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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"1700",leadTitle:null,fullTitle:"Embryogenesis",title:"Embryogenesis",subtitle:null,reviewType:"peer-reviewed",abstract:'The book "Embryogenesis" is a compilation of cutting edge views of current trends in modern developmental biology, focusing on gametogenesis, fertilization, early and/or late embryogenesis in animals, plants, and some other small organisms. Each of 27 chapters contributed from the authorships of world-wide 20 countries provides an introduction as well as an in-depth review to classical as well as contemporary problems that challenge to understand how living organisms are born, grow, and reproduce at the levels from molecule and cell to individual.',isbn:null,printIsbn:"978-953-51-0466-7",pdfIsbn:"978-953-51-5276-7",doi:"10.5772/2143",price:159,priceEur:175,priceUsd:205,slug:"embryogenesis",numberOfPages:666,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"3f9b9a95bfaabcf31b5c860a9faec044",bookSignature:"Ken-ichi Sato",publishedDate:"April 20th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1700.jpg",numberOfDownloads:94394,numberOfWosCitations:89,numberOfCrossrefCitations:29,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:80,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:198,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 10th 2011",dateEndSecondStepPublish:"June 7th 2011",dateEndThirdStepPublish:"October 12th 2011",dateEndFourthStepPublish:"November 11th 2011",dateEndFifthStepPublish:"March 10th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"104122",title:"Dr.",name:"Ken-Ichi",middleName:null,surname:"Sato",slug:"ken-ichi-sato",fullName:"Ken-Ichi Sato",profilePictureURL:"https://mts.intechopen.com/storage/users/104122/images/system/104122.png",biography:"Ken-ichi Sato was born in Hokkaido, Japan. He graduated from Faculty of \nScience, Kobe University, Kobe, Japan, in 1988. He obtained his Ph.D. \ndegree in biology from the Graduate School of Science and Technology, \nKobe University, in 1996. From 1991 to 2007, he worked as an Assistant \nProfessor at the Research Center for Environmental Genomics, Kobe \nUniversity. In 2007, he launched his own research group of Cell \nSignaling and Development in Kyoto Sangyo University, Kyoto, Japan. His \nresearch interest is the role played by protein-tyrosine kinases in \ntransmembrane signal transduction mechanisms such as in the cancer cells \nand in the fertilized eggs. Currently, he is a Professor at the \nDepartment of Industrial Biosciences, Faculty of Life Sciences, Kyoto \nSangyo University.",institutionString:"Kyoto Sangyo University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Kyoto Sangyo University",institutionURL:null,country:{name:"Japan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"392",title:"Embryology",slug:"developmental-genetics-embryology"}],chapters:[{id:"35559",title:"Clathrin Heavy Chain Expression and Subcellular Distribution in Embryos of Drosophila melanogaster",doi:"10.5772/36596",slug:"clathrin-heavy-chain-expression-and-subcellular-distribution-in-embryos-of-drosophila-melanogaster-",totalDownloads:2975,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Georg Petkau, Christian Wingen, Birgit Stümpges and Matthias Behr",downloadPdfUrl:"/chapter/pdf-download/35559",previewPdfUrl:"/chapter/pdf-preview/35559",authors:[{id:"108982",title:"Dr.",name:"Matthias",surname:"Behr",slug:"matthias-behr",fullName:"Matthias Behr"},{id:"113688",title:"Mr.",name:"Georg",surname:"Petkau",slug:"georg-petkau",fullName:"Georg Petkau"},{id:"113689",title:"MSc.",name:"Christian",surname:"Wingen",slug:"christian-wingen",fullName:"Christian Wingen"},{id:"113690",title:"MSc.",name:"Birgit",surname:"Stümpges",slug:"birgit-stumpges",fullName:"Birgit Stümpges"}],corrections:null},{id:"35560",title:"Human Embryogenesis",doi:"10.5772/36871",slug:"human-embryogenesis",totalDownloads:3242,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Charles E. 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Neutrophils are the most abundant cell type in human blood. They are produced in the bone marrow and then released into the circulation. At sites of infection or inflammation, neutrophils migrate to tissues, where they complete their functions. Finally, neutrophils die by apoptosis and are eliminated by macrophages. Neutrophils are an essential part of the innate immune system [1], with significant antimicrobial functions, including phagocytosis, degranulation, and the formation of neutrophil extracellular traps (NETs). These antimicrobial functions were believed to be the only goal of neutrophils. However, it has recently become clear that neutrophils display many functional responses that go beyond the simple killing of microorganisms. Neutrophils produce cytokines [2] and other inflammatory factors [3] that regulate the whole immune system [4, 5]. Consequently, neutrophils are also key effector cells of the adaptive immune system.
