 2003; Rosen et al., 2008; Gerlai et al., 2009). But behavioral analysis is often deceptively simple (Gerlai, 2001) and this is especially true for anxiety paradigms (Bouwknecht & Paylor, 2008). It is therefore important to consider what approach, behavioral method, has the highest possibility for success. Classical laboratory rodents including the rat and the mouse have been successfully employed in anxiety research using antipredatory paradigms (e.g. Hendrie et al., 1996). In these tests the subject is exposed to stimuli specific to its natural predator, and the species-typical antipredatory responses of the subject (e.g. freezing) are quantified. Rosen et al. (2008), for example, use trimethylthiazoline, a chemical that is present in the fox’s urine and is known to be effective for rodents. Barros et al. (2008), who studied the marmoset, used a cat (a taxidermied wild oncilla cat, the natural predator of the marmoset) as a predator stimulus. Apfelbach et al. (2005) review a large variety of predator odors and their fear inducing effects in different prey species, including cat odor induced antipredatory responses in the rat. Others have utilized eye spots or eye like structures placed on objects mimicking the appearance of predators, an approach that has been effective in a variety of species including rodents, birds and fish (e.g. Gerlai et al., 2000; Miklosi et al., 1997 and references therein). The argument for using ethologically relevant stimuli and measuring species-specific responses in laboratory model organisms is principally based upon the notion that human anxiety disorders are likely to develop as a result of abnormal functioning of neurobiological mechanisms (brain areas, circuits and/or molecular mechanisms) that have evolved to subserve avoidance of predators or other harmful or dangerous agents in nature during our evolutionary past. Given that our species shares its evolutionary past with those of others this approach may have translational relevance. For example, Denver (2009) reviews the structural and functional evolution of vertebrate neuroendocrine stress systems and explains that “Recent findings suggest that the proteins, gene structures, and signaling pathways of the HPA [hypothalamus-pituitary-adrenal] axis were present in the earliest vertebrates and have been maintained by natural selection owing to their critical adaptive roles”. This author also concludes that numerous neurotransmitters and neuromodulators influencing stress-related behaviors, such as anxiety and fear, are evolutionarily conserved. Others also argue that the basic neuronal mechanisms are shared across mammalian species, and, for example, the same set of genes may regulate critical aspects of anxiety in humans and in lower species (e.g. Hovatta and Barlow, 2008). Briefly, the translational relevance of fear/anxiety paradigms is expected to be high as long as the mechanisms that evolved in the brain to subserve these behaviors are properly engaged by the experimental set up.
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6. Zebrafish in the analysis of fear and anxiety
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As outlined above there have been a large number of studies devoted to the analysis of the biological mechanisms of anxiety and a considerable amount of effort has been invested in the development of pharmacological treatments of anxiety related disorders For preclinical research most of these studies used rodents. As we have accumulated a large amount of data on these rodent species, it may be logical to think that building upon this excellent foundation may be the only way to proceed. In the subsequent pages, however, I will try to persuade the reader that although abandonment of rodent research is certainly not to be recommended, utilization of another vertebrate, the zebrafish may be a good idea.
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6.1. Practical simplicity meets system complexity: zebrafish as an optimal compromise for research
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A commonplace in research known to many scientists is shown by the following equation: C = E x T, where E is a measure of the ease of use of a research species in the laboratory, T is the translational relevance of this species, and C is a constant. In other words, the more translationally relevant a species is for human, the less easy it is to use in the lab, and vica versa. Importantly, however, C, as defined above, may not be a universal constant: for some species C may be higher than for others. I argue that zebrafish represents an optimal compromise between practical simplicity and system complexity, i.e. its C is large. It is a small (4 cm long) freshwater fish which is easy to maintain and breed in the laboratory. Due to its highly social nature (shoaling) and its small size, a large number of zebrafish can be housed in small fish tanks. A single female may lay 2-300 eggs at every spawning and may spawn 2-3 times a week. Briefly, a large number of experimental subjects can be obtained quickly and utilized for research in a cost effective manner. These features make the zebrafish particularly appropriate for high-throughput screening applications including forward genetic mutagenesis screens or large scale drug (pharmacological compound) screens. But there are other important features of zebrafish one needs to consider for translational research.
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Notably, zebrafish possess high nucleotide sequence homology (60-80%) with that of human genes. Importantly, this sequence homology is functionally relevant as the amino acid sequence of zebrafish proteins (60-90% sequence homology) especially at the functionally relevant catalytic or ligand binding domains of the proteins (approaching 100% sequence homology), has been found highly similar between zebrafish and human (Renier et al., 2007; Reimers et al., 2004), which demonstrates evolutionary conservation of function and allows one to use this relatively distantly related species for translational research. It is notable that evolutionary conservation, i.e. functional and structural homologies, do not end at the nucleotide or amino acid sequence levels, but have been demonstrated at numerous other levels of the biological organization of zebrafish, including, for example, its neurotransmitter systems (Mueller et al., 2004; Panula et al., 2006; also see Chatterjee & Gerlai, 2009\n\t\t\t\t\t; Gerlai et al., 2009) and its neuroendocrine responses to stress (Alsop & Vijayan, 2008). Conservation of function (at the gene expression level) has been found in zebrafish even in such responses as neuro-adaptation to drugs of abuse (Kily et al., 2008). Therefore I and others (Shin & Fishman, 2002) have argued that the zebrafish is an appropriate model organism for the analysis of a range of human diseases.
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6.2. Genetics: the strength of zebrafish
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A strength of zebrafish as a research tool is that by now an arsenal of genetic tools have been developed for this species and the amount of information on the zebrafish genome has also become substantial. For example, a large number of genetic markers crucial for the localization and identification of randomly induced mutations have been established. These include rapid amplification of polymorphic DNA (RAPD) and amplified fragment length polymorphisms (AFLP) (Donovan et al., 2000; Guo et al., 2000; Zhang et al., 1998), polymorphic microsatellite markers and radiation hybrid maps with microsatellite markers and expressed sequence tags (ESTs) (Geisler et al., 1999) as well as single nucleotide polymorphisms (SNPs) (Stickney et al., 2002). The latter study also utilized oligonucleotide microarrays, the gene chip technology that is rapidly spreading in zebrafish research (Sipe & Saha, 2007). A viral infection-based mutagenesis technique has been established for the generation of insertional mutations that could be rapidly cloned due to the presence of the viral tag in the genome (Amsterdam et al., 1999). An entire company was formed to use this methodology and by now a large library of mutants has been generated (see e.g. http://www.znomics.com/; also see Wang et al., 2007). A gene-breaking transposon-based method to generate mutations has also been developed for zebrafish (Sivasubbu et al., 2006). In addition to forward genetic approaches, reverse genetic methods have been implemented. Morpholino antisense knockdown allows the inactivation of known genes in embryos (Nasevicius & Ekker, 2000; also see Bill et al. 2009 for more recent review). Targeted-induced local lesions in genomes (TILLING) has been successfully adapted to zebrafish (Wienholds et al., 2002). Targeted gene disruption has also been achieved with the use of zinc-finger nucleases (Doyon et al., 2008). More recently, a Gal4/Upstream Activating Sequence approach has been employed for the flexible deployment of transgenes in the analysis of expression patterns of target genes (Scott, 2009), and a transposon-based genetic approach has been proposed for zebrafish (Ni et al., 2009). Importantly, all these tools and pieces of information are in the public domain (e.g., GenBank, Sanger Center website, and ZFIN, see Sprague et al., 2001). Briefly, the zebrafish has become one of the most preferred laboratory animal species of geneticists.
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6.3. Behaviour: The weakness of zebrafish
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An important drawback one has to face when using zebrafish is that the behaviour of this species is not well characterized. This is not to say that there are no behavioural studies on zebrafish or that these behavioural studies are unimportant or inappropriate. On the contrary, there is an increasing number of behavioural neuroscience studies published on zebrafish. Nevertheless, compared to classical laboratory study species such as the rat, mouse, or even the fruit fly zebrafish behavioural research is in its infancy, the number of studies, and with it the amount of information on the behaviour of this species is orders of magnitude less than what is available for classical laboratory model organisms (Sison et al., 2006). Without proper behavioural tests, and without thorough understanding of the behavioural features of zebrafish, it is not possible to utilize behavioural phenotyping of mutation or drug effects, and how these manipulations may influence brain function becomes difficult to investigate (Gerlai 2002). Briefly, behavioural analysis is s a major bottleneck in zebrafish research. A simple literature search in Medline with the keyword “behavior” and “rat” reveals over 100 thousand papers, and another with keywords “behavior” and “mouse” returns about 50 thousand papers. But even for the fruit fly one finds about 5 thousand publications in this area of investigation while for zebrafish this number is less than 100. Although this number is indeed orders of magnitude less than the above, it is notable that the majority of these zebrafish publications were published only recently demonstrating a clear upsurge of interest in this species. It appears that, behavioural brain research and behaviour genetics have discovered the utility of zebrafish. Perhaps one of the best studied of the behaviour of zebrafish is their fear responses. Below I briefly discuss what we know about zebrafish fear and its quantification with an emphasis on how screening applications may be developed and utilized.
