Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7853",leadTitle:null,fullTitle:"Cytokines",title:"Cytokines",subtitle:null,reviewType:"peer-reviewed",abstract:"The human immune system is a complicated biological network that employs a collection of cells, molecules, and proteins. Cytokines play an important role in regulating the innate and adaptive immune systems by different receptors and signaling pathways. As such, they are also implicated in the occurrence of different disorders and diseases. This book presents a comprehensive overview of immunology, the immune system, and cytokines. Chapters cover such topics as the role and importance of tumor necrosis factor (TNF) in the human body, the association of cytokines with different disorders and diseases, and the role of cytokines in dentistry.",isbn:"978-1-78984-859-5",printIsbn:"978-1-78984-858-8",pdfIsbn:"978-1-83968-339-8",doi:"10.5772/intechopen.77671",price:119,priceEur:129,priceUsd:155,slug:"cytokines",numberOfPages:180,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"8f4e8633673d74a52a8394aa6c7b68f2",bookSignature:"Payam Behzadi",publishedDate:"August 19th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7853.jpg",numberOfDownloads:7922,numberOfWosCitations:4,numberOfCrossrefCitations:12,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:22,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:38,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 27th 2018",dateEndSecondStepPublish:"February 26th 2019",dateEndThirdStepPublish:"April 27th 2019",dateEndFourthStepPublish:"July 16th 2019",dateEndFifthStepPublish:"September 14th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",slug:"payam-behzadi",fullName:"Payam Behzadi",profilePictureURL:"https://mts.intechopen.com/storage/users/45803/images/system/45803.jpg",biography:"Dr. Payam Behzadi was born in Tehran, Iran, in 1973. He began his collaboration with the Department of Microbiology, College of Basic Sciences, Shahr-e-Qods Branch, Islamic Azad University as a faculty member in 2004. He has a BSc and MSc in Microbiology and a Ph.D. in Molecular Biology and now continues his scientific activities in the position of assistant professor at Islamic Azad University. He has authored and edited more than twenty chapters and academic books and more than seventy original and review articles. His scientific research interests include urinary tract infections, antibiotics, bioinformatics, genetics, gene profiling, molecular biology, and cellular and molecular immunology. Dr. Behzadi trains as an ice skater in his free time.",institutionString:"Islamic Azad University, Tehran",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"Islamic Azad University, Tehran",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1040",title:"Immunoproteomics",slug:"immunoproteomics"}],chapters:[{id:"72734",title:"Introductory Chapter: Cytokines - The Diamonds and Pearls of Biological Systems",doi:"10.5772/intechopen.93197",slug:"introductory-chapter-cytokines-the-diamonds-and-pearls-of-biological-systems",totalDownloads:761,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:1,abstract:null,signatures:"Márió Gajdács and Payam Behzadi",downloadPdfUrl:"/chapter/pdf-download/72734",previewPdfUrl:"/chapter/pdf-preview/72734",authors:[{id:"45803",title:"Ph.D.",name:"Payam",surname:"Behzadi",slug:"payam-behzadi",fullName:"Payam Behzadi"},{id:"325481",title:"Dr.",name:"Márió",surname:"Gajdács",slug:"mario-gajdacs",fullName:"Márió Gajdács"}],corrections:null},{id:"66336",title:"In vitro Cell-Based Assays for Potency Testing of Anti-TNF-α Biological Drugs",doi:"10.5772/intechopen.85237",slug:"-em-in-vitro-em-cell-based-assays-for-potency-testing-of-anti-tnf-biological-drugs",totalDownloads:1244,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Human cell-based assays for in vitro testing of drugs in preclinical and research studies, as well as in clinical practice, are gaining greater importance especially in view of personalized medicine, which is tailored to the individual needs and benefits of a patient. This chapter begins with an overview of contemporary cell-based assays, routinely used for a comparative in vitro potency testing of anti-TNF-α innovator biologics and their biosimilars. In sequel, based on the results of our original work, we will further discuss the establishment and use of 2D normal and osteoarthritic primary chondrocyte monolayer cultures and 3D microspheroidal articular cartilage tissues, prepared in hanging drops from osteoarthritic chondrocytes and chondrogenically differentiated mesenchymal stem cells. Both 2D and 3D cultures will be presented as models for assessing the neutralizing potency of the three well-known anti-TNF-α biological drugs: adalimumab, etanercept, and infliximab.",signatures:"Sara Žigon-Branc, Ariana Barlič and Matjaž Jeras",downloadPdfUrl:"/chapter/pdf-download/66336",previewPdfUrl:"/chapter/pdf-preview/66336",authors:[{id:"287411",title:"Associate Prof.",name:"Matjaž",surname:"Jeras",slug:"matjaz-jeras",fullName:"Matjaž Jeras"},{id:"287423",title:"Dr.",name:"Ariana",surname:"Barlič",slug:"ariana-barlic",fullName:"Ariana Barlič"},{id:"287425",title:"Dr.",name:"Sara",surname:"Žigon-Branc",slug:"sara-zigon-branc",fullName:"Sara Žigon-Branc"}],corrections:null},{id:"68123",title:"Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation",doi:"10.5772/intechopen.85476",slug:"tumor-necrosis-factor-alpha-a-major-cytokine-of-brain-neuroinflammation",totalDownloads:979,totalCrossrefCites:8,totalDimensionsCites:14,hasAltmetrics:0,abstract:"Tumor necrosis factor (TNF) is one of the most extensively studied cytokine with about 19 distinct superfamily members and many more to be found. Prominent among these members is tumor necrosis factor alpha (TNF-α) that is known to be a potent promoter of inflammation, as well as many normal physiological functions in homeostasis and health and antimicrobial immunity. Nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) is one of the most important transcription factors that activate transcription of many proinflammatory genes, and the unraveling of TNF-α induced NFκB activation forms the foundation of TNF-α as major cytokine of neuroinflammation. This review discusses summary of literature on unique role of TNF-α in neuroinflammation and various agents that mediate neuroinflammation via TNF-α modulation.",signatures:"Mubarak Muhammad",downloadPdfUrl:"/chapter/pdf-download/68123",previewPdfUrl:"/chapter/pdf-preview/68123",authors:[{id:"284676",title:"M.Sc.",name:"Mubarak",surname:"Muhammad",slug:"mubarak-muhammad",fullName:"Mubarak Muhammad"}],corrections:null},{id:"66411",title:"TNFR2 and Regulatory T Cells: Potential Immune Checkpoint Target in Cancer Immunotherapy",doi:"10.5772/intechopen.85632",slug:"tnfr2-and-regulatory-t-cells-potential-immune-checkpoint-target-in-cancer-immunotherapy",totalDownloads:982,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"TNF has both proinflammatory and antiinflammatory effects. It binds to two structurally related but functionally distinct receptors TNFR1 and TNFR2. Unlike TNFR1 that is ubiquitously expressed, TNFR2 expression is more limited to myeloid and lymphoid cell lineages including a fraction of regulatory T cells (Treg). In general, TNFR1 is responsible for TNF-mediated cell apoptosis and death, and mostly induces proinflammatory reactions. However, TNFR2 mainly leads to functions related to cell survival and immune suppression. Treg play an indispensable role in maintaining immunological self-tolerance and restraining excessive immune reactions deleterious to the host. Impaired Treg-mediated immune regulation has been observed in various autoimmune diseases as well as in cancers. Therefore, Treg might provide an ideal therapeutic target for diseases where the immune balance is impaired and could benefit from the regulation of Treg properties. TNFR2 is highly expressed on Treg in mice and in humans, and TNFR2+ Treg reveal the most potent suppressive capacity. TNF-TNFR2 ligation benefits Treg proliferation, although the effect on Treg suppressive function remains controversial. Here, we will describe in detail the TNF-mediated regulation of Treg and the potential clinical applications in cancer immunotherapy as well as in autoimmune diseases, with the focus on human Treg subsets.",signatures:"Xuehui He and Xinhui Wang",downloadPdfUrl:"/chapter/pdf-download/66411",previewPdfUrl:"/chapter/pdf-preview/66411",authors:[{id:"284559",title:"Dr.",name:"Xuehui",surname:"He",slug:"xuehui-he",fullName:"Xuehui He"},{id:"296531",title:"Dr.",name:"Xinhui",surname:"Wang",slug:"xinhui-wang",fullName:"Xinhui Wang"}],corrections:null},{id:"67905",title:"Innate Immunity and Neuroinflammation in Neuropsychiatric Conditions Including Autism Spectrum Disorders: Role of Innate Immune Memory",doi:"10.5772/intechopen.87167",slug:"innate-immunity-and-neuroinflammation-in-neuropsychiatric-conditions-including-autism-spectrum-disor",totalDownloads:1399,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:1,abstract:"The neuroimmune network represents a dense network of multiple signals mediated by neurotransmitters, hormones, growth factors, and cytokines produced by multiple lineage cells and is crucial for maintaining neuroimmune homeostasis. Endogenous and exogenous stimuli, which are dangerous to the body, are detected by sensor cells, and they rapidly inform the brain through this network. Innate immunity is thought to play a major role in the neuroimmune network, through cytokines and other mediators released from secretary innate immune cells. Recent research has revealed that innate immunity has its own memory. This is accomplished by metabolic and epigenetic changes. Such changes may result in augmenting immune protection with a risk of excessive inflammatory responses to subsequent stimuli (trained immunity). Alternatively, innate immune memory can induce suppressive effects (tolerance), which may impose a risk of impaired immune defense. Innate immune memory affects the neuroimmune network for a prolonged period, and dysregulated innate immune memory has been implicated with pathogenesis of neuropsychiatric conditions. This chapter summarizes a role of innate immune memory (trained immunity vs. tolerance) in neuroinflammation in association with neuropsychiatric conditions including autism spectrum disorders (ASD).",signatures:"Harumi Jyonouchi",downloadPdfUrl:"/chapter/pdf-download/67905",previewPdfUrl:"/chapter/pdf-preview/67905",authors:[{id:"289040",title:"Dr.",name:"Harumi",surname:"Jyonouchi",slug:"harumi-jyonouchi",fullName:"Harumi Jyonouchi"}],corrections:null},{id:"72664",title:"Cytokines in Scar Glial Formation after an Acute and Chronic Spinal Cord Injury",doi:"10.5772/intechopen.93005",slug:"cytokines-in-scar-glial-formation-after-an-acute-and-chronic-spinal-cord-injury",totalDownloads:710,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The inflammatory response after a spinal cord injury (SCI) is a secondary mechanism of damage, this involves alterations at the local and systemic level, and it is mediated by cytokine participation that takes part actively. The excessive inflammatory response causes an autoreactive response that targets against components of the nervous tissue; this response lengthens the inflammatory process initiated during the acute phase. The participation of immune cells in acute phases is characterized by the arrival of neutrophils, macrophages, and microglia, as well as T lymphocytes, which express their peaks on different days post-injury (1st, 3rd, and 11th respectively). The chronic phase of the injury begins 14 days after it occurred, reaching its highest point at 60 days, and can still be detected the following 180 days. One of the outcomes of the inflammatory process and cytokine synthesis is the generation of glial scar. In this chapter, we will review the different cytokine mechanisms involved in the formation of glial scar in acute and chronic phases, as well as the modulating treatments of glial scar.",signatures:"Roxana Rodrígez-Barrera, Adrián Flores-Romero, Julián García-Sánchez, Lisset Karina Navarro-Torres, Marcela Garibay-López and Elisa García-Vences",downloadPdfUrl:"/chapter/pdf-download/72664",previewPdfUrl:"/chapter/pdf-preview/72664",authors:[{id:"207140",title:"Dr.",name:"Elisa",surname:"García-Vences",slug:"elisa-garcia-vences",fullName:"Elisa García-Vences"},{id:"280102",title:"Dr.",name:"Roxana",surname:"Rodríguez-Barrera",slug:"roxana-rodriguez-barrera",fullName:"Roxana Rodríguez-Barrera"},{id:"280110",title:"BSc.",name:"Julián",surname:"García-Sánchez",slug:"julian-garcia-sanchez",fullName:"Julián García-Sánchez"},{id:"291737",title:"Dr.",name:"Lisset Karina",surname:"Navarro-Torres",slug:"lisset-karina-navarro-torres",fullName:"Lisset Karina Navarro-Torres"},{id:"303310",title:"MSc.",name:"Adrián",surname:"Flores- Romero",slug:"adrian-flores-romero",fullName:"Adrián Flores- Romero"},{id:"303311",title:"BSc.",name:"Marcela",surname:"Garibay Lopéz",slug:"marcela-garibay-lopez",fullName:"Marcela Garibay Lopéz"}],corrections:null},{id:"68977",title:"The Genetic Aspects of Behçet’s Disease: Role of Cytokine Genes Polymorphisms",doi:"10.5772/intechopen.88856",slug:"the-genetic-aspects-of-beh-et-s-disease-role-of-cytokine-genes-polymorphisms",totalDownloads:657,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Behçet’s disease (BD) is a complex, multisystemic inflammatory disorder characterized