\nImmunoglobulin (Ig) G antibody molecules are an essential part of the adaptive immune system. IgGs recognize antigens via their two Fab portions and are in turn linked through their Fc portion to specific Fcγ receptors (FcγRs) on the membrane of leukocytes [6, 7]. In this way, antibodies function as a bridge between the specific adaptive immune response and the potent innate immune functions of leukocytes. In the human neutrophil, two types of FcγR exist. Thus, antibodies are important activators of neutrophils. The Fcγ receptors on the neutrophil are considered to be redundant in inducing cell responses [8, 9]. However, recent findings on how a particular IgG subclass and the glycosylation pattern of the antibody regulate the IgG–FcγR interaction suggest that a particular effector function may in fact be activated in response to a specific type of FcγR. It is the purpose of this chapter to describe the FcγRs on human neutrophils and present our current view of how particular FcγRs activate various signaling pathways to promote unique effector cell functions.
\nNeutrophils are the most abundant leukocytes in blood and because they are the first cells to appear at sites of inflammation and infection; they are regarded as the first line of defense of the innate immune system [10]. Neutrophils can rapidly move from the blood into affected sites through a process known as the leukocyte adhesion cascade. Once in the tissues, they perform important antimicrobial functions, including phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) [11, 12].
\nNeutrophils leave the blood circulation at sites of infection or inflammation by binding to the endothelial cells and then transmigrating into the tissues [13]. This process known, as the leukocyte adhesion cascade (Figure 1), begins with the activation of endothelial cells at the affected site. Activated endothelial cells upregulate the expression of adhesion receptors such as E- and P-selectins. Neutrophils bind to these selectins via glycoprotein ligands on their membrane. As a consequence, neutrophils can then roll on endothelial cells. Next, neutrophils get activated by chemokines, which induce a high affinity state on integrins, another group of adhesion receptors. Binding of integrins with their corresponding ligands, such as intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on endothelial cells, results in slower neutrophil rolling and then firm adhesion that makes neutrophils stop. Finally, neutrophils transmigrate the endothelium into the tissues. Engagement of endothelial-cell adhesion molecules seems to provoke the opening of endothelial-cell contacts by redistributing junctional molecules in a way that promotes transmigration of neutrophils. Molecules that do not help neutrophil migration, such as vascular endothelial cadherin (VE-cadherin), are moved away from junctional regions. Other endothelial junctional molecules for which neutrophils express ligands concentrate on the endothelial cell luminal surface creating an adhesive environment for the neutrophil. Platelet/endothelial-cell adhesion molecule 1 (PECAM1) and CD99 support homophilic interactions between endothelial cells and neutrophils. While, junctional adhesion molecule (JAM)-1 and JAM-2 on the endothelial cell bind to the β1 integrin VLA4, and the β2 integrins LFA-1 and Mac-1 on the neutrophil, respectively. The endothelial cell-selective adhesion molecule (ESAM) is also involved in transmigration by binding to an unknown ligand on neutrophils [12, 14]. Once neutrophils move into tissues, they follow chemoattractant gradients to reach affected sites using now adhesion of β1 integrins to proteins of the extracellular matrix, such as collagen and fibronectin [15] (Figure 1). Important chemoattractants for neutrophils are activated complement components, such as the anaphylatoxin C5a, bacterial components, such as formyl-methionyl-leucyl-phenylalanine (fMLF) and cytokines, such as interleukin (IL) 8.
\nNeutrophils recruited from the circulation into infected tissues can eliminate microorganisms by phagocytosis, by releasing antimicrobial substances or by forming NETs [11, 12] (Figure 2).