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6.4. Induction of fear in zebrafish using ecologically relevant stimuli: The effect of the natural alarm substance
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Predator-prey encounters have not been documented for zebrafish in nature but numerous piscivores have been found to inhabit the slowly moving creeks and small lakes of India and Nepal where zebrafish have been found (Engeszer et al., 2007). The zebrafish belongs to the Osterophisan superorder of fishes, and numerous species of this superorder have been demonstrated to respond to alarm substances, natural “pheromones” first described by von Frisch (1938; 1941). These substances are released from epidermal club cells of the fish upon infury of the skin (e.g. Pfeiffer, 1972). The zebrafish was known to respond to its natural alarm substance (Schutz, 1956; Pfeiffer, 1963) and later a number of other fish species were also found to exhibit such a response (for a review see Pfeiffer, 1977). The range of behavioural reactions exhibited by fish in response to the alarm substance was also described in a detailed manner (Pfeiffer, 1977) and it was concluded that these responses may significantly differ from species to species but may include “A) fish swimming excitedly with their heads against the bottom and with their bodies at an angle of about 60o to the floor; B) becoming motionless and showing no movement for several minutes; C) sinking to the bottom and spitting gas for a considerable time; D) fleeing to the surface when they are alarmed, crowding together there and swimming hastily, frequently jumping out of the water; or E) fleeing towards the depth where they form a dense school”. Waldman (1982) analyzed the effect of alarm substance on shoaling as well as the position of zebrafish in the vertical column of the water and found that it induces fish staying closer to each other and closer to the bottom tank he used. Waldman also described his personal observation regarding a potential developmental trajectory of the alarm substance induced behavioural reactions and theorized that zebrafish may only start exhibiting the alarm reaction after their age of 50 days post-hatching. Pfeiffer and Waldman had no access to technologically advanced video-recording and analysis methods such as tracking systems, thus many of their observations may only be regarded as working hypotheses. By now the technology allows us to precisely track the location as well as movement pattern of fish (see e.g. Blaser & Gerlai, 2006; Miller & Gerlai, 2007; 2008), which has enabled us to confirm many of the intuitions of the above authors. Furthermore, these behaviour quantification methods now allow automated measuring of behaviour, a prerequisite for high-throughput screening.
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Another important factor one has to discuss is the origin of the fish used in the behavioural studies. In the early studies with the alarm substance, the zebrafish studied were purchased from local pet-stores and thus numerous factors potentially influencing the behaviour of the experimental fish could not be controlled. For example, the age, potential exposure to other fish species, housing density, type and amount of food prior to experimentation, temperature and water chemistry were all among the environmental conditioned that remained uncontrolled prior to arrival of the fish to the laboratory. The first paper in which the effect of alarm substabce was analyzed with all these factors rigorously monitored and experimentally controlled was conducted by Speedie & Gerlai (2008). This study confirmed that zebrafish not previously exposed to any predatory, harmful, or aversive stimuli would still show a robust alarm reaction to the natural alarm substance, i.e. the alarm response to the substance is innate and represents a genetic predisposition. Speedie & Gerlai (2008) found a significant increase of shoal cohesion, i.e. a decrease of distance between members of the zebrafish group being tested in response to administration of the alarm substance. These authors also found the duration and the number of episodes of erratic movement (zig-zagging) to increase. Freezing (complete immobility) and bottom dwell time also appeared to increase as a result of exposure to the substance. Notably, the alarm substance induced behavioural changes were observed independently of whether the experimental zebrafish were or were not exposed to a live predator during the experiment. In other words, the alarm substance alone could elicit the full repertoire of alarm reactions (Speedie & Gerlai, 2008).
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In summary, the induction of fear responses in zebrafish was found possible under controlled laboratory conditions. This is an important step foreward but the difficulty with the studies employing the natural alarm substance has been that the exact concentration of the substance cannot be determined. The dose response analysis in the above cited zebrafish studies was based upon relative doses only, i.e. the experimenters utilized a dilution sequence but could not really ascertain what and how much was in the starting solution. This may not be an important issue as long as the relative doses are compared WITHIN a study. The absolute amount of alarm substance to be extracted from the skin of zebrafish almost certainly varied from study to study no matter how precisely the extraction protocol was followed and thus comparison of effects BETWEEN experiments was impossible to make. Without establishing the exact chemical identity of the alarm substance and without precisely measuring its concentration it was impossible to establish identical doses across different studies. This is a major issue for large scale behavioural screens.
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6.5. H3NO, the synthetic alarm substance
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The above problem was successfully addressed recently (Parra et al., 2009): a synthetic alarm substance was found just as effective in inducing fear in zebrafish as the natural alarm substance. Alarm substances of the Osteriophysan superorder of fishes were identified from numerous species in the past (Pfeiffer, 1977; Pfeiffer et al., 1985). A common chemical structure shared across these multiple species was found (Kelly et al., 2006; Brown et al., 2000; 2003). Based upon this discovery, a compound mimicking this common chemical element was synthesized. The compound is called hypoxanthine 3-N-oxide, or H3NO, a purine derivative oxidized at the 3-position. Hypoxanthine 3-N-oxide has now been shown to induce alarm responses in numerous fish species including the ones that belong to the Osteriophysan superorder (Pfeiffer, 1977; Pfeiffer et al., 1985; Brown et al., 2003; 2002; 2001; 2000). Zebrafish also belong to this superorder and thus it was hoped that this species too would respond to the synthetic alarm substance with species specific alarm reactions. This is what Parra et al. (2009) have now demonstrated. Their findings are not surprising from an evolutionary stand point. If a prey species is too selective about the taxonomic origin of the odour cue that signals danger, members of such a species would be in a disadvantage as they would not be able to recognize imminent danger, the presence of a hunting predator. It should really not matter what prey species the predator catches, and thus being selective about the alarm cue would be an evolutionary failure. Indeed as Parra et al. (2009) found, the synthetic alarm substance did induce a full fledged alarm reaction in zebrafish. These reactions included erratic movements and jumps, typically observed in response to the natural alarm substance. Thus, now we have a compound whose concentration can be precisely determined and thus its alarm inducing effects are no longer dependent upon the method of alarm substance extraction. Briefly, now we can expect high replicability across laboratories or across different independent experiments or across a large number of experimental subjects, prerequisites for high throughput screening.
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6.6. Visual cues as fear inducing stimuli: The sight of the sympatric predator
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It is important to realize that although the use of alarm substance in anxiety research is highly promising, the utility of olfactory cues such as this may be limited, or at least complicated from a practical standpoint. For example, although such an olfactory cue is clearly ethologically relevant and induces robust and species specific fear responses, odour cues are not easy to control in terms of the timing of their delivery, their removal, and their spatial localization. Briefly, its hard to precisely control when and where they are perceived. For example, although one may think the precise delivery time is easy to establish, it must be noted that it may take time for the substance to diffuse well enough to reach the target subject. It is also notable that removal of such an odour cue is also complicated. For example, residual odour cues left behind from a prior session may influence the behaviour of subsequent subjects. Cleaning the test tanks is labour intensive, and one may not be entirely certain whether the cleaning indeed removed all cues. Ascertaining that the substance used remains active also requires some attention. For example, in our hand even when stored in dry powder format at -20º C, H3NO did deteriorate over a period of several months. Also, as explained above, the on-set and offset of the administration of the odour cue is not precise and for example, multiple on and off time periods are next to impossible to accomplish. Therefore it is likely that cues of other modalities, particularly visual cues, may hold better practical utility (Bass & Gerlai, 2008).
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Sympatric predators may induce alarm responses as prey species that coinhabit and thus co-evolved with them may have developed genetic predisposition to innately “recognize” such predators. This was, for example, shown with another fish species, paradise fish (Macropodus opercularis), which was found to respond both to the sight and the smell of the snakehead fish (Chana) without any prior exposure to this predatory fish (Gerlai, 1993). Paradise fish were also found to exhibit some flexibility and learn to associate otherwise harmless visual stimuli with aversive stimuli (pain or predators), a response that was dependent upon genetic factors (Miklosi et al., 1997 and references therein). These results suggest that innate predator recognition and plastic learning-based antipredatory responses are not mutually exclusive features. Zebrafish have also been found to exhibit learning based alarm reactions (Hall & Suboski, 1995) and more recently they were also shown to respond to their sympatric predator without prior learning (Bass & Gerlai, 2008). The latter authors found zebrafish to exhibit elevated number of jumps in response to the sight of the Indian leaf fish (Nandus nandus), a sympatric predator that lives in the same geographical region where zebrafish are found. Importantly, the antipredatory response was elicited by the Indian leaf fish the very first time the experimental subjects were presented with it, demonstrating the lack of need to learn. Also importantly, when zebrafish were exposed to an allopatric predator or to non-predatory fish species, they did not exhibit the antipredatory reactions, which demonstrates that the Indian leaf fish induced responses were indeed specific to this sympatric predator. It is also notable that the Indian leaf fish was not presented in the same water where the experimental zebrafish were swimming, that is the predatory fish was physically isolated from the zebrafish subjects (Bass & Gerlai, 2008). Thus, the only modality the experimental zebrafish could utilize was visual. Admittedly predator-prey interaction between the Indian leaf fish and zebrafish has not been observed in nature (Engeszer et al., 2007). Nevertheless, the above results imply that the zebrafish may have a genetic predisposition to be sensitive to the visual cues that characterize its sympatric predators. From a practical perspective this is great news for the experimenter. Visual cues are easy to control and thus perhaps high throughput behavioural screening may be more feasible using such cues. In the above studies, however, live stimulus fish were presented. This poses a problem. The live predatory fish may change its behaviour from trial to trial. That is, consistent stimulus presentation across multiple experimental zebrafish subjects is difficult to ascertain. This may be a crucial issue for high throughput screening where thousands of zebrafish may need top be tested in a consistent and highly controlled manner before a behavioural outlier, presumably a mutant, may be identified. One way to address the issue of experimental control and consistent stimulus delivery is to walk away from the presentation of live stimulus fish and use instead computerized images. Could the image of a sympatric predator induce alarm reactions?