by recurrent oral aphthous ulcers, ocular symptoms, skin lesions, and genital ulcerations. The etiology of BD is not yet clear though various factors including environmental, genetic and immunological ones have been implicated. Genetic predisposition is a major factor in disease susceptibility and multiple host genetic factors have been suggested to be involved in the development of BD. In addition to the positive association of HLAB*51, recent studies report additional independent associations in the non HLA loci. Single nucleotide polymorphisms (SNPs) in various genes including cytokines have been implicated in susceptibility to BD. However, the results are inconsistent and variation are found in several ethnic populations. Therefore, further genetic studies on BD patients of different ethnicity and genes associated with immunity are expected to elucidate BD pathogenesis and will contribute to the development of more targeted therapies and biomarkers.",signatures:"Abdulrahman Al Asmari and Misbahul Arfin",downloadPdfUrl:"/chapter/pdf-download/68977",previewPdfUrl:"/chapter/pdf-preview/68977",authors:[{id:"33426",title:"Dr.",name:"Misbahul",surname:"Arfin",slug:"misbahul-arfin",fullName:"Misbahul Arfin"},{id:"48372",title:"Dr.",name:"Abdulrahman",surname:"Al-Asmari",slug:"abdulrahman-al-asmari",fullName:"Abdulrahman Al-Asmari"}],corrections:null},{id:"72582",title:"IL-21 Signaling and Induction of Cytokine Expression in Human Leukemia Cells and Monocytes",doi:"10.5772/intechopen.93004",slug:"il-21-signaling-and-induction-of-cytokine-expression-in-human-leukemia-cells-and-monocytes",totalDownloads:538,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Interleukin-21 (IL-21) is produced by activated T cells and it plays many diverse roles by regulating the functions of normal and abnormal cells. Its roles include regulation of proliferation, promotion of immune system and activation of apoptosis in B cells. IL-21R is a type-1 cytokine receptor and belongs to the IL-2R and IL-15R family. The signaling mechanisms of IL-21 in different cell types have been identified. However, we know less about the biological effects of IL-21 and its signaling mechanisms in leukemia cells and monocytes. In this chapter, we will focus on IL-21’s biological effects and signaling pathways as well as discuss the potential implications and applications of IL-21 in leukemia cells. In these cells, IL-21 does not promote proliferation but enhances apoptosis and chemotaxis. Furthermore, IL-21 promotes differential expression of many cytokines including interleukins and chemokines. IL-21 activates both the Raf-ERK-MAPK and the Jak/STAT signaling pathways. These pathways mediate some of the effects of IL-21. Lastly, IL-21 also promotes activation of the STAT3 promoter and other transcriptional factors. These findings may be relevant to IL-21’s potential clinical implications and applications.",signatures:"Chantel F. Faqua, Richard Akomeah and Samuel Evans Adunyah",downloadPdfUrl:"/chapter/pdf-download/72582",previewPdfUrl:"/chapter/pdf-preview/72582",authors:[{id:"298401",title:"Prof.",name:"Samuel Evans",surname:"Adunyah",slug:"samuel-evans-adunyah",fullName:"Samuel Evans Adunyah"},{id:"303135",title:"Dr.",name:"Chantel F.",surname:"Fuqua",slug:"chantel-f.-fuqua",fullName:"Chantel F. Fuqua"},{id:"303136",title:"Dr.",name:"Richard",surname:"Akomeah",slug:"richard-akomeah",fullName:"Richard Akomeah"}],corrections:null},{id:"70168",title:"Cytokines’ Involvement in Periodontal Changes",doi:"10.5772/intechopen.89999",slug:"cytokines-involvement-in-periodontal-changes",totalDownloads:658,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The bacterial challenge on the periodontal tissues triggers an inflammatory reaction, driven by pro-inflammatory cytokines, that eventually leads to the periodontal structures’ damage. The pathogenic mechanisms of this inflammatory reaction are complex and are influenced by the type of host-immune response and certain local and systemic factors. These factors can influence periodontal inflammation, through the action of the various pro-inflammatory cytokines. Periodontal disease and certain systemic conditions can have a mutual association, as the pathogenic mechanisms of these diseases can involve similar molecular and cellular elements. The concept of ‘periodontal medicine’ comprises these pathogenic connections, focusing on the key role that periodontal health has on the general homeostasis and well-being.",signatures:"Petra Surlin, Liliana Foia, Sorina Solomon, Dora Maria Popescu, Dorin Nicolae Gheorghe, Adrian Camen, Maria Alexandra Martu, Anne Marie Rauten, Madalina Olteanu, Allma Pitru, Vasilica Toma, Simona Popa, Mihail Virgil Boldeanu, Silvia Martu and Ion Rogoveanu",downloadPdfUrl:"/chapter/pdf-download/70168",previewPdfUrl:"/chapter/pdf-preview/70168",authors:[{id:"44560",title:"Dr.",name:"Simona",surname:"Popa",slug:"simona-popa",fullName:"Simona Popa"},{id:"67378",title:"Prof.",name:"Liliana",surname:"Georgeta Foia",slug:"liliana-georgeta-foia",fullName:"Liliana Georgeta Foia"},{id:"171921",title:"Prof.",name:"Petra",surname:"Surlin",slug:"petra-surlin",fullName:"Petra Surlin"},{id:"172585",title:"Dr.",name:"Anne Marie",surname:"Rauten",slug:"anne-marie-rauten",fullName:"Anne Marie Rauten"},{id:"210191",title:"Prof.",name:"Adrian",surname:"Camen",slug:"adrian-camen",fullName:"Adrian Camen"},{id:"235560",title:"Ph.D.",name:"Dorin Nicolae",surname:"Gheorghe",slug:"dorin-nicolae-gheorghe",fullName:"Dorin Nicolae Gheorghe"},{id:"245303",title:"Dr.",name:"Vasilica",surname:"Toma",slug:"vasilica-toma",fullName:"Vasilica Toma"},{id:"296937",title:"Dr.",name:"Dora-Maria",surname:"Popescu",slug:"dora-maria-popescu",fullName:"Dora-Maria Popescu"},{id:"296942",title:"Dr.",name:"Maria-Alexandra",surname:"Martu",slug:"maria-alexandra-martu",fullName:"Maria-Alexandra Martu"},{id:"296943",title:"Prof.",name:"Silvia",surname:"Martu",slug:"silvia-martu",fullName:"Silvia Martu"},{id:"296944",title:"Prof.",name:"Sorina-Mihaela",surname:"Solomon",slug:"sorina-mihaela-solomon",fullName:"Sorina-Mihaela Solomon"},{id:"296954",title:"Dr.",name:"Allma",surname:"Pitru",slug:"allma-pitru",fullName:"Allma 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\r\n\tMedicinal herbs and culinary spices are very important sources of bioactive compounds for different kinds of industries. They accompany a person's life from birth to grave almost every day, in various forms is, served to our table as a part of the food. Many plants are necessary for technical and bioenergetic purposes, and a large group of plants is used in medicine, pharmacy, cosmetics as well as in folk medicine, and gastronomy. Approximately one thousand types of medicinal plants grow in Europe – about 800 are used in folk medicine, more than 300 in European officinal medicine. Nowadays, people have started to be more interesting in this kind of plant due to the benefits. The style "return back to tradition" is one of the more popular trends. The aim of this book is brought to information about medicinal herbs and spices – botany characteristics, chemical components, and the possibility of use in different kinds of industries.
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1. Introduction
The ocular surface is an anatomic entity that is composed of different ocular structures: conjunctiva, limbus, and cornea. A healthy ocular surface should have a healthy tear film overlying it. The maintenance of ocular surface in an optimal and healthy state contributes both esthetic and functional wellness of the eye.
From the anatomic point of view, the ocular surface includes the mucosal epithelium limited by the skin of the free edge of the eyelids. It includes the cornea and the conjunctiva. The interdependence of the structures integrated into this system and their influence on the corneal epithelium and ultimately on the eyeball makes them of great importance to the health of the eye. In addition, the primordial cells of the corneal epithelium are located at the corneoscleral limbus.
Tumors of the conjunctiva can arise from any of the cells that are naturally present and are evident histologically; thus, there is a wide variety of these tumors. They originate from the squamous epithelium, melanocytes, and lymphocytic cells found in the conjunctival stroma. The epithelial and melanocytic origins are more frequent.
This chapter will start by describing the normal histology of the ocular surface with selected correlated functional aspects of the biologic micro-design. Afterward, the most important malignant neoplastic processes affecting the conjunctiva will be reviewed along with the latest updates in the medical literature.
2. Histology of ocular surface
2.1. Conjunctiva
The conjunctiva is a transparent mucous membrane that covers the ocular surface from the limbus to the mucocutaneous junction. It plays an essential role in maintaining a healthy and optically clear cornea. The part covering the sclera is known as the bulbar conjunctiva, while the palpebral conjunctiva lines the posterior surface of the eyelids. The forniceal conjunctiva is the portion that connects the bulbar with the palpebral parts. The bulbar conjunctiva is loosely attached to the underlying Tenon’s capsule except at the limbus where they fuse together. The palpebral part is tightly adherent to the tarsus, while the forniceal portion is loose and redundant. A crescent-shaped fold of the conjunctiva called the plica semilunaris is found nasally. Medial to the plica lies the caruncle, a pinkish globular nodule that contains sebaceous glands and hair follicles in addition to the adnexal elements of the conjunctival stroma.
The surface layer of the conjunctiva is composed of non-keratinizing stratified squamous epithelium with numerous goblet cells. Melanocytes are normally present in the basal layer of the epithelium. The morphology and the number of layers of the conjunctival epithelial cells change according to the region from which a biopsy was taken. There are approximately six to nine layers of stratified squamous epithelium in the bulbar conjunctiva. The epithelial cells are columnar in the forniceal part and cuboidal in the area attached to the tarsus where the epithelial cells are packed in two to five layers. The goblet cells are distributed throughout the bulbar and tarsal conjunctiva and are most concentrated inferonasally and in the region of the caruncle and plica semilunaris.
The conjunctival stroma (substantia propria) is a thin, richly vascularized layer enclosing scattered lacrimal glands (based on the anatomic location), lymphatics, plasma cells, macrophages, and mast cells. Additionally, it comprises numerous elastic fibers that facilitate globe movement in all gazes. Specialized collections of T and B lymphocytes underlying a modified epithelium is known as conjunctiva-associated lymphoid tissue (CALT). It functions to process antigens and provides immunity against pathologic microbes on the ocular surface [1]. Conjunctival stem cells are scattered throughout the bulbar or forniceal conjunctiva.
2.2. Corneoscleral limbus
The limbus is the transitional region between the corneal margin and the anterior sclera. It is approximately 1–1.5 mm wide. The limbus contains the corneal stem cells located in the basal cell layer. There are histological, pathological, and surgical definitions of the limbus. Histologically, the central margin of the limbus is limited by a line connecting the peripheral termination of Bowman’s layer externally and Schwalbe’s line, the peripheral termination of Descemet’s membrane, internally. The peripheral margin of the limbus is bounded by the central margin of the scleral spur. The peripheral margin from pathologist’s point of view is formed by a vertical line that is perpendicular to the scleral spur [1].
Surgically, the limbus is divided into two zones: a central blue-gray zone and a peripheral white zone. The central zone corresponds to the area connecting Bowman’s layer and Descemet’s membrane. The peripheral zone overlies the trabecular meshwork [2].
2.3. Cornea
The cornea is the anterior and transparent portion of the fibrous tunic of the eye globe and is the most powerful refractive element of the optical system of the eye. Its transparency is a function of different factors: avascularity, relative acellularity, relative dehydration, and the remarkable organization of the stromal collagen lamellae. The anterior surface of the cornea measures 11–12 mm horizontally and 10–11 mm vertically. The thickness of the cornea is 0.52 mm centrally and 0.65 mm peripherally. The water content is 78% and is controlled by intact epithelium and endothelium. Its refractive index is 1.376 [1].
In the following sections, the histology of the different layers of the cornea will be described from anterior to posterior: the epithelium, Bowman’s layer, stroma, Descemet’s membrane, and endothelium.
2.3.1. Epithelium
The corneal epithelium is the outermost layer of the cornea and is derived from the embryonic surface ectoderm. It is composed of 4–5 multilayered stratified, non-keratinized squamous epithelium with an underlying single layer of basal cells. It is continuous with the conjunctival epithelium at the limbus. Its overall thickness is approximately 50 μm with a complete turnover in 7–10 days. This multilayered epithelium is distributed in three strata: superficial flattened cells, middle wing cells, and deep basal cells [1].