\nPhagocytosis is the process by which particles larger than 5 μm get internalized by the cell into a vacuole called the phagosome. Neutrophils recognize pathogens directly through pattern-recognition receptors (PAMPs), or indirectly through opsonin receptors. Opsonins are host proteins, such as antibody molecules or complement components, that bind to microorganisms and facilitate their detection and destruction by leukocytes [16, 17]. After internalization, the nascent phagosome matures by fusing with lysosomes [18]. During maturation, antimicrobial molecules are delivered into the phagosomal lumen, and the vesicle is transformed into a phagolysosome [19]. In the phagolysosome, reactive oxygen species (ROS) are produced by the NADPH oxidase on the phagosomal membrane, and the pH inside drops to 4.5–5. Also, hydrogen peroxide (H2O2) is converted to hypochlorous acid (HOCl) in a reaction catalyzed by myeloperoxidase (MPO) [20]. Together, these actions form a toxic environment for the microorganism.
\nDuring neutrophil formation in the bone marrow, immature neutrophils synthesize proteins that are sorted into different granules [10]. Granules are classified into three different types based on their content. Azurophilic granules contain mainly myeloperoxidase, elastase, and cathepsin G. Specific granules contain mainly collagenase, lactoferrin, and lysozyme. Gelatinase granules contain mainly gelatinase, lysozyme, and cytochrome b558 [21]. Neutrophils also form secretory vesicles at the last step of their differentiation. These secretory vesicles contain several important receptors on their membrane, including complement receptors (CR1), Fc receptors (CD16), lipopolysaccharide (LPS) receptors (CD-14), and fMLF receptors. Granule heterogeneity is due to the controlled expression of the granule protein genes [22]. Mature neutrophils are released into the circulation and when they reach sites of infection, neutrophils can degranulate in order to deliver their antimicrobial proteins. Secretory vesicles present the greatest predisposition for extracellular release, followed by gelatinase granules, specific granules, and azurophil granules [23]. The hierarchical mobilization of neutrophil granules and secretory vesicles depend on intracellular Ca2+-level [24].
\nWhen neutrophils cannot ingest large microorganisms, they can display another antimicrobial strategy [25]. Neutrophils can release long chromatin fibers that are decorated with proteins from their granules. These fibers can trap microorganisms, and therefore, they have been called neutrophil extracellular traps (NETs) [26]. The process of NETs formation is called NETosis [27]. NETosis has been described as a special form of programmed cell death. The complete mechanisms of NETs formation are still unknown; it seems that NETosis requires NADPH oxidase activation, reactive oxygen species (ROS) production, myeloperoxidase (MPO), and neutrophil elastase (NE) release [28, 29] (Figure 2).
\nAntibodies produced by the adaptive immune response are mainly of the IgG class. These antibodies present higher affinity and greater specificity for their particular antigen. Thus, IgG antibodies are key for controlling infections from all types of pathogens, including viruses, bacteria, fungi, and protozoa [30]. However, IgG molecules do not directly damage the microorganisms they recognize. It is in fact, the cells of the innate immune system, which are responsible for the antimicrobial functions of these antibodies. Although, some antibodies can activate complement, which is then deposited on microorganisms to promote phagocytosis via complement receptors [17, 31], or to induce bacterial lysis via the formation of the membrane attack complex [32], most IgG antibodies bind to specific receptors on the membrane of leukocytes [7, 8]. These receptors recognize the fragment crystallizable (Fc) portion of IgG molecules and are therefore known as Fcγ receptors (FcγR). Cross-linking of FcγR on the surface of cells activates several antimicrobial functions [6].
\nHuman Fcγ receptors comprise a family of glycoproteins expressed on the membrane of immune cells [7, 8]. These receptors can bind to the various IgG subclasses with different affinities [7], and induce different cellular responses [6]. FcγR can be classified as activating receptors (FcγRI/CD64, FcγRIIa/CD32a, FcγRIIIa/CD16a, and FcγRIIIb/CD16b), and one inhibitory receptor (FcγRIIb/CD32b) [7, 9, 33, 34] (Figure 3).
\nFcγRI is a high affinity receptor, having three Ig-like extracellular domains. It binds mainly monomeric IgG [9]. In contrast, FcγRII and FcγRIII are low-affinity receptors, having two Ig-like extracellular domains. They bind only multimeric immune complexes [9, 35]. FcγRI is associated with a dimer of the common Fc receptor γ chain, which contains an immunoreceptor tyrosine-based activation motif (ITAM) sequence (Figure 3). The ITAM sequence is important for receptor signaling [36].