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6.7. The computerized predator: Animated image to induce fear
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To answer the above question, Gerlai et al. (2009) experimented with using computerized image presentation to induce fear responses in zebrafish. The authors presented animated (moving) images of the Indian leaf fish to zebrafish and demonstrated that this stimulus elicited erratic movement and jumping from zebrafish, behaviours that were found to be also induced by the alarm substance or by the live Indian leaf fish. At this point it is not known what feature(s) of the computerized image induced the fear responses. In other words, we do not know what makes a good predator for zebrafish. Possible visual properties of the predator zebrafish may respond to include color and pattern (brown patches and markings on a silver background), size (about 10-12 cm long), body proportions (relatively large head and mouth), and/or movement pattern (slow or stationary ambush predator) or any combination of these features. It is possible that when certain key features of a sympatric predator are exaggerated one could induce a further elevated fear response in zebrafish. And clearly, many parameters of the fear paradigm may need to be optimized. Since the publication of the Gerlai et al. (2009) paper, we have already completed another study in which all we did was to lengthen the test tank. The slight change in the dimension of the test apparatus resulted in a robust behavioural change in the zebrafish. In this apparatus, the image of the Indian leaf fish now induced a robust avoidance reaction (increased distance from the image) as well as an increased bottom dwell time. This is noteworthy for two reasons. One concerns the different strategies prey may engage in under specific circumstances. When the prey is within striking distance from the appearing predator swimming away may not be an optimal antipredatory response. Thus in a small test tank other behaviours may be seen, which in our case included erratic movement and jumping. However, if a larger (longer) tank is used, the natural behavioural response of zebrafish to the approaching predator is escape, i.e. increase of the distance between the predator and the prey presumably because this larger tank placed the zebrafish subject outside of the striking distance of the (image of the) predator. The second point concerns the practical aspect of this finding. Measuring distance is much easier and can be better automated than measuring a complex motor pattern like erratic movement. Thus, the longer tank offers the ability to automate the behavioural test. But other modifications beyond changing the dimensions of the tank may also enhance its ability to induce and record fear responses. For example, freezing may be more robustly induced if the tank provides hiding places (e.g. artificial plants). Again, quantification of immobility is achievable using video-tracking systems and thus this behaviour, similarly to measuring distance, can be precisely quantified using automated methods. In summary, the computerized presentation of visual cues have already been shown to induce robust fear and the induced fear responses have been shown to be quantifiable using also computerized video-tracking methods. Thus, the fear paradigm presented above is fully automatable and is ready for high throughput screening of mutations or compounds that alter such fear responses.
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6.8. Automation is the key for high throughput screening
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As explained above, automated stimulus delivery and automated quantification of behaviour are the two important components of high throughput behavioural tests because such automation allows one to run the tests in parallel, i.e. scale up. In this section I explore further the question of automation. Undoubtedly, so far the most sophisticated pattern detection device has been the human brain: the experimenter can identify complex motor and posture patterns as he/she observes the behaving fish (e.g. \n\t\t\t\t\t\tGerlai & Csányi, 1990\n\t\t\t\t\t). This is what classical ethologists have been advocating for decades: observe your subject and measure the elements of the ethogram, i.e. how much time the animal spends doing certain things and how often these things (behaviours) occur. A notable drawback of this method, however, is that it is painstakingly slow and extremely labour intensive. The experimenter has to watch video-recordings and key in his/her observations. This is definitely not high throughput! Observation-based behaviour analysis thus have no place in large scale screens. But this method does have merits and certainly makes sense at the earliest phases of characterization of behavioural responses. This is because it allows one to obtain highly detailed information about animal behaviour and perhaps unexpected changes in the behaviour. But once this preliminary idea-generating pilot work is complete and once the experimenter established how the animal responds in the given behavioural task the next step must be to develop automated behaviour quantification techniques. As we have seen, automated induction and quantification of fear responses is already a reality for zebrafish research.
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Numerous commercially produced video-tracking systems are available for the researcher and the utility of video-tracking as compared to other behavioural quantification methods has already been systematically analyzed specifically for zebrafish (e.g. Blaser & Gerlai, 2006). But other automated behaviour measuring methods including the force transducer method may also be considered (e.g. Fitch et al. (2002) that allow automated quantification of behaviour. Some commercially available force transducer based methods are claimed to be able to detect particular “force-prints” that correspond to specific motor and posture patterns. If indeed these force prints correspond to motor patterns, the force transducer method could in principle replace the labour intensive observation-based method of ethologists. For aquatic organisms, however, force transducer-based detection is inappropriate because in the water environment the test subject will not generate acceleration forces detectable by the system. Video-image or video-tracking analysis systems have not been successfully employed in motor pattern quantification, although the claim has been made that they are capable of doing so at least for the house mouse (for a review see e.g. Gerlai, 2002). Despite the infrequent use of zebrafish in behavioural studies, we already have evidence showing that videotracking-based automated quantification of fear responses of zebrafish can reveal significant changes in complex motor patterns (Gerlai et al., 2009). For example, reduced swimming speed, increased within individual temporal variability of swimming speed, increased turn angle and increased within individual temporal variability of turn angle upon presentation of the predator image correlated well with certain complex motor patterns, such as erratic movement and jumping, one would expect to be able to quantify only using observation based methods. The close correlation between the above video-tracking and observation based parameters is not surprising: erratic movement is associated with rapid changes in the direction and speed of swimming, i.e. increased variability of swim speed and increased turn angle and increased variability of turn angle. Similarly, jumping is a rapid and transient increase of swim speed which is expected to translate to increased swim speed variability. In summary, quantification of fear responses has already been automated using videotracking so has the induction of fear responses thus, as we already argued above, a high-throughput fear paradigm is now available for zebrafish (Gerlai et al., 2009).
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6.9. Light vs. dark, novel vs. familiar places: Other methods to measure fear responses
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There may be several ways one can induce and study the effect of fear. Novelty has long been known to induce fear responses in a variety of species including humans. For example, the open field task has been extensively used with rodents (e.g. Prut & Belzung, 2003; Crusio & Abeelen, 1984) or other animals including fish (Egan et al., 2009; Csányi & Gerlai, 1988). In this task, the subject is exposed to an unfamiliar environment. The response to this novel environment is believed to arise as a result of a compromise between opposing forces or tendencies: exploration, which is believed to be associated with active responses, and fear, which is often associated with passive responses. Exploratory activity is considered adaptive as it may lead to finding food, mates and escape routes, for example, while passive fear induced responses (immobility) is argued to reduce predation risk (Crusio & Abeelen, 1986). The adaptive aspect of these responses may seem speculative but quantitative genetic analyses did confirm ambidirectional selection force underlying open field behaviour. That is, in the evolutionary past of the house mouse individuals that performed at intermediate levels (not too active but not too passive either) had been favoured (Crusio & Abeelen, 1986), a finding that extends to other vertebrates including fish (\n\t\t\t\t\t\tGerlai et al., 1990\n\t\t\t\t\t). It is likely that the evolutionary past of zebrafish is similar and this species too has been under ambidirectional selection as far as novelty induced behavioural responses are concerned. Therefore, exposing this fish to a novel environment is expected to induce moderate levels of fear reactions. Importantly, behavioural experimentation always includes at least some level of handling of animals by humans, which is also expected to induce fear.
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Novelty induced fear responses have been analyzed in zebrafish by Levin et al. (2007) who showed an initially low level of exploratory activity of zebrafish that gradually increased with time. These authors also described a “diving” response, i.e. increased amount of time spent on the bottom of the test tank, a response that slowly habituated as the fish got accustomed to their novel environment. Egan et al. (2009) also reported similar findings. Levin et al. (2007) showed nicotine had anxiolytic properties as this drug reduced novelty induced fear responses. In addition to novelty, different levels of illumination have also been explored to induce and test fear responses.
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The light-dark preference paradigm has been often utilized especially with rodents (e.g. Hascöett et al., 2001; Belzung & Griebel, 2001), but more recently with zebrafish too (see below). The assumption underlying this paradigm is that the nocturnal rodent is expected to prefer, i.e. hide in dark places and avoid well illuminated areas. The evolutionary, i.e. adaptive significance of this behaviour is believed to be associated with predator avoidance. A well illuminated rodent can be easily picked up by an aerial or terrestrial predator. Whether zebrafish prefer well illuminated or dark places, has been somewhat controversial in the literature. The starting assumption was that as a result of the zebrafish being diurnal, active during the day and sleeping during the dark phase of the photoperiod, this species should prefer well illuminated areas where it can visually detect approaching predators more easily. And indeed, this was exactly what was found in a light dark preference task: zebrafish avoided the dark compartment and preferred a well illuminated compartment of a two compartment shuttle box (Gerlai et al., 2000). However, Serra et al. (1999) showed that zebrafish prefer areas of the test environment with a dark background. The difference in the results of these two studies is not easy to explain but may be due to numerous methodological differences. For example, Serra et al (1999) used a dark background but the compartment was well illuminated. Whereas Gerlai et al. (2000) used a dark compartment that was truly dark as it was covered on all sides and the top. One may argue that a dark background, however well illuminated it may be, allows zebrafish to camouflage well (zebrafish has a dark olive-brown back), but a dark cave may harbour predators that remain undetectable for the diurnal zebrafish that uses vision as one of its primary senses.
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6.10. Pharmacological analysis of fear responses of zebrafish: The first pioneering studies
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Many pharmaceutical research companies have been searching for anxiolytic compounds. This is despite that there are numerous prescription medications already available for anxiety and related disorders. The reason for the continued search for better drugs is that we do not really have a complete understanding of how anxiety develops and what biological mechanisms may underlie this disease cluster. The other reason is that the currently available, however numerous, drugs are often not efficacious or do not work for all patients. Briefly, there is still a large unmet medical need for anxiety related disorders. One way zebrafish may be beneficial for such research is to speed up discovery of the biological mechanisms. This may be achieved using, for example forward genetic screens that identify mutations leading to the isolation of underlying genes. Another completely different approach has been to search for compounds, small molecules as they are called in pharmaceutical research jargon, which may alter fear responses. It is thus important to consider what is known about the psychopharmacological properties of zebrafish in the context of fear and anxiety. For example, could one detect the efficacy of known anxiolytic drugs using zebrafish. That is does the zebrafish model have predictive validity. Predictive validity is an important question for the use of novel model organisms. The main point with regard to the translational relevance of laboratory model organisms concerns the notion “evolutionary of homology”, i.e. conservation of biological function across previously utilized species (e.g. rodents), the novel laboratory species (e.g. zebrafish), and humans. Admittedly, zebrafish have been used very infrequently in psychopharmacological analyses. Nevertheless, the few studies that have been completed suggest a possibly bright future for drug development with the use of zebrafish.