The basal cell layer is considered the mother of the overlying cells, i.e., wing and the superficial cells. The basal cell density is approximately 6000 cells/mm2. They originate from the corneal limbal stem cells. The new cells travel from the limbus in a centripetal manner at a rate of approximately 120 μm/week. The cells communicate with each other through gab junctions and actively secrete their basal lamina (50 nm thick, type IV collagen) where they adhere to it via hemidesmosomes. Alteration of hemidesmosomes can result in recurrent epithelial erosions, as seen in patients with epithelial basement membrane dystrophy (EBMD) [1].
Wing cell layer is composed of 2–3 cell rows that overly the basal cells. These cells are given this name because they have extensions that make them resemble wings in cross section. They are attached to each other by zonulae occludentes that form a semipermeable membrane, an important factor preventing components of the tear film to get into the corneal stroma. The outermost layer is 2–3 rows of flattened cells that are shed in the tear film to be replaced by other cells. The ultrastructure of their apical surfaces is rough and quite irregular owing to the presence of countless microplicae and microvilli. All epithelial cells are connected to each other by desmosomes and communicate via gap junctions. Reduction of the number of desmosomes is noted in patients with topical anesthetic abuse [3].
Growth factors secreted by the lacrimal glans and corneal epithelial cells play an essential role in the maintenance of healthy epithelial cells. Among which, insulin-like growth factor (IGF-1) and its receptor IGF-1R alterations have been implicated in cases of hyperglycemia with resultant diabetic keratopathy. This disease is associated with superficial punctate keratitis, recurrent corneal erosions, and persistent epithelial defects in addition to severe neuroepithelial dysfunction. Moreover, the interaction of IGF-1R with its twin insulin receptor (INSR) to form a hybrid receptor (the Hybrid-R) has been reported. The Hybrid-R was detected in the corneal epithelial cell nuclei where it interacts with DNA and is proposed to control gene expression important in maintaining ocular surface biology [4].
2.3.2. Bowman’s layer
Bowman’s layer lies directly underneath the basal lamina. As the name implies, this stratum is a layer and not a true membrane with the absence of staining by periodic acid-Schiff (PAS) stain. It is an acellular layer that cannot regenerate forming a scar after injury. It has a thickness of 8–12 μm. Similar to the corneal stroma, it is composed of type I and type V collagen, but in contrast to the stroma, the ratio of type V to type I is higher. In addition, unlike the stroma, the collagen lamellae are smaller and more randomly arranged. The limbus starts at the peripheral termination of this layer [1].
Bowman’s layer is a key factor in maintaining the corneal biomechanical properties by its stiff and tough nature. Abnormalities of this layer can result in corneal ecstatic disorders such as keratoconus due to biomechanical failure [5].
2.3.3. Stroma
The corneal stroma occupies 90–95% of the thickness of the cornea. It is derived from the neural crest cells. In the center, it measures about 500 μm, while it becomes thicker toward the periphery. It is formed by proteoglycans (keratan sulfate and dermatan sulfate) covalently linked to a nucleus of a protein and a large number of collagen fibrils arranged parallel to the surface of the cornea. These corneal stromal collagen lamellae (200–250 lamellae) are composed principally of type I and type V, with lesser amounts of types III and VI. The distance between these lamellae, occupied by proteoglycans, is constant. This property is very important in maintaining the corneal transparency by eliminating any interference with light transmission [1]. A relatively recently introduced layer, the pre-Descemet’s layer (Dua’s layer), is an acellular layer measuring approximately 10 μm and is found in the posterior stroma [6]. Among these collagen fibrils, we find the keratocytes, which are specialized fibroblasts that synthesize collagen and proteoglycans. There are about 2.4 million keratocytes spread within the stroma with higher density being anterior. They are extremely active cells evident by abundant mitochondria, rough endoplasmic reticulum, and Golgi apparatuses. They are flat and evenly distributed. Their plasma membranes are fenestrated. Gap junctions are the conduits through which communication occurs. The cell density decreases with age at a slower rate than the corneal endothelium [1].
The posterior portion of the stroma is typically wetter than the anterior one. This occurs because of the wetting effect of the aqueous humor posteriorly and the drying effect of the atmosphere anteriorly. Corneal stromal edema, as seen in cases of endothelial failure, will result in enlarged spacing between the lamellae and subsequent visual compromise [1].
2.3.4. Descemet’s membrane
Descemet’s membrane corresponds to the basal lamina of the corneal endothelium. It is a true basement membrane that is PAS-positive. Its thickness is variable and linked to the age of the individual as it is continuously secreted by the endothelium. In neonates, it measures 2–4 μm thick and reaches up to 10–12 μm by adulthood [1]. It has two histologically distinct layers: the anterior banded layer produced in utero and the posterior non-banded layer produced throughout life. It is composed of type IV collagen, laminin, and fibronectin [1].
Descemet’s membrane is fundamental in providing support and adhesion to the endothelial cells. In addition, it is resistant to the phagocytic, toxic, and enzymatic insults. However, it is relatively weakly attached to the overlying stroma and, thus, can be surgically dissected as one piece [1].
2.3.5. Endothelium
The corneal endothelium is a monolayer located on the inner side of the cornea and is about 4–6 μm thick. Similar to the stroma, the endothelium comes from neural crest cells. The cells cannot regenerate after birth. The endothelial cell density is about 3000 cells/mm2 with 500,000 cells covering the posterior surface of the cornea. This number decreases slowly with age at a rate of 0.6% per year. The most common cell shape is hexagonal. Minimal variation in cell size (polymegathism) and cell shape (pleomorphism) can be seen in normal individuals. The endothelium has two principal functions aiming to maintain the corneal clarity: the barrier and the metabolic pump functions [1]. These cells are joined together by interdigitations that are only visible by an electron microscope. In addition, focal tight junctions can be seen in the apicolateral membranes. They communicate through gap junctions. The endothelial cell layer is relatively semipermeable to allow some nutrients to pass paracellularly to the remaining corneal layers [1].
The high metabolic demand of the endothelial cells is evident by the presence of numerous mitochondria, the prominent smooth and rough endoplasmic reticulum, ribosomes, and Golgi apparatuses. Pinocytic vesicles can be seen in the cytoplasm pumping fluid from the stroma to the anterior chamber [1]. The endothelial pump requires the existence of bicarbonate, the membrane bicarbonate transporters, Na-K ATPase, and carbonic anhydrase activity. Thus, corneas with low or relatively dysfunctional endothelial cells contraindicate the use of topical carbonic anhydrase inhibitors [4].
Peripheral corneal guttae (Hassall-Henle bodies) are minute excrescences that can be observed in the peripheral part of Descemet’s membrane. It is considered a natural aging process. They represent focal thickening of Descemet’s membrane. A histologically similar but pathological in nature is the appearance of central cornea guttae. They are associated with progressive corneal stromal and epithelial edema representing Fuch’s endothelial dystrophy [1].
3. Histopathology of ocular surface
Tumors of the ocular surface are the most frequent of the eye and appendages along with those of the eyelids. They cover a wide spectrum from benign lesions such as papilloma to others that may endanger the visual function and the life of the patient, such as squamous cell carcinoma and melanoma [6, 7]. They can arise from any of the cells that make up the conjunctiva although the most frequent are those of epithelial and melanocytic origins. The tumors of the conjunctiva can be epithelial (non-melanocytic and melanocytic) and stromal (lymphoproliferative, vascular, neural, lipomatous, histiocytic, myogenic, fibrous, and choristomatous). In addition, tumors of the ocular surface encompass caruncular and metastatic tumors. This chapter will focus on the epithelial tumors.
3.1. Non-melanocytic epithelial tumors
3.1.1. Squamous papilloma
Squamous papilloma appears at any age with variable presentation [8]. Human papilloma viruses (HPV) 6, 11, or 16 result in the development of squamous papillomas in children [9]. Patients can present with pink, single or multiple, sessile, or pedunculated lesion in the inferior fornix and less commonly the bulbar conjunctiva. In older patients, papilloma can result in relation to HPV infection or in patients with compromised immunity [10]. Clinically, it usually presents as unilateral light pink mass at the limbus or the caruncle. It may have the appearance of squamous cell carcinoma (SCC). In addition, squamous papilloma is a premalignant lesion and has been reported to transform to SCC, transitional cell carcinoma, or mucoepidermoid carcinoma particularly in the inverted growth pattern [11, 12, 13]. The lesion classically demonstrates many vascularized papillary fronds lined by the acanthotic epithelium with no evidence of pleomorphism or dysplasia (Figure 1).
Figure 1.
Histopathological image of a conjunctival squamous papilloma (original magnification ×50 hematoxylin and eosin).
This lesion is a benign inflammatory lesion manifested by a reactive proliferation of the conjunctival epithelium. It is also called pseudocarcinomatous hyperplasia as it resembles malignant lesions in clinical and histopathological examinations [7]. It is caused by irritation of the conjunctiva by a coexisting or previously existing stromal inflammation, foreign body, vernal keratoconjunctivitis, pterygium, and pinguecula. Clinically, a rapidly progressing elevated pink limbal lesion with leukoplakia and hyperkeratosis is seen. The histopathology shows an extensive acanthosis and hyperkeratosis in addition to parakeratosis of the conjunctival epithelium. There is no cytological atypia.
3.1.3. Keratoacanthoma
It is a rare variant of conjunctival pseudoepitheliomatous hyperplasia. A rapidly progressing hyperkeratotic lesion is seen [8, 14, 15, 16]. The documented cases have occurred on the bulbar conjunctiva, within the palpebral aperture, and adjacent to the limbus.
3.1.4. Dacryoadenoma
Dacryoadenoma is an exceedingly rare condition occurring in children and adolescents. It is a benign tumor originating from the conjunctival epithelium and grows into the stroma forming glandular lobules analogous to the lacrimal gland with goblet cells. Clinically, it appears as a translucent fleshy lesion anywhere in the conjunctiva [8, 12, 17].
3.1.5. Conjunctival keratotic plaque and actinic keratosis
These leukoplakic conjunctival lesions cannot be differentiated clinically. They usually arise in the interpalpebral region. Histologically, a conjunctival keratotic plaque is characterized by acanthosis, hyperkeratosis, and parakeratosis. There is no dyskeratosis. Typically, it has no malignant potential.
In actinic keratosis, a gradually progressing flat leukoplakic lesion that may frequently be indistinguishable from conjunctival intra-epithelial neoplasia (CIN) is observed [8, 12, 18]. Positive rose bengal staining of the lesion surface is seen in cases of CIN. Epithelial hyperplasia acanthosis, keratosis, or parakeratosis are found in addition to some atypia. The basement membrane is intact.
3.1.6. Ocular surface squamous neoplasia (OSSN)
Ocular surface squamous neoplasia (OSSN) is a common term that describes a spectrum of benign, premalignant, and malignant epithelial lesions of the conjunctiva and cornea. Thus, OSSN encompasses conjunctival or corneal intraepithelial dysplasia, carcinoma in situ, and invasive squamous cell carcinoma (SCC) [19]. Previously, the terms used to describe the spectrum of OSSN were Bowen’s disease, Bowenoid epithelioma, and intraepithelial epithelioma [20].
CIN approximately accounts for 4% of all conjunctival lesions and 39% of premalignant and malignant lesions of the ocular surface [21]. The incidence of invasive SCC is ranging from 0.02 to 3.5/100,000 population [22]. Three quarters of cases occur in men and older patients and at the limbus, although any part of the conjunctiva or cornea may be affected mostly within the interpalpebral fissure [12, 21].
Risk factors associated with the development of OSSN are exposure to sunlight, HPV type 16 infections, and immunodeficiency [12, 23]. In addition, xeroderma pigmentosum and Papillon-Lefevre syndrome are associated with recurrent OSSN, occurring in younger individuals [24]. Rarely, OSSN can be bilateral in immunosuppressed patients. Regional lymph node involvement and infrequently distant metastasis may occur.
Clinically, the lesion may appear fleshy, gelatinous, leukoplakic, or papillomatous. Leukoplakia is most likely due to hyperkeratosis or surface keratinization. Feeder vessels may be prominent, or the lesion may be avascular. As mentioned earlier, rose bengal staining can support the diagnosis and help in the demarcation of the tumor extent. It is essential to examine the tarsal conjunctiva with upper eyelid eversion to look for extension or multifocal involvement. Clinical correlation with histological severity is unpredictable. Intraocular extension occurs in 2–15% of SCC patients for which enucleation and sometimes exenteration, if the orbit is invaded by the malignant process resulting in proptosis, are often needed [22, 25]. The limbal lesion may invade the adjacent corneal epithelium and appear as advancing superficial faint opacity that may be associated with subtle vascularization. Rarely, primary SCC of the cornea can occur. Additionally, there are no reliable clinical measures for characterizing the differences between CIN and invasive SCC. However, leukoplakia raises the suspicion of malignancy and is generally absent or insignificant in CIN. Extensive vascularity and nodularity of the lesion are in favor of SCC. Tumor thickness is not a reliable sign of malignant potential, as there are thick tumors that remain confined within the epithelium. Diffuse conjunctival involvement can masquerade as conjunctivitis-type symptoms and signs [26].