\nFcγRIIa contains its own ITAM within its cytoplasmic tail. In contrast, the inhibitory receptor FcγRIIb contains an immunoreceptor tyrosine-based inhibition motif (ITIM) within its cytoplasmic tail (Figure 3). The FcγRIIb negatively regulates various cell functions including antibody production by the B cell [37], proliferation, degranulation, and phagocytosis in other leukocytes when it is cross-linked with activating FcγRs [38, 39]. Most leukocytes express both activating and inhibitory FcγRs, hence simultaneous cross-linking establishes a threshold for cell activation [40] that maintains a balanced immune response [41, 42].
\nFcγRIII has two isoforms: FcγRIIIa is a receptor with a transmembrane domain and a cytoplasmic tail, associated with an ITAM-containing homodimer of Fc receptor γ chains (Figure 3). It is expressed mainly on macrophages, natural killer (NK) cells, and dendritic cells [7, 8]. In contrast, FcγRIIIb is expressed exclusively on neutrophils and it is a glycosylphosphatidylinositol (GPI)-linked receptor missing a cytoplasmic tail. Also, no other subunits are known to associate with it (Figure 3). It is important to mention that human FcγRIIa and FcγRIIIb are exclusive receptors that are not found in other species [33, 43].
\nAs mentioned before, there is one high-affinity Fcγ receptor, FcγRI (CD64), and two groups of low-affinity Fcγ receptors, FcγRII and FcγRIII (Figure 3). This causes that a single IgG molecule cannot bind to most Fcγ receptors. However, when IgG molecules form antigen-antibody (immune) complexes, they can have many low affinity interactions with Fcγ receptors. Thus, only immune complexes are able to induce the cross-linking of FcγR required for the activation of various antibody-mediated cell functions. It is clear then that depending on the nature of the immune complex, the interaction with various FcγR will change. Several factors have been identified as having an important influence on the affinity of antibody molecules for particular FcγRs. These factors include the type of IgG subclass [7, 44], the IgG glycosylation pattern [45, 46], and receptor polymorphisms.
\nThere are four subclasses of IgG (IgG1, IgG2a, IgG2b, and IgG3 in mice; and IgG1, IgG2, IgG3, and IgG4 in humans) [47]. This leads to the formation of different types of immune complexes. Several
Obviously, this selectivity depends mainly on the affinities of different IgG subclasses to particular Fcγ receptors. For this reason, detailed studies to measure the affinities of IgG subclasses to the various Fcγ receptors have been conducted both for mice FcγRs [51] and for all human FcγRs [35]. Through these studies, it was found that IgG1 and IgG3 bind to all FcγR. IgG2 binds mainly to FcγRIIa (H131 isoform), and FcγRIIIa (V158 isoform), but not to FcγRIIIb [35]. IgG4 binds to many FcγRs [35]. Thus, it is clear that different IgG subclasses engage different Fcγ receptors depending on the relative affinity of these receptors for a particular IgG class [33].
\nAll IgG molecules are glycoproteins with an N-glycosylated carbohydrate side chain that is important for antibody function [52]. Deletion of this carbohydrate (sugar) side chain results in poor binding to FcγRs [53]. The N-glycans are heterogeneous in their sugar composition and are attached to asparagine 297 (Asp297) in the Fc portion of the IgG [54]. The carbohydrate side chain may contain sugar residues such as galactose, fucose, and sialic acid in straight or branching patterns [46], and the differences in the glycosylation pattern seem to regulate IgG activity [55].
\nMany IgG antibodies present a fucose residue linked to an N-acetylglucosamine residue [56]. When this residue is removed, IgG molecules present an increased affinity to the FcγRIIIa [57], and also an increase in antibody-dependent cell cytotoxicity (ADCC) activity against various tumor cells [51, 57, 58]. Based on these findings, recombinant IgG antibodies with low fucose levels have been produced in order to increase their ADCC activity. Several of these antibodies are now in clinical trials to test their therapeutic potential [59].
\nMany IgG antibodies also present a carbohydrate side chain that terminates with sialic acid residues [60]. Contrary to antibodies without fucose, terminal sialic acid usually correlates with low affinity for FcγRs and also with lower ADCC activity [61, 62]. Interestingly, these sialic acid-rich antibodies seem to preferentially bind other receptors different from FcγRs. The receptor dendritic cell specific ICAM-3 grabbing nonintegrin (DC-SIGN) was identified as a receptor for sialic acid-rich IgG [63]. Therefore, terminal sialic acid can modify IgG activity by promoting less binding to FcγRs and more binding to other receptors [45].