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Alcohol (ethanol, ethyl alcohol or EtOH) is one of the best studied drugs in zebrafish research. For example, the effect of developmental alcohol exposure was shown to be strain dependent (Loucks & Carvan, 2004), early embryonic alcohol exposure were found to exert significant behavioural effects in the adult (Fernandes & Gerlai, 2009\n\t\t\t\t\t), adaptation (tolerance) after chronic alcohol exposure as well as alcohol withdrawal induced behavioural responses were all demonstrated (Gerlai et al., 2009; 2006), and numerous changes induced by acute alcohol administration have also been revealed (Gerlai et al., 2000). Importantly, alcohol has both anxiolytic (for the effects of lower doses of alcohol in zebrafish see Gerlai et al., 2000, also see Egan et al., 2009) as well as anxiogenic properties (for the effects of prolonged exposure to alcohol and during withdrawal in zebrafish see Gerlai et al., 2009, also see Egan et al., 2009) depending on concentration and mode or regime of its administration. Other drugs of abuse have also been shown to exert significant behavioural effects in zebrafish. For example, the rewarding properties of cocaine have been shown and mutants with altered cocaine reinforced place preference have already been identified in forward genetic screens (Darland & Dowling, 2001). The reinforcing properties of drugs of abuse have also been analyzed (Ninkovic & Bally-Cuif, 2006). Drugs of abuse, similarly to alcohol, often have anxiety altering properties again depending on concentration and dosing regimen employed. For example, a cocaine withdrawal induces anxiety responses in zebarfish (Lopez-Patino et al., 2008). Some classical anti-anxiety drugs have also been tested using zebrafish, e.g. α-fluromethylhistidine exhibited an anxiolytic profile (Peitsaro et al., 2003), diazepam reversed cocaine withdrawal induced anxiety, and the benzodiazepine inverse agonist FG-7142 induced anxiety in zebrafish (Lopez-Patino et al., 2008). Also, acute administration of caffeine, known to induce anxiety in humans (e.g. Childs et al., 2008) and rodents (e.g. El Yacoubi et al., 2000), also led to increased anxiety responses, e.g. reduced frequency of visits to the upper water layer and increased erratic movements in zebrafish (Egan et al., 2009).
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Levels of stress hormones have also been analyzed in zebrafish (Alsop & Vijayan, 2008a) and numerous similarities between zebrafish and human stress responses have been revealed, which strengthen the translational relevance of zebrafish in fear and anxiety research. For example, the sight of a predator elevates cortisol levels in zebrafish (Barcellos et al., 2007). It is important to note that cortisol, as in zebrafish, is also the primary stress hormone of the HPA axis in human but not in rodents. In the latter corticosterone plays a more important role instead. Last, treatment with the widely prescribed antidepressant Prozac, i.e. fluoxetine (a selective serotonin reuptake inhibitor) zebrafish reduced their fear responses and spent more time in the top portion of a novel tank and also performed fewer erratic movements. Interestingly, these behavioural changes were accompanied by reduced whole-body cortisol levels (Egan et al., 2009), responses that parallel those seen in rodents (Dulawa et al., 2004).
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7. Outlook to the future
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It is difficult to forecast how useful zebrafish may become in the modeling and analysis of the biological mechanisms of human fear and anxiety. At this point, however, it seems that the main components necessary for such a research to be successful in the future already exist. While only distantly related to human, the zebrafish has already proven its translational relevance. But perhaps the most important advantage of this species as a laboratory tool may be best described with one word: numbers. Complex biological phenomena are associated with large number of mechanisms. These may be discovered using broad screens, genetic or pharmacological. Zebrafish have been proven to be ideal for large scale screens due to several of its features, but mainly to the fact that a large number of these little fish can be produced fast and can be maintained and now tested efficiently in the laboratory. Given the complexity of the mechanisms of fear and anxiety, one may expect the need to identify a large number of molecular players, i.e. genes and their protein products and the biochemical interactions between the proteins. I argue that this complexity may be best tackled, at least initially, using large scale screens for mutations and drugs. These screens are the key to the identification of potential targets and leads that may subsequently be followed up on by more targeted hypothesis driven analyses. These big “fishing” experiments may be best conducted using the easy to keep and highly prolific zebrafish. It is important to note that I am not advocating the screening approach as the only possible or only potentially fruitful one. Obviously as our knowledge accumulates, increasingly directed and hypothesis driven in depth analyses become possible. But what I am arguing is that the notion of hypotheses having to drive our research somewhat clouded our judgement and we perhaps started the in depth analyses too soon. There expected to be a large number of unknown mechanisms waiting to be discovered and their discovery may be significantly facilitated by “blind”, i.e. unbiased, screening applications. And this is exactly where zebrafish has a major advantage over other laboratory organisms.
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Acknowledgments
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Supported by NIH/NIAAA 1R01AA015325-01A2.
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/19363.pdf",chapterXML:"https://mts.intechopen.com/source/xml/19363.xml",downloadPdfUrl:"/chapter/pdf-download/19363",previewPdfUrl:"/chapter/pdf-preview/19363",totalDownloads:2312,totalViews:112,totalCrossrefCites:2,totalDimensionsCites:9,totalAltmetricsMentions:0,impactScore:6,impactScorePercentile:95,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"December 2nd 2010",dateReviewed:"March 13th 2011",datePrePublished:null,datePublished:"September 12th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/19363",risUrl:"/chapter/ris/19363",book:{id:"511",slug:"different-views-of-anxiety-disorders"},signatures:"Robert Gerlai",authors:[{id:"55503",title:"Prof.",name:"Robert",middleName:null,surname:"Gerlai",fullName:"Robert Gerlai",slug:"robert-gerlai",email:"robert_gerlai@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Human anxiety remains a major unmet medical need despite decades of preclinical and clinical research",level:"1"},{id:"sec_3",title:"3. Laboratory animals: Efficient tools of discovery",level:"1"},{id:"sec_4",title:"4. Naturalistic (ethological) approaches should be employed when the question concerns the biological mechanisms of behaviour ",level:"1"},{id:"sec_5",title:"5. Antipredatory behaviour: An ethologically relevant method to study anxiety ",level:"1"},{id:"sec_6",title:"6. Zebrafish in the analysis of fear and anxiety ",level:"1"},{id:"sec_6_2",title:"6.1. Practical simplicity meets system complexity: zebrafish as an optimal compromise for research ",level:"2"},{id:"sec_7_2",title:"6.2. Genetics: the strength of zebrafish ",level:"2"},{id:"sec_8_2",title:"6.3. Behaviour: The weakness of zebrafish ",level:"2"},{id:"sec_9_2",title:"6.4. Induction of fear in zebrafish using ecologically relevant stimuli: The effect of the natural alarm substance",level:"2"},{id:"sec_10_2",title:"6.5. H3NO, the synthetic alarm substance",level:"2"},{id:"sec_11_2",title:"6.6. Visual cues as fear inducing stimuli: The sight of the sympatric predator ",level:"2"},{id:"sec_12_2",title:"6.7. The computerized predator: Animated image to induce fear",level:"2"},{id:"sec_13_2",title:"6.8. Automation is the key for high throughput screening",level:"2"},{id:"sec_14_2",title:"6.9. Light vs. dark, novel vs. familiar places: Other methods to measure fear responses",level:"2"},{id:"sec_15_2",title:"6.10. Pharmacological analysis of fear responses of zebrafish: The first pioneering studies ",level:"2"},{id:"sec_17",title:"7. 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I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBartels\n\t\t\t\t\t\t\tB. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTien\n\t\t\t\t\t\t\tA. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTien\n\t\t\t\t\t\t\tD. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMohnot\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeeson\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGlasgow\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmri\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZukowska\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKalueff\n\t\t\t\t\t\t\tA. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009Understanding behavioral and physiological phenotypes of stress and anxiety in zebrafish. Behav Brain Res.\n\t\t\t\t\t205\n\t\t\t\t\t38\n\t\t\t\t\t44\n\t\t\t\t\n\t\t\t'},{id:"B30",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEl Yacoubi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLedent\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParmentier\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCostentin\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVaugeois\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000The anxiogeniclike effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A(2A) adenosine receptor antagonists. Psychopharmacology (Berl); 148\n\t\t\t\t\t153\n\t\t\t\t\t163\n\t\t\t\t\n\t\t\t'},{id:"B31",body:'\n\t\t\t\t\n\t\t\t\t\tEngeszer RE, Patterson LB, Rao AA, Parichy DM.\n\t\t\t\t\t2007\n\t\t\t\t\tZebrafish in the wild: a review of natural history and new notes from the field\n\t\t\t\t\tZebrafish\n\t\t\t\t\t4\n\t\t\t\t\t21\n\t\t\t\t\t40\n\t\t\t\t\n\t\t\t'},{id:"B32",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFernandes\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerlai\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tLong-term behavioral changes in response to early developmental exposure to ethanol in zebrafish\n\t\t\t\t\tAlcoholism: Clinical and Experimental Research\n\t\t\t\t\t33\n\t\t\t\t\t601\n\t\t\t\t\t609\n\t\t\t\t\n\t\t\t'},{id:"B33",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFitch\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdams\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChaney\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerlai\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tForce transducer based movement detection in fear conditioning in mice: A comparative analysis.\n\t\t\t\t\tHippocampus\n\t\t\t\t\t12\n\t\t\t\t\t4\n\t\t\t\t\t17\n\t\t\t\t\n\t\t\t'},{id:"B34",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFlint\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShifman\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tAnimal models of psychiatric disease\n\t\t\t\t\tCurr Opin Genet Dev.; 18\n\t\t\t\t\t235\n\t\t\t\t\t240\n\t\t\t\t\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrisch\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1938\n\t\t\t\t\tZur Psychologie des Fisch- Schwarmes. Naturwissenschaften\n\t\t\t\t\t26\n\t\t\t\t\t601\n\t\t\t\t\t606\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrisch\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1941Uber einen Schrecksto’f der Fisch- haut und seine biologische Bedeutung. Z. vergl. Physiol. 29\n\t\t\t\t\t46\n\t\t\t\t\t145\n\t\t\t\t\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarakani\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMathew\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDS\n\t\t\t\t\t\t\tCharney\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tNeurobiology of anxiety disorders and implications for treatment. Mt Sinai J Med.; 73\n\t\t\t\t\t941\n\t\t\t\t\t949\n\t\t\t\t\n\t\t\t'},{id:"B38",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeisler\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRauch\n\t\t\t\t\t\t\tG. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaier\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVan Bebber\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrobeta\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDekens\n\t\t\t\t\t\t\tM. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFinger\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFricke\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999A radiation hybrid map of the zebrafish genome. Nat Genet; 23\n\t\t\t\t\t86\n\t\t\t\t\t89\n\t\t\t\t\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerlai\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002Phenomics: Fiction or the Future? Trends Neurosci.; 25\n\t\t\t\t\t506\n\t\t\t\t\t509\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerlai\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tBehavioral tests of hippocampal function: Simple paradigms, complex problems\n\t\t\t\t\tBehav. Brain Res.; 125\n\t\t\t\t\t269\n\t\t\t\t\t277\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerlai\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993Can paradise fish (Macropodus opercularis) recognize its natural predator? An ethological analysis. Ethology; 94\n\t\t\t\t\t127\n\t\t\t\t\t136\n\t\t\t\t\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerlai\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClayton\n\t\t\t\t\t\t\tN. 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Proc Natl Acad Sci U S.; A 104\n\t\t\t\t\t12428\n\t\t\t\t\t12433\n\t\t\t\t\n\t\t\t'},{id:"B101",body:'\n\t\t\t\t\n\t\t\t\t\tWeisberg RB.\n\t\t\t\t\t2009\n\t\t\t\t\tOverview of generalized anxiety disorder: epidemiology, presentation, and course\n\t\t\t\t\tJ Clin Psychiatry.; Suppl 2\n\t\t\t\t\t4\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B102",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWienholds\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchulte-Merker\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWalderich\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPlasterk\n\t\t\t\t\t\t\tR. H. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002Target selected inactivation of the zebrafish rag1 gene. Science; 297\n\t\t\t\t\t99\n\t\t\t\t\t102\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Robert Gerlai",address:"",affiliation:'
University of Toronto Mississauga, Canada
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1. Introduction
Widespread usage of communication technology, intended to transfer information from one person to another, is moving rapidly towards information exchange between man and machine. The advent of computer along with digital formatted communication in light of advanced algorithms, low cost VLSI (Very Large Scale Integration) and high efficiency in computation paves the way for massive information exchange among individuals.
Simultaneously, ubiquitous computing paradigm with sensor based data communication presents unique man-to-machine information exchange which not only spread across large area but is also found to be a source of voluminous data, that needs to be carefully segregated and segmented for figuring out intelligence from a large pile of existing data.
Conventionally, middleware is said to be collection of algorithms, components and devices which enables the information exchange between different entities. As per the OSI model, middleware can be placed between the transport and the application layer, as shown in Figure 1.
Figure 1.
Location of middleware in OSI reference model.
In existing literature, the concept of middleware was discussed starting in the year 1968 in a report of the North Atlantic Treaty Organization [1], where it was placed between the application programs and the service routines. This paradigm was quite pragmatic due to its ability to interconnect new components with the existing hardware within the same distributed system.
With the advent of the recent 5G technologies along-with strong data networking capability, a plethora of innovative sensor-based application are appearing over the horizon. This motivates us to look at the middleware architecture at a microscopic level as it involves different sensors with their applications without considering the interconnection involved i.e. it hides the heterogeneous nature of the underlying sensing data to yield the support system with the help of unified interface for the final application. This results in an easy access of the network by sensors as well as different applications, which can call the sensing network with the middleware open interface. This helps in the reduction of the design and the development cost with improved efficiency.
2. History and motivation
The initial development of the computer was based on the premise and promise of high-speed calculations which was iterative in nature. It was initially proposed through mechanical gear system but was found to be excessively time consuming. With the advent of vacuum tubes, the hurdle of timing is attended to and further, investigation in the field of solid state electronics which results in devices such as, diodes, transistors and operation amplifiers paves way for low power consuming, portable size devices which are termed as analog computers. This was the first era of computers [2]. The more robust, fast and complex Integrated Circuits (IC) were responsible for the design and development of digital computers which are having tremendous capability to perform high speed and complex calculations [3].
With the elaboration of theoretical concepts and their implementation in terms of ideas such as, distributed computing, abstraction, object-oriented programming, etc., results in the coding of complex software programs to an easily solvable problem at hand. At the same time, in order to reduce the design and development cost of the software and its interaction with the hardware, the concept of re-usability comes into software design paradigm [4].
The parallel progress in networking paradigm, which was simply started with possible interconnection of machines, later resulted in the development of OSI model to yield a layered structure of communication among different machines [5]. The layered architecture is profoundly based on the software abstraction model which felicitates a very specific section/property of the network to change without hampering the process of communication among other machines through different layers. This paradigm was the primary basis of middle ware architecture which was placing it between the transport and the application layer, as shown in Figure 1.
With the expansion of networking paradigm, Middleware architecture found its place among the widely used concepts, especially in the era of plug and play design methodology. In the subsequent section, we will look at the different attributes which Middleware workable.
2.1 Features of middleware
As discussed in the introduction, middleware is a set protocol for data exchange between the transport and the application layer. It helps different machines to share the data with the network and vice versa without considering the heterogeneity of the underlying data from both sides, and results in reduced development cost and improvement in the efficiency [6].
The following features are the major attributes of the middleware architecture:
From the Software management perspective, Middleware is found to be more and more integrated into the operating system, which results in the application evolved in a machine to be safely ported on the network as well, wherein the network is acting as an up-scaled version of the machine. Also, this results in resource management mechanism based on service quality and the flexible configuration capability [7].
With the widespread availability of the Internet, middleware architecture provides web-based services and resource sharing capacity, making middleware architecture almost like connecting glue which supports in the running of the application software successfully. Also, the resource sharing methods based on Internet services are more universal, cost effective and efficient.
Middleware architecture has transformed the conventional spoke and wheel system into the distributed system by combining different technologies such as, cloud computing, big data and virtualization, which provides the capacity to integrate different resources and yields more robust service capability. With this architecture, one can solve the issue of data storage, processing and transmission among the different internetworked systems.
Depending on the different attributes, the middleware architecture can be classified into four types [8, 9].
Transaction Processing Monitors (TPM)
Remote Procedure Call (RPC)
Message-Oriented Middleware (MOM)
Object Request Brokers (ORB)
These types are based on the varied services offered by the specific process.
Transaction Processing Monitors (TPM) is designed to monitor the successful transactions from one stage to another stage. In case of any error, TPM takes an appropriate action to rectify the error. A TPM supports optimal resource sharing among the applications with the following functionalities:
Monitoring operation/transactions
Managing queues
Coordination among resources
Creating new processes on requirement
Secure access to services
Wrapping data messages into messages
Unwrapping messages into data packets
Handling errors
Hiding the details of inter-process communications from programmer
Remote Procedure Call (RPC) is an inter-process communication facility generally used in a client server based model with the following functionalities:
Supports process-oriented or thread-oriented models
Hiding details of inter-process communications from programmer
Useful in local environment as well as distributed environment
Performance improvement can be achieved by omitting unwanted protocol layers
Message-Oriented Middleware (MOM) is an asynchronous technique that passes the messages between transmitting and receiving application with a communication channel. Its asynchronous nature makes the applications decoupled from each other as MOM is responsible for message management system.
Object Request Brokers (ORB) acts like a broker between a client request for a service from a distributed object and the completion of that request with following functionalities:
Life cycle service
Persistence service
Naming service
Event Service
Concurrency control service
Transaction service
Relationship service
Externalization service
Query service
In view of the above-mentioned services offered by the different types of middleware, following are the major attribute of services offered by any middleware structure [8]:
Presentation management: Forms manager, graphics manager, hypermedia linker, and printing manager.
Computation: Sorting, math services, internationalization services (for character and string manipulation), data converters, and time services.
Information management: Directory server, log manager, file manager, record manager, relational database system, object-oriented database system, repository manager.
The emerging trend of wireless technology and the associated innovative applications has changed the communication landscape drastically. Now, the reduced cost of data, high computation power of smartphones and the 5G enabled sensor technology is the major driving force behind the widespread adaptation of network services such as, map enabled movement, shipment tracking, and interactive gaming such as, Pokemon.
Inherently, multimedia services are found to be wideband in nature which, with the unpredictable channel characteristic of wireless medium, place a challenging condition to maintain reliable communication with a predefined Quality of Service (QoS).
IEEE 802.11 standard, proposed by IEEE for local area network (LAN) protocol, specifies the physical layer (PHY) and media access control (MAC) protocols for the implementation of wireless local area network (WLAN) communication in the frequency bands such as, 2.4 GHz, 5 GHz, 6 GHz, and 60 GHz. Presently, various tributaries of IEEE 802.11 are framing our day-to-day communication across the world. As per the convention, IEEE 802.11 standards are defined for physical and data link layer of the OSI data communication network protocol and become the de facto standard for wireless communication.