The typical cytological features that are seen in OSSN on impression cytology include pleomorphic cells with hyperchromatic nuclei having an irregular outline and prominent nucleoli. However, the diagnosis of OSSN using this tool is controversial as the previously mentioned features might not be seen in the superficial layers overlying the tumor [27]. Thus, it is less sensitive in regard to the diagnosis of SCC. In addition, it cannot differentiate between CIN and invasive SCC. Hence, biopsy in suspected cases is advisable [28].
The histopathological examination of an incisional or excisional biopsy is of central role in OSSN diagnosis and treatment plan. The submitted conjunctival tissue is flattened with the mucosal surface directed upward using a filter paper with special attention to the proper orientation of the specimen. After being left to dry, it is placed in 10% buffered formalin [19]. Histopathologically, the lesion can show any of the following spectra: conjunctival epithelial dysplasia in which dysplastic cells are confined to the basal epithelial layer and/or carcinoma in situ where the full thickness of the epithelium is occupied by dysplastic cells with characteristic abrupt demarcation between the dysplastic epithelium and the normal epithelium (Figures 2 and 3). Invasive squamous cell carcinoma occurs when the underlying basement membrane is violated (Figure 4). The first two are sometimes termed conjunctival/corneal intraepithelial neoplasia (CCIN). The dysplasia is further classified into mild, moderate, and severe grades based on the level of epithelial thickness involvement. Mild dysplasia shows dysplastic cells in the lower one-third of the epithelium, while moderate dysplasia is involving the lower two-thirds. The histological characteristics of epithelial dysplasia include loss of polarity, increased nuclear-cytoplasmic ratio, increased number of mitotic figures, cellular polymorphism, nuclear hyperchromatism, and enlarged nucleoli. Conjunctival SCC that closely resembles the structure of the normal epithelium with keratinization is described as being well-differentiated. A tumor that resembles the original tissue to a lesser extent is termed poorly differentiated.
Figure 2.
A case of conjunctival squamous cell carcinoma in situ with a transition from normal conjunctival epithelium to the dysplastic epithelium (original magnification ×200 hematoxylin and eosin).
Figure 3.
Another case of conjunctival squamous cell carcinoma in situ with intact basement membrane and adjacent area of normal conjunctival epithelium (original magnification ×200 hematoxylin and eosin).
Figure 4.
A case of conjunctival invasive squamous cell carcinoma with superficial keratinization (original magnification ×200 hematoxylin and eosin).
Increasing age, large size tumors, involvement of the surgical margins, and high Ki-67 proliferation index are risk factors for recurrence of OSSN [25]. Fortunately, with the invention of new treatment modalities, the prognosis has improved with an overall recurrence rate of approximately 5% and regional lymph node metastasis of less than 2% [19].
SCC is classified depending on the size, tumor location, and the extent of involvement as per the American Joint Committee on Cancer (AJCC) with consideration to the primary tumor features, lymph node involvement, and metastasis represented using (TNM) classification. Highly malignant variants include spindle cell squamous carcinoma (Figure 5), mucoepidermoid carcinoma, and adenoid SCC [8, 12, 23, 29, 30, 31].
Figure 5.
A case of conjunctival spindle cell carcinoma with wavy pattern of spindle cells and high degree of pleomorphism (original magnification ×100 Periodic acid-Schiff).
The concept of molecular genetics in cases of OSSN and ocular oncology has expanded in the recent years. It studies the interaction between genes and protein with attention to the activity patterns in different neoplastic cells. Alterations on chromosome 8 with 8p11.22 amplifications have been described in 75% of the tumors. This region encompasses a group of genes that code for ADAM proteins. One of the genes in this group is involved in oral SCC. In addition, Collagen type I alpha1 (COL1A1) is also found in ocular cases and was identified to be upregulated in oral squamous cell carcinoma [32, 33].
3.2. Melanocytic epithelial tumors
Melanocytic conjunctival lesions have a wide spectrum of disorders. They range from benign to highly malignant fatal tumors. In the following subsections, the most common differential diagnoses of melanocytic conjunctival lesions will be discussed.
3.2.1. Conjunctival nevus
Conjunctival nevi are the most common melanocytic conjunctival tumors. Conjunctival nevi usually start to appear in children or adolescents as a group of pigmented cells in the basal layer of the conjunctival epithelium. Conjunctival nevi are more prevalent in Caucasians (89%) with Africans (6%) and Asians (5%) being less commonly affected [33]. Conjunctival nevi are typically pigmented, but approximately 16% can be amelanotic or partially pigmented [12, 34]. Juxta-limbal location is the most common location occurring in more than two-thirds of patients. Other locations include the caruncle, plica semilunaris, fornix, tarsus, and cornea [34, 35].
There are three types of conjunctival nevi based on their histological location: compound, subepithelial, and junctional nevi being the least common. Compound nevi are characterized by the presence of melanocytic cells at the epithelial-subepithelial junction and within the stroma (Figure 6). Subepithelial lesions are located solely in the subepithelial area. They are often associated with epithelial inclusions cysts and goblet cells (Figure 7). Junctional nevi consist of nests of nevus cells at the epithelial-subepithelial junction. They are rare except in children. These types are considered more of phases of migration of the nevus cells from the basal epithelium to the conjunctival stroma.
Figure 6.
Histopathological appearance of a compound conjunctival nevus with nests of nevus cells at the base of the conjunctival epithelium and within the substantia propria (original magnification ×50 hematoxylin and eosin).
Figure 7.
Histopathological appearance of a subepithelial conjunctival nevus with cystic areas lined by the conjunctival epithelium and goblet cells within the substantia propria (original magnification ×100 periodic acid-Schiff).
Malignant transformation was estimated to be <1% [21, 35]. However, new onset in middle age or later in life, unusual location (i.e., fornix, tarsus, caruncle, plica), large lesions more than 10 mm in diameter, prominent feeder vessel or intrinsic vascularity with hemorrhage, non-cystic lesions, and non-mobile lesions (i.e., fixed to the underlying episclera) are clinical indications to excise the lesion [36].
3.2.2. Complexion-associated melanosis (CAM)
CAM, also known as racial melanosis, is a benign bilateral conjunctival lesion found among darkly pigmented individuals [8, 12]. It is typically observed in the peri-limbal area and uncommonly in the fornix or palpebral conjunctiva. On examination, variably pigmented non-cystic flat lesions are observed.
3.2.3. Primary acquired melanosis (PAM)
PAM is defined as melanocytic proliferation in the conjunctival epithelium. It is more frequent in light-skinned individuals and is usually unilateral. It typically begins insidiously in the middle age. Sunlight exposure may be a risk factor in the development of PAM. It may originate from an abnormality in neural crest as it has also been seen in patients with neurofibromatosis [37].
It presents as a flat brown, superficial, non-cystic, solitary, patchy, diffuse, or multifocal pigmentation involving bulbar, forniceal, and palpebral conjunctiva or cornea. Amelanotic PAM can be occasionally seen [8, 21, 38]. Cellular atypia, determined by biopsy and careful histopathological examination, aided by immunohistochemical staining (using Melan-A stain to highlight the melanocytes), is the principal risk factor for progression to melanoma (Figures 8 and 9). In one study of 311 eyes with PAM, lesions without atypia or with mild atypia demonstrated 0% progression into melanoma. On the other hand, 13% of patients having PAM with severe atypia progressed into melanoma [21].
Figure 8.
Histopathological appearance of conjunctival primary acquired melanosis (PAM) with melanocytic proliferation at the base of the conjunctival epithelium without evidence of atypia (original magnification ×200 hematoxylin and eosin).
Figure 9.
Immunohistochemical staining of another case of conjunctival primary acquired melanosis (PAM) showing clearly the melanocytic proliferation at the base of the conjunctival epithelium without evidence of atypia (original magnification ×200 Melan-A).
Clinical indications to perform a biopsy include ≥5 mm lesion diameter, progression, thickening, the appearance of a nodule, vascularity, involvement of the palpebral conjunctiva or cornea, patients with personal or family history of dysplastic nevus syndrome, and history of ocular or extraocular melanoma [12].
3.2.4. Conjunctival melanoma
Conjunctival melanoma, although rare, represents the second most frequent malignant conjunctival lesion after squamous cell carcinoma [39]. In the past, its evolution almost invariably resulted in an unfavorable prognosis, resulting in orbital exenteration in an attempt to eradicate the highly invasive disease. It represents a challenge for the clinician and pathologist because it can present in several pictures and originates from apparently benign lesions such as conjunctival nevi [40]. Conjunctival melanoma most frequently affects white individuals with an incidence varying from 0.24 to 0.80/1,000,000 population [41, 42]. It is more frequent in elderly individuals with a mean age ranging from 55 to 70 years [41, 42, 43, 44, 45, 46, 47]. Although rare in young people, there are reports of conjunctival melanoma cases in patients less than 20 years of age [48, 49]. There is no significant difference between men and women [41, 42, 43, 44, 45, 46, 47].
Conjunctival melanoma arises from PAM in 75% of cases, preexisting nevus in 20%, and de novo in 5% [8, 12]. Systemic risk factors include dysplastic nevus syndrome, neurofibromatosis, and xeroderma pigmentosum [38]. Sunlight exposure is also suggested as a cause in the development of bulbar conjunctival melanoma. The most frequent location of conjunctival melanoma is the bulbar conjunctiva in the peri-limbal area, but it can occur in any location, such as the palpebral or forniceal conjunctiva, the plica, or the region of the caruncle [45, 47, 50, 51].
Clinically, conjunctival melanomas may have variable presentations. Classically, it presents as a mass or an elevated pigmented conjunctival lesion. In some cases, it may appear more diffuse or multiple, with poorly defined borders, particularly when associated with PAM [22]. Less commonly, conjunctival melanomas can present as a pink or reddish pigmented lesion or can be even amelanotic, making it difficult to recognize and, thus, delaying its diagnosis and treatment [47]. Moreover, the recurrence of conjunctival melanoma after excision is typically amelanotic [12]. Repeated and continuous contact of the conjunctiva from an adjacent eyelid margin melanoma may cause a secondary conjunctival melanoma (implantation melanoma) [52]. Like SCC, conjunctival melanoma is classified according to the AJCC-TNM classification. Conjunctival melanomas can metastasize regionally to pre-auricular and submandibular lymph nodes. Distant metastasis involves the brain, liver, skin, and bone [53].
Conjunctival melanocytic intra-epithelial neoplasia (C-MIN) is a term used to describe lesions exhibiting proliferation of melanocytes. Scoring of C-MIN is based on several factors including the pattern of horizontal and vertical epithelial involvement, the degree of cellular atypia, nuclear and cellular diameter, and the presence of nucleoli and mitotic figures. Then, C-MIN is graded from 0 to 10 with 0 corresponding to an absence of any melanocytic proliferation or atypia (i.e., melanosis only), 1–4 corresponding to the severity of PAM (i.e., mild, moderate, and severe atypia), and 5–10 corresponding to conjunctival melanoma in situ (Figure 10) [54].
Figure 10.
Histopathological appearance of conjunctival melanoma in situ with atypical melanocytic proliferation involving the full thickness of the conjunctival epithelium (original magnification ×200 periodic acid-Schiff).
The lesions usually demonstrate atypical melanocytic proliferation characterized by abundant cytoplasm, prominent nucleoli, and atypical mitotic figures with invasion of the underlying conjunctival stroma as well as the adjacent epithelium. Atypical melanocytic proliferation can be limited to the epithelium in the early stages in cases arising from PAM (melanoma in situ) with radial spread in a similar way to cutaneous melanomas. The entire lesion should be removed in one piece without touching it by excising it along the limbus to prevent seeding of the tumor cells in the surgical area.
Pathological examination of the excised lesion should include observation of important features such as ulceration, thickness of the tumor and its predominant histologic cell type (i.e., epithelioid or spindle), and the vertical growth phase. Other important characteristics include lymphocytic infiltration, vascular or perineural invasion, and the mitotic activity detected using Ki-67 index. In addition, microscopic satellitosis—defined as separate nests of tumor disconnected from the main malignant mass—should be also observed [55].
Evident histopathological features that are associated with worse survival include tumor thickness more than 2 mm, the presence of ulceration, epithelioid morphology, higher count of mitotic figures (>1/mm2), lymphovascular invasion, and microsatellitosis [55, 56]. Extra-bulbar conjunctival melanoma is found in a multivariate analysis study to be associated with poor outcome [57].
Immunohistochemical (IHC) stains for melanocytes such as Melan-A red, MART-1, S-100 protein, HMB-45, and the cell proliferative marker Ki-67 may help to identify melanocytic problematic cases. In conjunctival melanomas, the immunohistochemical expression of HMB-45 and Ki-67 is higher than what is observed in PAM or conjunctival nevi [58]. Beta-catenin is an IHC marker that was more strongly expressed in conjunctival melanomas compared to nevi and PAM. Thus, its role in conjunctival melanomas is different than cutaneous melanoma, in which loss of beta-catenin expression has been associated with a more aggressive course [58]. Programmed cell death protein 1 (PD-1) and its interaction with its ligand PD-L1 studied in patients with conjunctival melanoma has shown increased risk of distant metastases and worse survival when expressed by the tumor [59].
BRAF is a human gene that encodes a protein called B-Raf, a proto-oncogene. Conjunctival melanoma is one of the BRAF mutation-associated malignancies. A higher chance of distant metastasis might be seen in conjunctival melanomas expressing BRAF mutations. Conjunctival melanoma and cutaneous melanoma show resemblance in the significance of this type of mutation and its relevance to the clinical presentation [57, 60].
Advanced therapy of conjunctival melanomas using cryotherapy, radiotherapy, and chemotherapy has lowered the frequency of surgical exenteration. It is essential to perform periodic systemic screening in high-risk patients [54]. Local recurrence after therapy ranges from 50 to 70% at 10 years with an overall mortality rate of 25% at 10 years and more than 30% at 15 years [21]. Multifocal melanomas, extra-limbal location, incomplete surgical excision, and the lack of additional treatment are considered to be risk factors for recurrence [54, 57].
Acknowledgments
This work was supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia.
Conflict of interest
Authors do not have conflict of interest or any financial disclosures related to the above work or any of the listed items in this chapter.
\n',keywords:"histology, histopathology, ocular surface, conjunctiva, limbus, cornea, epithelium, stroma, endothelium, squamous cell carcinoma, melanoma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/59788.pdf",chapterXML:"https://mts.intechopen.com/source/xml/59788.xml",downloadPdfUrl:"/chapter/pdf-download/59788",previewPdfUrl:"/chapter/pdf-preview/59788",totalDownloads:1214,totalViews:261,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:66,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"September 29th 2017",dateReviewed:"February 7th 2018",datePrePublished:null,datePublished:"September 19th 2018",dateFinished:"March 7th 2018",readingETA:"0",abstract:"Three integral parts that cover the ocular surface are the conjunctiva, limbus, and cornea. The conjunctiva is a see-through mucous membrane that lines the internal surface of the eyelids and the front surface of the eyeball, ending at the limbus. It is highly vascular with a dense lymphatic network. The limbus forms the boundary between the transparent cornea and the opaque sclera. The cornea is a complex structure that provides a protective function and is responsible for about 75% of the optical power of the eye. Histology of these highly specialized biological materials as well as the ways in which individual components are structurally and functionally related will be discussed in this chapter. Then, we will go over the pathological oncology processes that can affect the ocular surface.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/59788",risUrl:"/chapter/ris/59788",book:{id:"6297",slug:"histopathology-an-update"},signatures:"Hind Alkatan and Tariq Alzahem",authors:[{id:"223782",title:"Dr.",name:"Hind",middleName:"Manaa",surname:"Alkatan",fullName:"Hind Alkatan",slug:"hind-alkatan",email:"hindkatan@yahoo.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223782/images/8837_n.jpg",institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"240501",title:"Dr.",name:"Tariq",middleName:null,surname:"Al-Zahem",fullName:"Tariq Al-Zahem",slug:"tariq-al-zahem",email:"t.a.z@mail.net.sa",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. Histology of ocular surface",level:"1"},{id:"sec_2_2",title:"2.1. Conjunctiva",level:"2"},{id:"sec_3_2",title:"2.2. Corneoscleral limbus",level:"2"},{id:"sec_4_2",title:"2.3. Cornea",level:"2"},{id:"sec_4_3",title:"2.3.1. Epithelium",level:"3"},{id:"sec_5_3",title:"2.3.2. Bowman’s layer",level:"3"},{id:"sec_6_3",title:"2.3.3. Stroma",level:"3"},{id:"sec_7_3",title:"2.3.4. Descemet’s membrane",level:"3"},{id:"sec_8_3",title:"2.3.5. Endothelium",level:"3"},{id:"sec_11",title:"3. Histopathology of ocular surface",level:"1"},{id:"sec_11_2",title:"3.1. Non-melanocytic epithelial tumors",level:"2"},{id:"sec_11_3",title:"3.1.1. Squamous papilloma",level:"3"},{id:"sec_12_3",title:"3.1.2. Conjunctival pseudoepitheliomatous hyperplasia",level:"3"},{id:"sec_13_3",title:"3.1.3. Keratoacanthoma",level:"3"},{id:"sec_14_3",title:"3.1.4. Dacryoadenoma",level:"3"},{id:"sec_15_3",title:"3.1.5. Conjunctival keratotic plaque and actinic keratosis",level:"3"},{id:"sec_16_3",title:"3.1.6. 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San Francisco, CA: American Academy of Ophthalmology; 2014. pp. 44-45'},{id:"B3",body:'American Academy of Ophthalmology. 2014-2015 Basic and Clinical Science Course. Section 8: External Disease and Cornea. San Francisco, CA: American Academy of Ophthalmology; 2014. p. 74'},{id:"B4",body:'Robertson DM, Alexander LJ, Bonanno JA, Fleiszig SMJ, McNamara N. Cornea and ocular surface disease: Application of cutting edge optometric research. Optometry and Vision Science: Official Publication of the American Academy of Optometry. 2014;91(401):S3-16. DOI: 10.1097/OPX.0000000000000226'},{id:"B5",body:'American Academy of Ophthalmology. 2014-2015 Basic and Clinical Science Course. Section 8: External Disease and Cornea. San Francisco, CA: American Academy of Ophthalmology; 2014. p. 9'},{id:"B6",body:'Dua HS, Faraj LA, Said DG, Gray T, Lowe J. Human corneal anatomy redefined: A novel pre-Descemet\'s layer (Dua\'s layer). Ophthalmology. 2013;120:1778-1785. 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Reliability of impression cytology for the diagnosis of ocular surface squamous neoplasia employing the biopore membrane. The British Journal of Ophthalmology. 2001;85(2):154-158. PMID: 11159477'},{id:"B28",body:'Nolan GR, Hirst LW, Wright RG, et al. Application of impression cytology to the diagnosis of conjunctival neoplasms. Diagnostic Cytopathology. 1994;11:246-249. DOI: 10.1002/dc.2840110310'},{id:"B29",body:'Searl SS, Krigstein HJ, Albert DM, Grove AS Jr. Invasive squamous cell carcinoma with intraocular mucoepidermoid features. Conjunctival carcinoma with intraocular invasion and diphasic morphology. Archives of Ophthalmology. 1982;100:109-111. PMID:7055460'},{id:"B30",body:'Johnson TE, Tabbara KF, Weatherhead RG, Kersten RC, Rice C, Nasr AM. Secondary squamous cell carcinoma of the orbit. Archives of Ophthalmology. 1997;115:75-78. PMID: 9006429'},{id:"B31",body:'Alkatan H, Al-Motlak M, Al-Shedoukhy A. Metastatic squamous spindle cell carcinoma of the conjunctiva. Saudi Journal of Ophthalmology. 2010;24:155-158'},{id:"B32",body:'Asnaghi L, Alkatan H, Mahale A, et al. Identification of multiple DNA copy number alterations including frequent 8p11.22 amplification in conjunctival squamous cell carcinoma. Investigative Ophthalmology & Visual Science. 2014;55(12):8604-8613. DOI: 10.1167/iovs.14-14920'},{id:"B33",body:'Mahale A, Alkatan H, Alwadani S, et al. Altered gene expression in conjunctival squamous cell carcinoma. Modern Pathology. 2016;29(5):452-460. DOI: 10.1038/modpathol.2016.41'},{id:"B34",body:'Shields CL, Fasiuddin AF, Mashayekhi A, Shields JA. Conjunctival nevi: Clinical features and natural course in 410 consecutive patients. Archives of Ophthalmology. 2004 Feb;122(2):167-175. DOI: 10.1001/archopht.122.2.167'},{id:"B35",body:'Zimmerman LE, Sobin LH. International Histological Classification of Tumors. No. 24: Histological Typing of Tumors of the Eye and its Adnexa. Geneva: World Health Organization; 1980. p. 30'},{id:"B36",body:'Honavar SG, Manjandavida FP. Tumors of the ocular surface: A review. Indian Journal of Ophthalmology. 2015;63(3):187-203. DOI: 10.4103/0301-4738.156912'},{id:"B37",body:'To KW, Rabinowi SM, Friedman M, Cavanaugh CP. Neuro fibromatosis and neural crest neoplasms: Primary acquired melanosis and malignant melanoma of the conjunctiva. Survey of Ophthalmology. 1989;33:373-379. PMID: 2497540'},{id:"B38",body:'Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96:147-166. PMID: 2649838'},{id:"B39",body:'Grossniklaus HE, Green WE, Luckenbach M, Chan CC. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea. 1987;6(2):78-116. PMID: 3301209'},{id:"B40",body:'Paridaens AD, MacCartney AC, Hungerford JL. Multifocal amelanotic conjunctival melanoma and acquired melanin sine pigment. The British Journal of Ophthalmology. 1992;76(3):163-165. DOI: 10.1136/bjo.76.3.163'},{id:"B41",body:'Seregard S, Kock E. Conjunctival malignant melanoma in Sweden 1969-91. Acta Ophthalmologica, Copenhagen. 1992;70(3):289-296. PMID: 1636385'},{id:"B42",body:'Lommatzsch PK, Lommatzsch RE, Kirsch I, Fuhrmann P. Therapeutic outcome of patients suffering from malignant melanomas of the conjunctiva. The British Journal of Ophthalmology. 1990;74(10):615-619. PMID: 2285686'},{id:"B43",body:'Novais GA, Fernandes BF, Belfort RN, Castiglione E, Cheema DP, Burnier MN Jr. Incidence of melanocytic lesions of the conjunctiva in a review of 10,675 ophthalmic specimens. International Journal of Surgical Pathology. 2010;18(1):60-63. DOI: 10.1177/1066896908319775'},{id:"B44",body:'Norregaard JC, Gerner N, Jensen OA, Prause JU. Malignant melanoma of the conjunctiva: Occurrence and survival following surgery and radiotherapy in a Danish population. Graefe\'s Archive for Clinical and Experimental Ophthalmology. 1996;234(9):569-572. PMID: 8880155'},{id:"B45",body:'Missotten GS, Keijser S, De Keizer RJ, De Wolff-Rouendaal D. Conjunctival melanoma in the Netherlands: A nationwide study. Investigative Ophthalmology & Visual Science. 2005;46(1):75-82. DOI: 10.1167/iovs.04-0344'},{id:"B46",body:'Anastassiou G, Heiligenhaus A, Bechrakis N, Bader E, Bornfeld N, Steuhl KP. Prognostic value of clinical and histopathological parameters in conjunctival melanomas: A retrospective study. The British Journal of Ophthalmology. 2002;86(2):163-167. PMID: 11815341'},{id:"B47",body:'Shields CL, Shields JA, Gündüz K, Cater J, Market GV, Gross N, et al. Conjunctival melanoma: Risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Archives of Ophthalmology. 2000;118(11):1497-1507. PMID: 11074806'},{id:"B48",body:'McDonnell JM, Carpenter JD, Jacobs P, Wan WL, Gilmore JE. Conjunctival melanocytic lesions in children. Ophthalmology. 1989;96(7):986-993. PMID: 2771364'},{id:"B49",body:'Strempel I, Kroll P. Conjunctival malignant melanoma in children. Ophthalmologica. 1999;213(2):129-132. PMID: 9885390'},{id:"B50",body:'Folberg R, McLean IW, Zimmerman LE. Malignant melanoma of the conjunctiva. Human Pathology. 1985;16(2):136-143. PMID: 3972396'},{id:"B51",body:'Jeffrey IJ, Lucas DR, McEwan C, Lee WR. Malignant melanoma of the conjunctiva. Histopathology. 1986;10(4):363-378'},{id:"B52",body:'Giblin ME, Shields JA, Shields CL, Eagle RC Jr. Primary eyelid malignant melanoma associated with primary conjunctival malignant melanoma. Australian and New Zealand Journal of Ophthalmology. 1988;16:127-131. PMID: 3179038'},{id:"B53",body:'Shields CL, Markowitz JS, Belinsky I, Schwartzstein H, George NS, Lally SE, et al. Conjunctival melanoma: Outcomes based on tumor origin in 382 consecutive cases. Ophthalmology. 2011;118:389-395. 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Arunakaran, S. Banudevi and A. Arunkumar",authors:[{id:"96274",title:"Dr.",name:"Arunakaran",middleName:null,surname:"Jagadeesan",fullName:"Arunakaran Jagadeesan",slug:"arunakaran-jagadeesan"}]},{id:"27767",title:"Endometrial Intraepithelial Neoplasia",slug:"endometrial-intraepithelial-neoplasia",signatures:"Nisreen Abushahin, Shuje Pang, Jie Li, Oluwole Fadare and Wenxin Zheng",authors:[{id:"85121",title:"Prof.",name:"Wenxin",middleName:null,surname:"Zheng",fullName:"Wenxin Zheng",slug:"wenxin-zheng"},{id:"91062",title:"Dr.",name:"Nisreen",middleName:null,surname:"Abushahin",fullName:"Nisreen Abushahin",slug:"nisreen-abushahin"},{id:"91069",title:"Dr.",name:"Suhje",middleName:null,surname:"Pang",fullName:"Suhje Pang",slug:"suhje-pang"},{id:"91072",title:"Dr.",name:"Oluwole",middleName:null,surname:"Fadare",fullName:"Oluwole Fadare",slug:"oluwole-fadare"},{id:"126301",title:"Dr.",name:"Jie",middleName:null,surname:"Li",fullName:"Jie Li",slug:"jie-li"}]},{id:"27768",title:"Cervical Intraepithelial Neoplasia – Clinical and Etiological Aspects",slug:"cervical-intraepithelial-neoplasia-clinical-and-etiological-aspects",signatures:"Raghad Samir and Dan Hellberg",authors:[{id:"66626",title:"Prof.",name:"Dan",middleName:null,surname:"Hellberg",fullName:"Dan Hellberg",slug:"dan-hellberg"},{id:"91814",title:"Dr.",name:"Raghad",middleName:null,surname:"Samir",fullName:"Raghad Samir",slug:"raghad-samir"}]},{id:"27769",title:"P16INK4A and MIB-1 Expression in Preneoplasia and Neoplasia of Cervix",slug:"p16ink4a-and-mib-1-expression-in-preneoplasia-and-neoplasia-of-cervix",signatures:"Supriya Srivastava",authors:[{id:"85273",title:"Dr.",name:"Supriya",middleName:null,surname:"Srivastava",fullName:"Supriya Srivastava",slug:"supriya-srivastava"}]},{id:"27770",title:"Cervical Intraepithelial Neoplasia (CIN) (Squamous Dysplasia)",slug:"cervical-intraepithelial-neoplasia-cin-squamous-dysplasia-",signatures:"Oguntayo Olanrewaju Adekunle",authors:[{id:"89228",title:"Dr.",name:"Adekunle",middleName:null,surname:"Oguntayo",fullName:"Adekunle Oguntayo",slug:"adekunle-oguntayo"}]},{id:"27771",title:"AKNA as Genetic Risk Factor for Cervical Intraepithelial Neoplasia and Cervical Cancer",slug:"akna-as-genetic-risk-factor-for-cervical-intraepithelial-neoplasia-and-cervical-cancer",signatures:"Kirvis Torres-Poveda, Ana I. 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1. Introduction
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The contamination of food and feed crops with mycotoxigenic fungi is a persistent problem contributing to food safety and security worldwide. The infection of crops by these fungal pathogens affects crop yield and quality but of greater concern are the secondary metabolites they produce, collectively known as mycotoxins. Ingestion of mycotoxin-contaminated products has been associated with a wide range of noxious effects on humans and livestock. The major food and feed crops affected by mycotoxigenic fungi and mycotoxins include rice, maize, wheat, soybean, sorghum and groundnut, although several other crops are also affected. The association of these crops with mycotoxigenic fungi is ubiquitous, and crops are affected wherever they are produced. Three major groups of mycotoxigenic fungi are associated with mycotoxin contamination namely Aspergillus, Fusarium and Penicillium. They each produce a number of mycotoxins, but six mycotoxins have been studied extensively and are considered among the most important and they include the aflatoxins (AF), fumonisins (FUM), trichothecenes (TCT), zearalenone (ZEA), ochratoxin (OT) and patulin (PAT). Mycotoxin contamination levels in food and feed crops have therefore elicited numerous countries to institute regulations regarding the maximum permissible levels of these mycotoxins in unprocessed and processed products.