Moreover, the heterogeneous nature of different services such as, Wi-max, Wi-Fi, Bluetooth, and many more, with their unique data link layer presentation have their own quality control mechanism for data transmission. This results in a complex connection strategy management at network, data link, and physical layer.
In comparison, at the application layer, the QoS management parameters such as, semantic, presentation etc., have their own constraints to be followed. These constraints may not be followed every time due to resource limitations at the physical layer or multiplexing issue due to the fluctuating number of users sharing the resource pool in the end system and the network.
In the process of communication, wireless channel demands adaptive QoS implementation for peer-to-peer communication, due to its dynamic behavior. This places a bound on the middleware to manage the communication as it connects the lower layers of the communication protocol (which actually perform the communication at the data level) to the application layer (which is responsible for communication in the correct semantic and form) [10, 11]. Thus, the unique position of middleware demands a monitoring as well as an adaptive perspective such that the desired QoS requirements can be maintained at the application layer without disturbing the underneath communication.
This QoS maintenance requires a two-fold strategy, first is the monitoring of application performance and the second is adaptation of service to maintain pre-specified quality of service [11]. This adaptation strategy requires a perfect synchronization of middleware level with lower level of protocols.
These conditions lay the foundation for the middleware control framework. The middleware control framework has three primary concerns to address [12]:
Coordinate the adaptation of all the concurrent application tasks in the end system globally i.e., maintain fairness in the architecture.
Increase the adaptation effectiveness to maintain the QoS.
To monitor on-the-fly dynamics in the heterogeneous environment to achieve optimum control over the smooth functioning of the applications.
3.1 IEEE 802.11 - an interesting journey
IEEE 802 project was aimed to establish the standards for physical layer (PHY) and medium access control (MAC) layer to support deployment of the local area network. The first candidate was IEEE 802.3, popularly known as Ethernet. It was a wired connection mechanism to connect devices based on carrier sense multiple access with collision detection (CSMA/CD) mechanism. Its wide acceptability with industry and home users, motivates the researcher to look for its replication in wireless domain as well which yields the IEEE 802.11 standard [13, 14].
Due to inherent unpredictable nature of radio/wireless medium paves the way for numerous deliverables of IEEE 802.11 standards, which have been flourished over the last twenty years [15, 16], such as 802.11a, 802.11e, 802.11f, 802.11 t and so on. Readers are encouraged to refer [17] to explore the need and their solutions under IEEE 802.11 horizon.
3.2 Middleware in IEEE 802.11 environment
Under the middleware architecture a brief account of various cases has been summarized below.
Authors in [18] address the issue of mobility management in increasing integration of Internet with telecommunication network which give rise to distributed computing environment. Authors proposed three mobile computing services by incorporating user virtual environment (UVE), mobile virtual terminal (MVT), and virtual resource management (VRM) based on mobility middleware solution for mobile agent.
In [19], the Authors illustrate Quality of Service (QoS) maintenance for multimedia applications over wireless network which are characterized by their limited bandwidth. Authors proposed a novel two level QoS architecture by providing service differentiation at network level and service adaptation at the middleware level. Authors validate their results with experiments and show that specific QoS levels for multimedia applications can be optimally achieved in IEEE 802.11 based wireless network.
Costa et al. in their path breaking work proposed the real time-WiFi architecture to address the issues faced by IEEE 802.11 networks in high density industrial environment [20]. Authors compare the performance of proposed architecture against the standard distributed coordination function (DCF), point coordination function (PCF), hybrid coordination function (HCF) controlled channel access (HCCA) and enhanced distributed channel access (EDCA) medium access control mechanism. Authors used a realistic error-prone model to monitor the impact of message losses in the real time Wi-Fi architecture and their result confirm that the proposed architecture performs better as compared to existing IEEE 802.11 standard mechanisms. Their architecture also offers almost consistent access delay which is one of the major requirements for real time applications.
Authors in [21] use context meta-information to improve the system performance by describing a context management middleware that can successfully handle context irrespective of the execution environment’s heterogeneity.
Cruz et al. in [22], reviewed the middleware framework for Internet of Things (IoT) from software perspective. Authors rigorously explored the existing literature and analyzed the reference model for IoT platforms and proposed the basic security feature for this software. Authors also detailed the difficulties in achieving and enforcing a universal standard for middleware in the IoT structure.
Authors in [23], present a fundamental analysis to quantify the goodput performance parameter for IoT. Authors show the closed form expression of goodput as a function of the data payload length, frame retry count, data rate of transmission and wireless channel condition. Authors proposed a novel link adaptation scheme for MAC protocol data units for known wireless channel model.
Increasing use of mobile devices for location sharing applications such as Google map, OLA, Uber, pose a challenge of maintaining adequate user privacy with location sharing services and exchange of information across high heterogeneity among connecting technologies and devices. Authors in [24] proposed a middleware prototype to answer these challenges with two level proxy-based architecture as a solution.
Hamidreza et al. in [25], proposed service-oriented architecture for middleware to resolve the issue of heterogeneity among various sensors in IEEE 802.15 based wireless sensor network.
Authors in [26] discuss different types of sensor network applications with overview of related middleware and infer that none of the existing approaches can provide all the management tools required by sensor network applications. Authors showcase their new middleware MILAN with sensor-based health monitoring system.
In [27], the authors explored the concept of inter-vehicular communications. The field of vehicle to infrastructure and vehicle to vehicle communications were undertaken as well. This work provides detailed account of underlying technology under each layer with rich resource references.
Authors in [28], address the combination of vehicular ad-hoc networks (VANETs) with the social Internet of things (SIoT). Their work describes two fold relations which can be established between the vehicles and between the vehicle and road side unit (RSU). Authors proposed a social Internet of vehicle middleware to incorporate the functionalities of the intelligent transportation systems station architecture, defined by ISO and ETSI standards to integrate VANET with SIoT. They present their proof of concept with simulation results.
Pease et al. in [29] present an adaptive middleware methodology to provide robust mission critical/ military communication by providing timely MANET communications with predictive selection and dynamic contention reduction, without going for invasive protocol modification. To address the issue they proposed a novel Real-time Optimized Ad hoc Middleware based architecture (ROAM). They demonstrate the adaptability, scalability of the architecture along-with the capability to bound maximum delay, jitter and packet loss in complex and dynamic MANET’s with extensive simulations.
In [30], the authors elaborated a novel mobile collaboration architecture (MoCA), a service oriented middleware architecture which support the development and deployment of distributed context-aware applications for mobile users. Authors explained the compatibility of proposed MoCA with existing software engineering principles responsible for design and implementation of context aware applications. Authors also present different prototype applications that have been developed on the top of MoCA.
Authors in [10] addressed end to end delays and security issues in application implementation. Authors proposed an integrated solution with middleware adaptation to provide tunable delay and security support according to network condition. To Support the proof of concept, authors perform test-bed experiments to showcase successful meeting of delay and security requirements in IEEE 802.11 based wireless environment.
4. Conclusion
Middleware architecture defines the connection protocol between the network layer and the application layer. In view of the on-going advances in the mobile communication, there is a requirement of a better understanding about Middleware functionality with IEEE 802.11 protocols which are responsible for the design rules of modern wireless communication.
In this chapter, we addressed the key functionalities of the middleware architecture in addition to its adaptation to the IEEE 802.11 protocols.
In the current scenario, where the need of ubiquitous connectivity is reality, the need of minimum end to end delay with almost no loss in data i.e. maintaining stringent Quality of Service at every end, is a challenging task.
This monograph will be helpful for the researchers to investigate middleware architecture in IEEE 802.11 framework to deliver robust design solution in wireless network.
Conflict of interest
“The authors declare no conflict of interest.”