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More than 100 countries have established mycotoxin regulations, including 15 African countries [1, 2, 3]. The European Union and United States Food and Drug Administration established maximum allowable levels for certain food contaminants, including mycotoxins, with the aim to reduce their presence in foodstuffs to the lowest levels reasonably achievable by means of good manufacturing or agricultural practices [4]. Most of the countries have mycotoxin regulations for at least AFB1, produced predominantly by Aspergillus spp., to aid in minimising food safety concerns. Although fewer countries regulate Fusarium mycotoxins, a marked increase in the regulation of this mycotoxin has been observed recently. These regulations have globally significant implications for the importation and exportation of products. Regulatory infrastructure, however, does not enable inspection and enforcement [5], making the regulatory control of mycotoxins in Africa largely ineffective [6].
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The management of mycotoxigenic fungi and their subsequent mycotoxins is therefore vital towards ensuring sustainable, safe food and feed production. Integrated management practises that reduce the incidence of mycotoxigenic fungi as well as the management of abiotic factors that contribute to mycotoxin contamination are required before and following harvest. However, preharvest management is considered the most important in limiting the overall contamination of crops. Therefore, the use of tolerant varieties is deemed the most proficient and environmentally sound approach to manage fungi and their toxins. In addition, several other management approaches such as optimal plant production, cultural practises, chemical control and the management of mycotoxigenic fungi by atoxigenic strains or bacteria could further reduce fungal incidence and subsequent mycotoxin contamination.
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2. Management of mycotoxigenic fungi and their mycotoxins
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Managing mycotoxigenic fungi and their mycotoxins in crop plants requires a proper understanding of the biology, epidemiology and genetics/genomics of the fungus and host plant. Major crops vary significantly in susceptibility to mycotoxigenic fungi and subsequent mycotoxin contamination. Maize is widely considered to be among the most susceptible of major crops to mycotoxins, while rice is considered among the least susceptible crop [7, 8, 9].
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2.1. Tolerance to mycotoxigenic fungi
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Crops with resistance to numerous mycotoxigenic fungi have been documented [10, 11, 12], but none of these are immune. Resistance to mycotoxigenic fungi therefore appears to be quantitative rather than qualitative. Breeding programmes at both public and private institutions are initiating and expanding their efforts to develop disease-resistant inbred and hybrid materials [13]. A number of international institutions such as the International Maize and Wheat Improvement Centre (CIMMYT) and the International Institute of Tropical Agriculture (IITA) in African countries including Kenya and Nigeria have established breeding programmes with the primary focus on producing inbred lines with improved resistance to A. flavus and AF. The development of tolerant cultivars, however, has been slow due to the polygenic, quantitative nature of resistance to mycotoxigenic fungi [14, 15, 16, 17], the unavailability of immune germplasm [11, 15] and the effect of the environment on disease development and mycotoxin production [18, 19, 20]. The development of tolerant varieties, therefore, may be a long (8–10 years) and costly process that needs to be conducted as effectively as possible. Little to no commercial plant crop, completely resistant to mycotoxigenic fungi and mycotoxins, has been produced by conventional breeding, with the exception of wheat [21, 22, 23].
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2.2. Conventional breeding strategies
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Diallel analysis to determine the general combinability (GC) and specific combinability (SC) of resistant genotypes has been reported for Aspergillus and Fusarium, mostly performed on maize [24, 25, 26, 27] and wheat [28, 29, 30]. The response of an inbred line to F. verticillioides and FUM, and the corresponding GC in hybrids, was significantly correlated. This indicates that an efficient way to improve resistance to F. verticillioides and FUM in maize hybrids, specifically, is to first evaluate and select resistant inbred lines that can be used to develop resistant hybrids [24]. This was also demonstrated for breeding resistance to Fusarium head blight (FHB) of wheat [30]. Maize hybrid performance for resistance to F. graminearum could, however, not be predicted based on the GC of inbred line parents [27]. Therefore, this relationship needs to be determined for each crop and fungal pathogen, respectively.
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Inbred lines with resistance to aflatoxin contamination were evaluated for GCA and SCA for resistance to fumonisin accumulation, and two lines with resistance to FUM and AF were registered [25]. That research demonstrated the ability to breed resistance to multiple mycotoxigenic fungi and/or their mycotoxins. Furthermore, improved resistance to F. verticillioides and FUM in inbred lines derived from cross-pollination of resistant and elite maize lines has been demonstrated [31]. The subsequent hybrids produced from the crossing of improved lines with elite lines, however, did not demonstrate an improved activity against Fusarium ear rot (FER) and FUM accumulation, although some improved lines performed well as an inbred line and as a component of a hybrid [31]. To date, little to no research is reported on the development of tolerant varieties using recurrent selection breeding methods. Considering that resistance to mycotoxigenic fungi is polygenic and quantitative, recurrent selection presents a feasible breeding strategy; however, time and cost involved in this breeding strategy may be strong deterrent factors.
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Quantitative trait loci (QTL) associated with resistance to mycotoxigenic fungi has been mapped in maize and wheat and can be used for marker-assisted selection [15, 16, 32, 33, 34, 35, 36]. Some QTLs, however, displayed pleiotropic effects, sometimes resulting in resistance to both traits [15, 32, 37]. QTL analyses have also demonstrated pleiotropic effects for resistance to other mycotoxigenic fungi and/or their associated mycotoxins. In QTL studies involving multiple ear rot pathogens, maize resistant to FER and FUM accumulation was also resistant to F. graminearum and/or A. flavus, with common loci for ear rots and FUM, respectively [15, 37, 38]. Research revealed that some of the genes involved in resistance to FER and Aspergillus ear rot (AER) of maize caused by A. flavus, as well as their associated mycotoxins (FUM and AF, respectively), were identical or genetically linked [38]. These studies highlighted common genes and/or resistance mechanisms to multiple mycotoxigenic fungi, demonstrating the potential for breeding resistance to one type of mycotoxigenic fungus, and its mycotoxin may lead to similar responses among other mycotoxigenic fungi and associated mycotoxin. The value of marker-assisted selection for improving Fusarium head blight resistance in wheat has been confirmed by numerous researchers and success stories from breeding programmes implementing MAS [39, 40, 41, 42, 43, 44, 45, 46, 47].
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2.3. Unconventional breeding strategies
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2.3.1. Genetic modification
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Genetically modified crops are plants of which the DNA has been altered through the introduction of a foreign gene to express a trait not inherent to the modified plant. Three transgene-mediated strategies have been proposed for the management of mycotoxigenic fungi and mycotoxins in maize [48]. These include (1) the reduction of fungal infection, (2) the degradation of mycotoxins and (3) interfering with the mycotoxin biosynthetic pathway. To reduce infection by the fungus, the incorporation of antifungal and/or resistance genes, as well as the overexpression of defence-related genes, is required. Catabolic enzymes from microbes have been used to detoxify certain mycotoxins both in vitro and in situ, before they accumulate in the plant [49, 50, 51]. Fumonisin esterase and amine oxidase genes encoding FUM-degrading enzymes have been identified in Exophiala spinifera de Hoog and Hasse [48]. None of these genes have, however, been successfully introduced into maize. Maize plants have, however, been genetically engineered to interfere with the biosynthesis of AF and TCT [52, 53]. The best-known example of using genetically modified maize for reducing FER and FUM contamination of grain is Bt maize [54, 55]. This is due to the close association between kernel damage by insects and infection by F. verticillioides [56]. Bt maize plants that prevent insect damage, therefore, also reduce FUM contamination of maize grain. Genetically modified maize is not authorised in all countries and, consequently, conventional breeding efforts are still commonly used.
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2.3.2. Mutation breeding
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Exposure of seeds or other heritable materials to chemicals or radiation with the purpose to induce DNA changes (mutations) is known as mutation breeding. Nuclear technology for crop improvement makes use of ionising radiation, which causes induced mutations with a high mutation frequency in plants [57]. These mutations might be beneficial and alter physiological characters of plants, including plant height, ear height and improved root architecture [58, 59]. The radiation of seeds may also cause genetic variability that enables breeders to select new genotypes with improved grain yield and quality [60]. Mutation breeding has been successfully used to generate genetic variation in cereal crops, including maize, for a number of aspects including enhanced yield and productivity, altered ear length, drought tolerance and enhanced stem structure [61, 62, 63]. It can thus potentially provide an attractive means for generating tolerance to mycotoxigenic fungi and their mycotoxins.
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2.4. Host-plant resistance
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The planting of disease-resistant plants is an effective, affordable and environmentally sound strategy to control ear rot diseases and mycotoxin accumulation [64]. Commercial hybrids differ in their ability to accumulate mycotoxins [64], while hybrids grown outside of their adapted range are more susceptible to mycotoxins than those grown within their adapted range [18]. Determining host-plant resistance to mycotoxigenic fungi and mycotoxin accumulation is a fundamental step towards developing commercially tolerant plant varieties. Several factors require careful consideration when screening materials for resistance to mycotoxigenic fungi and their mycotoxins. Inoculation technique significantly contributes to the efficacy of the screening protocol and should, therefore, be appropriate, produce consistent results and consider the disease cycle of the pathogen. Numerous studies relating to different crops report on the importance of screening for resistance under variable environmental conditions since genotype by environment interactions (GEI) plays such a vital role in disease development and mycotoxin contamination. Furthermore, GEI and stability indicators provide for the selection of material tolerant across a broad range of environments or alternatively exhibiting tolerance in specific environments.
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Various countries have reported on the tolerance levels of maize and wheat cultivars to mycotoxigenic fungi and associated mycotoxins [65, 66, 67]. However, focus has been placed on the characterisation of inbred lines for the identification of appropriate breeding material towards resistance to mycotoxigenic fungi and their toxins [68, 69, 70, 71, 72, 73, 74]. Genetically modified maize, expressing Bacillus thuringiensis genes (BT maize), has been found to accumulate less FUM than its non-modified isolines [54].
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2.5. Cultural preharvest management strategies
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2.5.1. Planting recommendations
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Adhering to planting dates and planting plants at lower or optimal densities reduces mycotoxin accumulation during production [75, 76, 77]. Plants should be planted at recommended row widths and densities to specifically reduce water stress [78] and ensure optimal nutrient availability. Maize ears should be harvested from the field as soon as possible because favourable conditions for ear rot and/or mycotoxin accumulation may occur if harvest is delayed, thus leading to elevated mycotoxin levels [79, 80].
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2.5.2. Crop rotation
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The primary objective of cultural control of mycotoxigenic fungi is to minimise factors that result in plant stress. Inoculum build-up on plant residues can be reduced by crop rotation practices, such as the rotation of maize with non-host crops [75, 81, 82]. Crop rotation with legumes, brassicas and potato could also significantly reduce F. graminearum contamination levels [83].
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\n
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2.5.3. Tillage practises
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Field preparation and cultivation practices play a central role in the management of Fusarium diseases and associated mycotoxins [84]. The burial of plant residues from a previous planting season by deep ploughing can reduce the primary inoculum that causes infections [85]. This is especially important when crops are affected by the same Fusarium species, such as F. graminearum on maize, wheat and sorghum grown in rotation [4]. While minimum tillage has significantly decreased stalk rot and increased grain yield of sorghum in South Africa [86], it has also increased inoculum build-up of mycotoxigenic fungi in maize cropping systems [84]. Alternate tillage practices, however, have had little effect on the incidence of FER in maize [87, 88].
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\n
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2.5.4. Managing plant stressors
\n
Limiting plant stress to increase plant vigour by adhering to optimum plant dates, preventing drought stress and the optimal use of fertilisers have reduced Fusarium infection in a number of grain crops [76, 89, 90, 91]. However, maize cultivated by means of organic agriculture does not accumulate less FUM than maize cultivated conventionally [92, 93]. Extended periods of heat and drought stress that lead to increased FUM levels could be managed with proper irrigation schedules [77, 94]. Managing plant stress conditions is also important as this is considered key in the symptomless endophytic relationship converting to a disease- and/or mycotoxin-producing interaction [95].
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\n
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2.5.5. Chemical control
\n
Fungicides have been shown to significantly reduce FHB and DON contamination of wheat grain. Triazole fungicides such as metconazole and tebuconazole have been shown to control FHB and DON contamination in wheat [96]. However, fungicides are neither effective in reducing F. verticillioides infection/FUM accumulation, nor A. flavus infection/AF accumulation in maize [97]. This may be due to the husks that cover maize kernels. FUM were, however, reduced by 95% in vitro when four fungicides and a biocontrol bacterium (Serenade, B. subtilis) were evaluated for the control of F. verticillioides and A. flavus [98]. No registered fungicides are available for the control of either F. verticillioides or A. flavus in any African country [98]. The use of insecticides can prevent insect wounds that contribute to fungal infection and mycotoxin accumulation in maize kernels [91].
\n
Reduced FHB severity and mycotoxin contamination of wheat under field conditions using tannic acid and the botanicals, Chinese galls and buckthorn, have been shown [100]. These researchers also reported disease and mycotoxin reduction efficacy close to that observed with a synthetic fungicide, thereby demonstrating the potential use of natural compounds in managing mycotoxigenic fungi and their toxins. Furthermore, several studies report on a reduced fungal growth and mycotoxin contamination for Aspergillus and Fusarium using natural oils and phenolic compounds in vitro; however, the commercial value of such products has not been explored and may not be feasible [101, 102].
\n
\n
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2.5.6. Managing mycotoxigenic fungi with other microorganisms
\n
The use of biological control agents to manage mycotoxigenic fungi has been reported. Atoxigenic F. verticillioides strains competitively excluded FUM-producing strains and prevented them from producing FUM [103]. When these strains were applied by themselves through the silk channel, however, they resulted in high levels of FER. The effective control of toxigenic F. verticillioides and F. proliferatum by non-toxigenic Fusarium species in maize residues has also been observed [104]. Most success, however, has been achieved with the use of atoxigenic strains of A. flavus to control toxigenic A. flavus and A. parasiticus. When introduced into the soil, these atoxigenic strains reduced AF contamination of peanuts in the USA by 74.3–99.9% [105]. Atoxigenic A. flavus strains are now widely used to control AF in maize in several African countries (www.aflatoxinpartnership.org). Endophytic bacteria have been reported to control FUM-producing fungi by competitive exclusion [106], while Trichoderma strains controlled them through competition for nutrients and space, fungistasis, antibiosis, rhizosphere modification, mycoparasitism, biofertilisation and the stimulation of plant-defence mechanisms [107].
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2.5.7. Prediction systems
\n
An epidemic can be described as a ‘change in disease intensity in a host population over time and space’ [108]. Mathematical modelling of crop disease is a rapidly expanding discipline within plant pathology [109] with the first models developed by Van der Plank [110, 111]. In epidemiology, modelling aims to understand the main determinants of epidemic development in order to address disease management in a sustainable and efficient manner. It can, therefore, serve as an instrument to monitor and assess the risk of mycotoxin contamination in crops that would drive agronomic decisions during cultivation, in order to enhance management strategies [112].
\n
Most research regarding disease forecasting of mycotoxigenic fungi has focussed on FHB of wheat. This disease is considered well suited for risk assessment modelling because of the severity of epidemics, compound losses resulting from mycotoxin contamination and relatively narrow time periods of pathogen sporulation, inoculum dispersal and host infection [113]. This can be seen from the online forecasting model FusaProg [114], which is a threshold-based tool to control F. graminearum with the optimised timing of fungicide applications and forecasts of DON content during flowering. DONCast is a prediction model from Canada that has been extensively validated and commercialised for wheat [112], while an adaption of this model has been proposed for maize. This model predicts the variation in mycotoxin levels associated with the year and agronomic effects from simple linear models using wheat samples from farmers. The DONCast model accounts for up to 80% of the variation in DON and is commercially employed for the past 10 years.
\n
Field-based models to predict FUM B1 contamination in maize grain have been elusive, most probably due to the complexity of interactions between numerous abiotic and biotic disease factors [115]. The concentration and severity of FUM produced by Fusarium spp. varies with meteorological conditions, genotype and location [19]. In general, favourable conditions for F. verticillioides infection include high temperatures [56], drought stress [56, 116] and insect damage stress [56]. A mathematical simulation of the growth of F. graminearum and F. verticillioides in maize ears was developed; however, the model only simulates fungal growth and not mycotoxin accumulation [117]. A preliminary model developed in the Philippines and Argentina identified four weather periods near silking as critical to FUM accumulation at harvest [19]. This model accounted for 82% of the variability of total FUM across all locations in 2 years of study, but did not consider meteorological conditions during grain maturation when FUM are synthesised.
\n
A risk assessment model (FUMAgrain) developed for FUM contamination of maize grain in Italy gives an initial risk alert at the end of flowering based on meteorological conditions [118]. A second alert follows at kernel maturation following assessments of grain moisture, European corn borer damage and FUM synthesis risk. FUMAgrain could simulate FUM synthesis in maize accounting for 70% of the variation for calibration and 71% for validation. The importance of meteorological conditions at flowering and the growth of F. verticillioides and FUM synthesis during grain maturation was emphasised as the most important factors contributing to FUM contamination [118]. Another model consistently identified mean maximum temperature and minimum humidity as driving variables in the colonisation of maize kernels by fumonisin-producing Fusarium spp [99]. Furthermore, Fusarium colonisation of grain and fumonisins were related to prevailing weather conditions during early post-flowering and dough stage of grain development, respectively [99]. A prediction model using variables such as cultivar, climate, management practice, soil type, phenological stages of the host plant and pathogen variation would be advantages in identifying areas with potentially dangerous levels of fungal contamination and associated mycotoxin production, enabling them to implement mycotoxin management strategies.
\n
\n
\n
\n
\n
3. Conclusion
\n
Food and feed crops are consistently threatened by mycotoxigenic fungi and compound their infection by depositing toxic metabolites, including mycotoxins. Preharvest management of mycotoxin contamination is vital to maintaining contamination levels below economically feasible and legislated thresholds. Planting genotypes with enhanced host resistance is considered the most practical, affordable and environmentally sound method of controlling mycotoxigenic fungi and their mycotoxins. However, integrating resistant varieties with good agricultural practises such as crop rotation, chemical/biological control and other strategies that optimise plant production by minimising stressors may further reduce the risks associated with mycotoxin contamination. Resistance to mycotoxigenic fungi exists and has been identified in appropriate breeding materials but such resistance needs to be introduced in high-yielding and locally adapted hybrids. To date, conventional breeding has not been able to introgress disease and/or mycotoxin resistance into important staple crops like maize. Therefore, further research is required into factors with a greater efficacy to reduce mycotoxigenic fungi and mycotoxins preharvest as resistant varieties are being developed.
\n
\n
Acknowledgments
\n
The South African Maize Trust and the National Research Foundation (NRF) of South Africa (Thuthuka; South Africa—Kenya Research Partnership Programme Bilateral); the MAIZE Competitive Grants Initiative, International Maize and Wheat Improvement Centre (CIMMYT), and CGIAR, the National Commission for Science, Technology and Innovation (NACOSTI) of Kenya; the Agricultural Research Council of South Africa are all acknowledged for funding.