\n',keywords:"Middleware architecture, Communication protocols, IEEE 802.11, Network layer, Application layer, TPM, RPC, MOM, ORB",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76136.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76136.xml",downloadPdfUrl:"/chapter/pdf-download/76136",previewPdfUrl:"/chapter/pdf-preview/76136",totalDownloads:204,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 24th 2021",dateReviewed:"March 9th 2021",datePrePublished:"May 4th 2021",datePublished:"December 22nd 2021",dateFinished:"April 7th 2021",readingETA:"0",abstract:"Communication, which intends to provide a link between any two people, is now moving towards man-to-machine and machine-to-machine connection for transferring different types of data. This transmission scenario, with and ever expanding number of active and passive users, lays the foundation to variety of communication protocols owing to the different types of data which is involved in the process. Within this ever expanding communication arena, Middle-ware can be thought of as a set of hardware and software which is used to connect different platforms with the end-users that are increasing in number day-by-day, with a possible wide spread over any region spanning from few meters to several kilometers. IEEE 802.11 is the set of standards which guides the wireless technology for device implementation and demands seamless integration across the entire protocol stack. This in turn demands an overview of the middleware architecture in broader perspective. This chapter explores the concept of middleware in the existing communication scenario, current trends and future scope.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76136",risUrl:"/chapter/ris/76136",signatures:"Rochak Bajpai, Atul Bansal, Jyoti Tripathi and Sridhar Iyer",book:{id:"10519",type:"book",title:"Middleware Architecture",subtitle:null,fullTitle:"Middleware Architecture",slug:"middleware-architecture",publishedDate:"December 22nd 2021",bookSignature:"Mehdia Ajana El Khaddar",coverURL:"https://cdn.intechopen.com/books/images_new/10519.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-407-3",printIsbn:"978-1-83969-406-6",pdfIsbn:"978-1-83969-408-0",isAvailableForWebshopOrdering:!0,editors:[{id:"26677",title:"Dr.",name:"Mehdia",middleName:null,surname:"Ajana El Khaddar",slug:"mehdia-ajana-el-khaddar",fullName:"Mehdia Ajana El Khaddar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"211351",title:"Mr.",name:"Rochak",middleName:null,surname:"Bajpai",fullName:"Rochak Bajpai",slug:"rochak-bajpai",email:"rochakbajpai@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"349930",title:"Prof.",name:"Atul",middleName:null,surname:"Bansal",fullName:"Atul Bansal",slug:"atul-bansal",email:"atul.bansal@gla.ac.in",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"349932",title:"Ms.",name:"Jyoti",middleName:null,surname:"Tripathi",fullName:"Jyoti Tripathi",slug:"jyoti-tripathi",email:"loginjyoti@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"349933",title:"Dr.",name:"Sridhar",middleName:null,surname:"Iyer",fullName:"Sridhar Iyer",slug:"sridhar-iyer",email:"sridhariyer1983@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. History and motivation",level:"1"},{id:"sec_2_2",title:"2.1 Features of middleware",level:"2"},{id:"sec_4",title:"3. IEEE 802.11 adaptation with middleware",level:"1"},{id:"sec_4_2",title:"3.1 IEEE 802.11 - an interesting journey",level:"2"},{id:"sec_5_2",title:"3.2 Middleware in IEEE 802.11 environment",level:"2"},{id:"sec_7",title:"4. Conclusion",level:"1"},{id:"sec_11",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Bauer F.L., Bolliet L., Helms H. J., “Software Engineering: Report on a conference sponsored by the NATO science committee”, Garmisch, Germany, Tech. Rep. Jan. 1969. \\url{ http://homepages.cs.ncl.ac.uk/brian.randell/NATO/nato1968.PDF} [Accessed: 04 January 2021'},{id:"B2",body:'Mindell DA. “Between human and machine: feedback, control, and computing before cybernetics”. JHU Press; 2002 Oct 11'},{id:"B3",body:'Graham S, Baliga G, Kumar PR. “Abstractions, architecture, mechanisms, and a middleware for networked control”. IEEE Transactions on Automatic Control. 2009 Jun 30;54(7):1490-503'},{id:"B4",body:'Prieto-Diaz R. “Status report: Software reusability”. IEEE software. 1993 May;10(3):61-6'},{id:"B5",body:'Kumar S, Dalal S, Dixit V. “The OSI model: Overview on the seven layers of computer networks”. International Journal of Computer Science and Information Technology Research. 2014 Jul;2(3):461-6'},{id:"B6",body:'Dong H. “Middleware Technologies”. Journal of Anhui Vocational College of Electronics \\& Information Technology. 2006:04'},{id:"B7",body:'Lu ZJ, Yan Z. “Middleware Technology Research and Interface Design in Ubiquitous Network”. In2015 Seventh IEEE International Conference on Measuring Technology and Mechatronics Automation 2015 Jun 13 (pp. 659-662)'},{id:"B8",body:'Bernstein PA. “Middleware: a model for distributed system services”. Communications of the ACM. 1996 Feb 1;39(2):86-98'},{id:"B9",body:'Tian Y, Geiger JV, Su H, Kumar SV, Houser PR. “Middleware-based sensor web integration”. IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing. 2010 Jun 21;3(4):467-72'},{id:"B10",body:'Li B, Nahrstedt K. “A control-based middleware framework for quality-of-service adaptations”. IEEE journal on selected areas in communications. 1999 Sep;17(9):1632-50'},{id:"B11",body:'Ong CS, Xue Y, Nahrstedt K. “A middleware for service adaptation in differentiated 802.11 wireless networks”. InProceedings. 2004 12th IEEE International Conference on Networks (ICON 2004)(IEEE Cat. No. 04EX955) 2004 Nov 19 (Vol. 1, pp. 364-368). IEEE'},{id:"B12",body:'Li B, Nahrstedt K. A control-based middleware framework for quality-of-service adaptations. IEEE journal on selected areas in communications. 1999 Sep;17(9):1632-50'},{id:"B13",body:'Tanenbaum AS, Wetherall D. Computer networks. 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Handling real-time communication in infrastructured IEEE 802.11 wireless networks: The RT-WiFi approach. Journal of Communications and Networks. 2019 May 29;21(3):319-34'},{id:"B21",body:'da Rocha RC, Endler M. Middleware: Context management in heterogeneous, evolving ubiquitous environments. IEEE Distributed Systems Online. 2006 May 15;7(4)'},{id:"B22",body:'da Cruz MA, Rodrigues JJ, Al-Muhtadi J, Korotaev VV, de Albuquerque VH. A reference model for internet of things middleware. IEEE Internet of Things Journal. 2018 Jan 23;5(2):871-83'},{id:"B23",body:'Qiao D, Choi S, Shin KG. Goodput analysis and link adaptation for IEEE 802.11 a wirelessLANs. IEEE transactions on Mobile Computing. 2002 Oct;1(4):278-92'},{id:"B24",body:'Bellavista P, Corradi A, Giannelli C. Efficiently managing location information with privacy requirements in wi-fi networks: a middleware approach. In2005 2nd International Symposium on Wireless Communication Systems 2005 Sep 5 (pp. 91-95). IEEE'},{id:"B25",body:'Abangar H, Barnaghi P, Moessner K, Nnaemego A, Balaskandan K, Tafazolli R. A service oriented middleware architecture for wireless sensor networks. InProceedings of future network and mobile summit conference 2010 Jun'},{id:"B26",body:'Heinzelman WB, Murphy AL, Carvalho HS, Perillo MA. Middleware to support sensor network applications. IEEE network. 2004 Jun 28;18(1):6-14'},{id:"B27",body:'Jawhar I, Mohamed N, Zhang L. Inter-vehicular communication systems, protocols and middleware. In2010 IEEE Fifth International Conference on Networking, Architecture, and Storage 2010 Jul 15 (pp. 282-287). IEEE'},{id:"B28",body:'Nitti M, Girau R, Floris A, Atzori L. On adding the social dimension to the internet of vehicles: Friendship and middleware. In2014 IEEE international black sea conference on communications and networking (BlackSeaCom) 2014 May 27 (pp. 134-138). IEEE'},{id:"B29",body:'Pease SG, Phillips IW, Guan L. Adaptive intelligent middleware architecture for mobile real-time communications. IEEE Transactions on Mobile Computing. 2015 Apr 27;15(3):572-85'},{id:"B30",body:'Viterbo J, Sacramento V, Rocha R, Baptista G, Malcher M, Endler M. A middleware architecture for context-aware and location-based mobile applications. In2008 32nd Annual IEEE Software Engineering Workshop 2008 Oct 15 (pp. 52-61). IEEE'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Rochak Bajpai",address:"rochakbajpai@gmail.com",affiliation:'
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In relation with their location, these sinuses contribute to the development of the facial structures, jaws and upper airway. During the developmental process of the paranasal sinuses, anatomic variations can occur in consequence of intra and extramural migration of the ethmoid air cells, overpneumatization or hypoplasia of the sinuses and bulging of the neurovascular structures to the sinuses. Some of these anatomic variations may affect the drainage pathways, pave the way for chronic infections and cause difficulties when performing paranasal sinuses surgery. Therefore, the aim of this chapter was to examine the paranasal sinus anatomic variations with cone beam computed tomography (CBCT).",book:{id:"5911",slug:"paranasal-sinuses",title:"Paranasal Sinuses",fullTitle:"Paranasal Sinuses"},signatures:"Kaan Orhan, Secil Aksoy and Ulas Oz",authors:[{id:"199784",title:"Ph.D.",name:"Seçil",middleName:null,surname:"Aksoy",slug:"secil-aksoy",fullName:"Seçil Aksoy"},{id:"199788",title:"Prof.",name:"Kaan",middleName:null,surname:"Orhan",slug:"kaan-orhan",fullName:"Kaan Orhan"},{id:"203116",title:"Prof.",name:"Ulas",middleName:null,surname:"Oz",slug:"ulas-oz",fullName:"Ulas Oz"}]},{id:"67836",doi:"10.5772/intechopen.86964",title:"The Immunology of Asthma and Allergic Rhinitis",slug:"the-immunology-of-asthma-and-allergic-rhinitis",totalDownloads:872,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"The immune system is a complex collection of cells, tissues, and chemical mediators positioned throughout the body, whose primary purpose is to protect us against infection. However, its function is not only fundamental in protection from infectious disease but also provides aberrant response in allergens such as with asthma and allergic rhinitis. Allergic diseases like asthma and allergic rhinitis are characterized by a distinct type of inflammatory response, driven by immunoglobulin E (IgE)-dependent mechanisms. In asthma and allergic rhinitis, the inflammatory response is mediated by interaction of several immune cells (monocytes, lymphocytes, and polymorphonuclear cells) and cellular chemical mediators. In particular, atopic allergic response leads to destruction of multiple target cells such as epithelial, parenchymal and vascular and connective tissue of the airways. In addition, in inflammatory response in asthma and allergic rhinitis, sensory nerves are sensitized, leading to clinical manifestations. Sneezing and coughing are hypersensitivity