\n
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"preharvest management, mycotoxins, tolerance, cereals, cultural practices",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/61941.pdf",chapterXML:"https://mts.intechopen.com/source/xml/61941.xml",downloadPdfUrl:"/chapter/pdf-download/61941",previewPdfUrl:"/chapter/pdf-preview/61941",totalDownloads:1564,totalViews:0,totalCrossrefCites:4,dateSubmitted:"December 7th 2017",dateReviewed:"March 27th 2018",datePrePublished:"November 5th 2018",datePublished:"August 28th 2019",dateFinished:"June 5th 2018",readingETA:"0",abstract:"Mycotoxigenic fungi that contaminate grain crops can lead to reduced grain quality, crop yield reduction and mycotoxicosis among humans and livestock. Preharvest management of fungi and mycotoxin contamination is considered among the most important mitigating strategies. Approaches include the breeding of resistant cultivars, use of microorganisms chemical control, production practises and the management of plant stressors. Resistant plants provide an effective and environmentally sound strategy to control mycotoxigenic fungi and mycotoxins; and have been documented. Their incorporation into commercial cultivars is, however, slow and complex. Therefore, emphasis should be placed on determining the resistance of cultivars and landraces currently used by producers. Chemical control has been successfully used for wheat; yet little to no research has been done on other important crops. Biological control strategies have focussed on Aspergillus flavus that produces aflatoxins and infects commercially important crops like maize and groundnuts. Commercial biological control products have been developed and field-tested in several African countries with promising results. The impacts of production practises are unclear under variable environmental conditions; but subsequent disease manifestation and mycotoxin contamination can be reduced. Each preharvest approaches contribute to managing mycotoxigenic fungi and their mycotoxins but integrating approaches may provide more effective management of fungal and mycotoxin contamination in crops.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/61941",risUrl:"/chapter/ris/61941",signatures:"Lindy J. Rose, Sheila Okoth, Bradley C. Flett, Belinda Janse van Rensburg and Altus Viljoen",book:{id:"6733",type:"book",title:"Mycotoxins",subtitle:"Impact and Management Strategies",fullTitle:"Mycotoxins - Impact and Management Strategies",slug:"mycotoxins-impact-and-management-strategies",publishedDate:"August 28th 2019",bookSignature:"Patrick Berka Njobeh and Francois Stepman",coverURL:"https://cdn.intechopen.com/books/images_new/6733.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83881-847-0",printIsbn:"978-1-83881-846-3",pdfIsbn:"978-1-83881-848-7",isAvailableForWebshopOrdering:!0,editors:[{id:"60387",title:"Prof.",name:"Patrick Berka",middleName:null,surname:"Njobeh",slug:"patrick-berka-njobeh",fullName:"Patrick Berka Njobeh"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Management of mycotoxigenic fungi and their mycotoxins",level:"1"},{id:"sec_2_2",title:"2.1. Tolerance to mycotoxigenic fungi",level:"2"},{id:"sec_3_2",title:"2.2. Conventional breeding strategies",level:"2"},{id:"sec_4_2",title:"2.3. Unconventional breeding strategies",level:"2"},{id:"sec_4_3",title:"2.3.1. Genetic modification",level:"3"},{id:"sec_5_3",title:"2.3.2. Mutation breeding",level:"3"},{id:"sec_7_2",title:"2.4. Host-plant resistance",level:"2"},{id:"sec_8_2",title:"2.5. Cultural preharvest management strategies",level:"2"},{id:"sec_8_3",title:"2.5.1. Planting recommendations",level:"3"},{id:"sec_9_3",title:"2.5.2. Crop rotation",level:"3"},{id:"sec_10_3",title:"2.5.3. Tillage practises",level:"3"},{id:"sec_11_3",title:"2.5.4. Managing plant stressors",level:"3"},{id:"sec_12_3",title:"2.5.5. Chemical control",level:"3"},{id:"sec_13_3",title:"2.5.6. Managing mycotoxigenic fungi with other microorganisms",level:"3"},{id:"sec_14_3",title:"2.5.7. 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Pakistan Journal of Agricultural Science. 2010;47:279-285\n'},{id:"B60",body:'Noreen Z, Ashraf M. Changes in antioxidant enzymes and some key metabolites in some genetically diverse cultivars of radish (Raphanus sativus L.). Environmental Experimental Botany. 2009;67:395-402\n'},{id:"B61",body:'Mashev N, Vassilev G, Ivanov K. A study of N-allyl N-2 pyridyl thiourea and gamma radiation treatment on growth and quality of peas and wheat. Bulgarian Journal of Plant Physiology. 1995;21:56-63\n'},{id:"B62",body:'Jain SM. Mutagenesis in crop improvement under the climate change. Romanian Biotechnological Letters. 2010;15:88-106\n'},{id:"B63",body:'Tomlekova NB. Induced mutagenesis for crop improvement in Bulgaria. Plant Mutation Reports. 2010;2:4-27\n'},{id:"B64",body:'Munkvold GP, Desjardins AE. Fumonisins in maize: Can we reduce their occurrence? The American Phytopathology Society. 1997;81:556-565\n'},{id:"B65",body:'Rheeder JP, Marasas WFO, Van Wyk PS, Van Schalkwyk DJ. 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Potential of fungal antagonists for biocontrol of Fusarium spp. in wheat and maize through competition in crop debris. Biocontrol Science and Technology 2005;15:229-242\n'},{id:"B105",body:'Dorner JW, Cole RJ, Blackenship PD. Effect of inoculum rate of biological control agents on preharvest aflatoxin contamination of peanuts. Biological Control. 1998;12:171-176\n'},{id:"B106",body:'Bacon CW, Yates IE, Hinton DM, Meredith F. Biological control of Fusarium moniliforme in maize. Environmental Health Perspectives. 2001;109:325-332\n'},{id:"B107",body:'Benítez T, Rincón MA, Limón MC, Codón CA. Biocontrol mechanisms of Trichoderma strains. International microbiology. 2004;7:249-260\n'},{id:"B108",body:'Madden LV, Hughes G, van den Bosch F. The Study of Plant Disease Epidemics. The American Phytopathological Society; 2007:33-61. DOI.org/10.1094/9780890545058.003\n'},{id:"B109",body:'Van Maanen A, Xu XM. Modelling plant disease epidemics. European Journal of Plant Pathology. 2003;109:669-682\n'},{id:"B110",body:'Van der Plank JE. Analysis of epidemics. In: Horsfall JG, Cowling EB, editors. Plant Pathology: An Advanced Treatise. New York, USA: Academic Press; 1960. pp. 229-289\n'},{id:"B111",body:'Van der Plank JE. Plant Diseases: Epidemics and Control. New York, USA: Academic Press; 1963\n'},{id:"B112",body:'Schaafsma AW, Hooker DC. Climatic models to predict occurrence of Fusarium toxins in wheat and maize. International Journal of Food Microbiology. 2007;119:116-125\n'},{id:"B113",body:'De Wolf ED, Madden LV, Lipps PE. Risk assessment models for wheat Fusarium head blight epidemics based on within-season weather data. Phytopathology. 2003;93:248-435\n'},{id:"B114",body:'Musa T, Hecker A, Vogelsang S, Forrer HR. Forecasting of Fusarium head blight and deoxynivalenol content in winter wheat with FusaProg. Bulletin OEPP/EPPO. 2007;37:283-289\n'},{id:"B115",body:'Parsons MW, Munkvold GP. 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He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:58,paginationItems:[{id:"81961",title:"Antioxidants as an Adjuncts to Periodontal Therapy",doi:"10.5772/intechopen.105016",signatures:"Sura Dakhil Jassim and Ali Abbas Abdulkareem",slug:"antioxidants-as-an-adjuncts-to-periodontal-therapy",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"82357",title:"Caries Management Aided by Fluorescence-Based Devices",doi:"10.5772/intechopen.105567",signatures:"Atena Galuscan, Daniela Jumanca and Aurora Doris Fratila",slug:"caries-management-aided-by-fluorescence-based-devices",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81894",title:"Diet and Nutrition and Their Relationship with Early Childhood Dental Caries",doi:"10.5772/intechopen.105123",signatures:"Luanna Gonçalves Ferreira, Giuliana de Campos Chaves Lamarque and Francisco Wanderley Garcia Paula-Silva",slug:"diet-and-nutrition-and-their-relationship-with-early-childhood-dental-caries",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81595",title:"Prosthetic Concepts in Dental Implantology",doi:"10.5772/intechopen.104725",signatures:"Ivica Pelivan",slug:"prosthetic-concepts-in-dental-implantology",totalDownloads:27,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Concepts in Dental Implantology - From Science to Clinical Research",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}}]},overviewPagePublishedBooks:{paginationCount:8,paginationItems:[{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}]},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. 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Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",institutionURL:null,country:{name:"India"}}}]}]},openForSubmissionBooks:{paginationCount:3,paginationItems:[{id:"11570",title:"Influenza - New Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11570.jpg",hash:"157b379b9d7a4bf5e2cc7a742f155a44",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11569",title:"Bacterial Sexually Transmitted Infections - New Findings, Diagnosis, Treatment, and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/11569.jpg",hash:"069d6142ecb0d46d14920102d48c0e9d",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 31st 2022",isOpenForSubmission:!0,editors:[{id:"189561",title:"Dr.",name:"Mihaela Laura",surname:"Vica",slug:"mihaela-laura-vica",fullName:"Mihaela Laura Vica"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11568",title:"Staphylococcal Infections - Recent Advances and Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11568.jpg",hash:"92c881664d1921c7f2d0fee34b78cd08",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"July 8th 2022",isOpenForSubmission:!0,editors:[{id:"59719",title:"Dr.",name:"Jaime",surname:"Bustos-Martínez",slug:"jaime-bustos-martinez",fullName:"Jaime Bustos-Martínez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:10,paginationItems:[{id:"82380",title:"Evolution of Parasitism and Pathogenic Adaptations in Certain Medically Important Fungi",doi:"10.5772/intechopen.105206",signatures:"Gokul Shankar Sabesan, Ranjit Singh AJA, Ranjith Mehenderkar and Basanta Kumar Mohanty",slug:"evolution-of-parasitism-and-pathogenic-adaptations-in-certain-medically-important-fungi",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fungal Infectious Diseases - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11400.jpg",subseries:{id:"4",title:"Fungal Infectious Diseases"}}},{id:"82367",title:"Spatial Variation and Factors Associated with Unsuppressed HIV Viral Load among Women in an HIV Hyperendemic Area of KwaZulu-Natal, South Africa",doi:"10.5772/intechopen.105547",signatures:"Adenike O. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"
\r\n\tIf we aim to prosper as a society and as a species, there is no alternative to sustainability-oriented development and growth. Sustainable development is no longer a choice but a necessity for us all. Ecosystems and preserving ecosystem services and inclusive urban development present promising solutions to environmental problems. Contextually, the emphasis on studying these fields will enable us to identify and define the critical factors for territorial success in the upcoming decades to be considered by the main-actors, decision and policy makers, technicians, and public in general.
\r\n
\r\n\tHolistic urban planning and environmental management are therefore crucial spheres that will define sustainable trajectories for our urbanizing planet. This urban and environmental planning topic aims to attract contributions that address sustainable urban development challenges and solutions, including integrated urban water management, planning for the urban circular economy, monitoring of risks, contingency planning and response to disasters, among several other challenges and solutions.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/95.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11979,editor:{id:"181079",title:"Dr.",name:"Christoph",middleName:null,surname:"Lüthi",slug:"christoph-luthi",fullName:"Christoph Lüthi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHSqQAO/Profile_Picture_2022-04-12T15:51:33.png",biography:"Dr. Christoph Lüthi is an urban infrastructure planner with over 25 years of experience in planning and design of urban infrastructure in middle and low-income countries. He holds a Master’s Degree in Urban Development Planning from the University College of London (UCL), and a Ph.D. in Urban Planning & Engineering from TU Berlin. He has conducted applied research on urban planning and infrastructure issues in over 20 countries in Africa and Asia. In 2005 he joined Eawag-Sandec as Leader of the Strategic Environmental Sanitation Planning Group. Since 2015 he heads the research department Sanitation, Water and Solid Waste for Development (Sandec) at the Swiss Federal Institute of Aquatic Research and Technology (Eawag).",institutionString:"Swiss Federal Institute of Aquatic Science and Technology, Switzerland",institution:null},editorTwo:{id:"290571",title:"Dr.",name:"Rui Alexandre",middleName:null,surname:"Castanho",slug:"rui-alexandre-castanho",fullName:"Rui Alexandre Castanho",profilePictureURL:"https://mts.intechopen.com/storage/users/290571/images/system/290571.jpg",biography:"Rui Alexandre Castanho has a master\\'s degree in Planning, Audit, and Control in Urban Green Spaces and an international Ph.D. in Sustainable Planning in Borderlands. Currently, he is a professor at WSB University, Poland, and a visiting professor at the University of Johannesburg, South Africa. Dr. Castanho is a post-doc researcher on the GREAT Project, University of Azores, Ponta Delgada, Portugal. He collaborates with the Environmental Resources Analysis Research Group (ARAM), University of Extremadura (UEx), Spain; VALORIZA - Research Center for the Enhancement of Endogenous Resources, Polytechnic Institute of Portalegre (IPP), Portugal; Centre for Tourism Research, Development and Innovation (CITUR), Madeira, Portugal; and AQUAGEO Research Group, University of Campinas (UNICAMP), Brazil.",institutionString:"University of Johannesburg, South Africa and WSB University, Poland",institution:{name:"University of Johannesburg",institutionURL:null,country:{name:"South Africa"}}},editorThree:null,series:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null},editorialBoard:[{id:"181486",title:"Dr.",name:"Claudia",middleName:null,surname:"Trillo",slug:"claudia-trillo",fullName:"Claudia Trillo",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSAZHQA4/Profile_Picture_2022-03-14T08:26:43.jpg",institutionString:null,institution:{name:"University of Salford",institutionURL:null,country:{name:"United Kingdom"}}},{id:"308328",title:"Dr.",name:"Dávid",middleName:null,surname:"Földes",slug:"david-foldes",fullName:"Dávid Földes",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002nXXGKQA4/Profile_Picture_2022-03-11T08:25:45.jpg",institutionString:null,institution:{name:"Budapest University of Technology and Economics",institutionURL:null,country:{name:"Hungary"}}},{id:"282172",title:"Dr.",name:"Ivan",middleName:null,surname:"Oropeza-Perez",slug:"ivan-oropeza-perez",fullName:"Ivan Oropeza-Perez",profilePictureURL:"https://mts.intechopen.com/storage/users/282172/images/system/282172.jpg",institutionString:"Universidad de las Américas Puebla",institution:{name:"Universidad de las Américas Puebla",institutionURL:null,country:{name:"Mexico"}}}]},onlineFirstChapters:{paginationCount:14,paginationItems:[{id:"82457",title:"Canine Hearing Management",doi:"10.5772/intechopen.105515",signatures:"Peter M. Skip Scheifele, Devan Marshall, Stephen Lee, Paul Reid, Thomas McCreery and David Byrne",slug:"canine-hearing-management",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"82285",title:"Parvovirus Vectors: The Future of Gene Therapy",doi:"10.5772/intechopen.105085",signatures:"Megha Gupta",slug:"parvovirus-vectors-the-future-of-gene-therapy",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"82170",title:"Equine Stress: Neuroendocrine Physiology and Pathophysiology",doi:"10.5772/intechopen.105045",signatures:"Milomir Kovac, Tatiana Vladimirovna Ippolitova, Sergey Pozyabin, Ruslan Aliev, Viktoria Lobanova, Nevena Drakul and Catrin S. 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