responses of sensory nerves in allergic rhinitis and asthma, respectively. Similarly, nasal congestion and discharge in allergic rhinitis are due to vasodilatation that leads to plasma exudates as well as mucous secretion. The allergic inflammatory response is regulated by several transcription factors, particularly nuclear factor-κb (NF-κB), GATA-3 protein 3, and GATA binding protein.",book:{id:"7062",slug:"rhinosinusitis",title:"Rhinosinusitis",fullTitle:"Rhinosinusitis"},signatures:"Andrew Kiboneka and Dan Kibuule",authors:[{id:"202850",title:"Mr.",name:"Dan",middleName:null,surname:"Kibuule",slug:"dan-kibuule",fullName:"Dan Kibuule"},{id:"280538",title:"Dr.",name:"Andrew",middleName:null,surname:"Kiboneka",slug:"andrew-kiboneka",fullName:"Andrew Kiboneka"}]},{id:"55472",doi:"10.5772/intechopen.69089",title:"Paranasal Sinus Anatomy: What the Surgeon Needs to Know",slug:"paranasal-sinus-anatomy-what-the-surgeon-needs-to-know",totalDownloads:5573,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Performing a smooth and clean sinus surgery goes hand in hand with a perfect understanding of the nasal and paranasal anatomy. Within this chapter, the paranasal and related structures surgical anatomy will be extensively reviewed, with emphasis on the anatomical landmarks and the normal anatomical variations, which have a significant impact on the function, pathology, and surgical procedures of the paranasal sinuses.",book:{id:"5911",slug:"paranasal-sinuses",title:"Paranasal Sinuses",fullTitle:"Paranasal Sinuses"},signatures:"Abdulmalik S. Alsaied",authors:[{id:"199716",title:"Dr.",name:"Abdulmalik",middleName:"Saad",surname:"Alsaied",slug:"abdulmalik-alsaied",fullName:"Abdulmalik Alsaied"}]},{id:"67186",doi:"10.5772/intechopen.86212",title:"Local Allergic Rhinitis: An Old Story but a New Entity",slug:"local-allergic-rhinitis-an-old-story-but-a-new-entity",totalDownloads:795,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Local allergic rhinitis (LAR) is a novel concept defining clinical allergic rhinitis with no evidence of systemic sensitization to aeroallergens. In this unique condition, the allergic response is confined to the nasal mucosa and can be demonstrated using different methods such as the immunoglobulin-E (IgE) level in the nasal secretions, nasal provocation test (NPT), or basophil activation test (BAT) with specific allergens or more sophisticated molecular diagnostic techniques. Furthermore, local allergic rhinitis can be relieved by interventions used to treat systemic allergic conditions such as antihistamines or anti-IgE monoclonal antibodies. Last but not least, several small studies demonstrated the efficacy of allergen immunotherapy for ameliorating LAR symptoms. In this chapter we reviewed old data and new concepts regarding clinical manifestation, plausible mechanisms, and treatments of LAR. The long-standing question whether LAR is an integral part of the “atopic spectrum” or it is a single-organ immune-mediated disease, is yet to be determined.",book:{id:"7062",slug:"rhinosinusitis",title:"Rhinosinusitis",fullTitle:"Rhinosinusitis"},signatures:"Ramit Maoz-Segal, Diti Machnes-Maayan, Irena Veksler-Offengenden, Shirly Frizinsky, Soad Hajyahia and Nancy Agmon-Levin",authors:[{id:"293794",title:"Dr.",name:"Ramit",middleName:null,surname:"Maoz-Segal",slug:"ramit-maoz-segal",fullName:"Ramit Maoz-Segal"},{id:"293823",title:"Dr.",name:"Diti",middleName:null,surname:"Machnes-Maayan",slug:"diti-machnes-maayan",fullName:"Diti Machnes-Maayan"},{id:"299506",title:"Dr.",name:"Irena",middleName:null,surname:"Veksler-Offengenden",slug:"irena-veksler-offengenden",fullName:"Irena Veksler-Offengenden"},{id:"299508",title:"Dr.",name:"Soad",middleName:null,surname:"Hajyahia",slug:"soad-hajyahia",fullName:"Soad Hajyahia"},{id:"299510",title:"Dr.",name:"Shirly",middleName:null,surname:"Frizinsky",slug:"shirly-frizinsky",fullName:"Shirly Frizinsky"},{id:"299511",title:"Prof.",name:"Nancy",middleName:null,surname:"Agmon-Levin",slug:"nancy-agmon-levin",fullName:"Nancy Agmon-Levin"}]}],mostDownloadedChaptersLast30Days:[{id:"63699",title:"Management of the Complications of Maxillary Sinus Augmentation",slug:"management-of-the-complications-of-maxillary-sinus-augmentation",totalDownloads:7747,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Dental implant rehabilitation of the posterior maxillary region has always been a challenging issue due to both alveolar ridge atrophy and sinus pneumatization. Maxillary sinus augmentation is a well-known and predictable procedure in vertical deficiencies of the posterior maxilla. To date, various techniques have been described based on the physiology of intrasinus bone repair to obtain better outcomes. Nevertheless, these procedures could also be associated with several intra- and postoperative complications such as perforation of the sinus membrane, hemorrhage, infection, graft resorption, and loss of the graft or implants. The aim of this chapter is to review the contemporary methods for maxillary sinus augmentation and to present both recommendations for prevention and management of the associated complications.",book:{id:"7245",slug:"challenging-issues-on-paranasal-sinuses",title:"Challenging Issues on Paranasal Sinuses",fullTitle:"Challenging Issues on Paranasal Sinuses"},signatures:"Alper Sindel, Mehmet Mustafa Özarslan and Öznur Özalp",authors:[{id:"244837",title:"Dr.",name:"Alper",middleName:null,surname:"Sindel",slug:"alper-sindel",fullName:"Alper Sindel"},{id:"244918",title:"Dr.",name:"Mehmet Mustafa",middleName:null,surname:"Özarslan",slug:"mehmet-mustafa-ozarslan",fullName:"Mehmet Mustafa Özarslan"},{id:"244919",title:"Ms.",name:"Öznur",middleName:null,surname:"Özalp",slug:"oznur-ozalp",fullName:"Öznur Özalp"}]},{id:"55472",title:"Paranasal Sinus Anatomy: What the Surgeon Needs to Know",slug:"paranasal-sinus-anatomy-what-the-surgeon-needs-to-know",totalDownloads:5569,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Performing a smooth and clean sinus surgery goes hand in hand with a perfect understanding of the nasal and paranasal anatomy. 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Since then, many authors have documented a large series showing the overall efficacy of combining the two procedures. The focus of this manuscript is to document the author’s recent experience with combining rhinoplasty and endoscopic sinus surgery and highlight the changes that have occurred during the author’s 2-years experience. A retrospective data review was performed on 53 (31 females and 22 men, age range 16–55 years) patients who underwent combined rhinoplasty and ESS between January 2016 and December 2018 at Pantai Hospital Kuala Lumpur by the same surgeon. The mean age was 31.8 years. All patients had severe nasal obstruction with chronic rhinosinusitis and were followed up for a minimum of 6 months post-surgery and underwent ENT workup, which included history, office rigid endoscopy, CT scans of paranasal sinuses and preoperative photography. Initially, the ESS was performed followed by the open rhinoplasty with or without osteotomy. The ESS consisted of middle turbinate reduction [15/53 (28.3%)], maxillary antrostomy [36/53 (67.9%)], ethmoidectomy [38/53 (71.6%)], frontal sinusotomy [7/53 (13.2%)], and sphenoidotomy [9/53 (16.9%)]. Most of the sinus symptoms resolved postoperatively with 47 (88.6%) of 53 patients describing their improvement as significant. Fifty (94.3%) of 53 patients stated that they would recommend the concurrent procedure. The benefits of these advances are illustrated by a review of the literature with good results (functional and cosmetic) and minimal complications.",book:{id:"7062",slug:"rhinosinusitis",title:"Rhinosinusitis",fullTitle:"Rhinosinusitis"},signatures:"Balwant Singh Gendeh",authors:[{id:"67669",title:null,name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}]},{id:"62774",title:"Orbital Cellulitis",slug:"orbital-cellulitis-1",totalDownloads:1004,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Infection in the soft tissues of the orbit, posterior to the orbital septum results in orbital cellulitis. This is a very serious condition, which may occur as a complication of sinusitis by contiguous spread or may result from haematogenous spread or from trauma. Orbital cellulitis presents with periorbital swelling, proptosis, conjunctival chemosis and injection, extraocular motility deficits and visual loss. It requires comanagement by the ophthalmologist and otorhinolaryngologist when secondary to sinusitis. It is important that this condition is recognized early, and immediate management is done to prevent impending visual loss and further complications of periosteal abscesses, meningitis, cavernous sinus thrombosis and death. This chapter reviews the epidemiology of orbital cellulitis, pathogenesis, causative organisms, investigations (including imaging of the sinuses) and treatment. Prognostic factors and conditions that complicate this such as diabetes will also be discussed.",book:{id:"7245",slug:"challenging-issues-on-paranasal-sinuses",title:"Challenging Issues on Paranasal Sinuses",fullTitle:"Challenging Issues on Paranasal Sinuses"},signatures:"Lizette Mowatt",authors:[{id:"31774",title:"Dr.",name:"Lizette",middleName:null,surname:"Mowatt",slug:"lizette-mowatt",fullName:"Lizette Mowatt"}]},{id:"55606",title:"Maxillary Sinus Augmentation for Dental Implants",slug:"maxillary-sinus-augmentation-for-dental-implants",totalDownloads:2107,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Pneumatization of the maxillary sinus secondary to posterior maxillary tooth loss is an extremely common finding. Significant atrophy of the maxilla prevents dental implant placement in this region. Grafting the floor of the maxillary sinus has emerged as the most common surgical modality for correcting this inadequacy. Graft material is introduced into the space created inferior to the sinus membrane. Various grafting materials and techniques might be used in this procedure. The aim of this article is to review the essentials of maxillary sinus augmentation, clarify this procedure for otolaryngologists, explain its function, and describe the augmentation materials, techniques, and complications.",book:{id:"5911",slug:"paranasal-sinuses",title:"Paranasal Sinuses",fullTitle:"Paranasal Sinuses"},signatures:"Gökhan Göçmen and Yasar Özkan",authors:[{id:"200960",title:"Ph.D.",name:"Gokhan",middleName:null,surname:"Gocmen",slug:"gokhan-gocmen",fullName:"Gokhan Gocmen"},{id:"206912",title:"Prof.",name:"Yaşar",middleName:null,surname:"Özkan",slug:"yasar-ozkan",fullName:"Yaşar Özkan"}]}],onlineFirstChaptersFilter:{topicId:"1100",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. 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Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:249,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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