\nAnother factor influencing the affinity of antibody molecules is the existence of several polymorphisms for the unique FcγRIIa and FcγRIIIb present on human neutrophils [64]. There are two isoforms for FcγRIIa with different amino acids at position 131. These are identified as low-responder (H131) and high-responder (R131) [65]. Similarly, for FcγRIIIb two isoforms exist differing at four positions, NA1 (R36 N65 D82 V106) and NA2 (S36 S65 N82 I106) [66], and with different glycosylation patterns [67]. In addition, another FcγRIIIb isoform named SH is generated by a point mutation (A78D) in the NA2 allele [68]. These multiple FcγR isoforms display diverse binding affinity for different IgG classes [35], creating variable cell responses to different antibodies.
\nThe human neutrophil expresses two unique activating Fc receptors: FcγRIIa and FcγRIIIb. FcγRIIa is a receptor containing ITAM sequences [36, 69], and it signals similarly to other typical immunoreceptors, such as the antigen receptor of T lymphocytes (TCR) and the antigen receptor of B lymphocytes (BCR) [70]. The initial signaling steps for all immunoreceptors are alike and involve first cross-linking of the receptors on the membrane of the cell, followed by the activation of Src family tyrosine kinases (Figure 4). These kinases lead to activation of spleen tyrosine kinase (Syk), which in turn phosphorylates tyrosines within the ITAM sequence. Phosphorylated ITAM then becomes a binding site for Syk. After binding to the receptor, Syk phosphorylates multiple substrates leading to different cell responses [6, 31, 71] (Figure 4). Syk can phosphorylate and activate phospholipase Cγ (PLCγ), which in turn generates diacylglycerol (DAG) and inositol triphosphate (IP3). DAG also activates protein kinase C (PKC), an important serine/threonine kinase that can lead to the activation of MAP kinases extracellular signal-regulated kinase (ERK) and p38 (Figure 4). IP3 induces release of intracellular calcium from the endoplasmic reticulum. Calcium regulates several proteins such as calmodulin and calcineurin. Syk can also induce activation of phosphatidylinositol-3 kinase (PI3K), which produces phosphatidylinositol 3,4,5-trisphosphate (PIP3). This phospholipid is relevant to the activation of small GTPases, such as Rho and Rac, which are involved in cytoskeleton remodeling for phagocytosis. Rac also leads to activation of the MAPK/ERK kinase (MEK)—ERK pathway, and to activation of c-Jun N-terminal kinases (JNK). These kinases are important for activation of nuclear factors, such as Elk-1, AP-1, and nuclear factor of activated T cells (NFAT) (Figure 4). These nuclear factors induce the expression of cytokines important for inflammation and immune regulation, such as IL-2, IL-6, IL-8, IL-10, tumor necrosis factor α (TNF-α), and IFN-γ [72, 73, 74] (Figure 4).
\nIn contrast, the human FcγRIIIb is a GPI-linked receptor that lacks an intracellular portion. Thus, it is not clear how it can connect to intracellular signaling molecules. However, there is no doubt that FcγRIIIb is an activating receptor inducing several neutrophil responses such as increase in calcium concentration [75], activation of the respiratory burst [76], activation of integrins [77], and induction of NETosis [78, 79]. Despite, the initial signaling mechanism for FcγRIIIb remains unknown, the signaling pathway for this receptor engages Syk and then transforming growth factor-β-activated kinase 1 (TAK1), as well as the MEK/ERK cascade [80] (Figure 5). One possibility to connect FcγRIIIb with Syk is that the receptor could link with signaling molecules such as Src family tyrosine kinases on the plane of the cell membrane. Because GPI-linked proteins, like the FcγRIIIb, concentrate in lipid rafts on the cell membrane together with Src kinases [81, 82], we can imagine that after cross-linking FcγRIIIb, it associates somehow with these kinases and activates Syk. A possible connection is the binding of the receptor, within the lipid rafts, to a putative ITAM-containing molecule [83]. Many steps are still unknown and future research will help in completely elucidate this signaling pathway.
\nThe signaling pathways activated by immune complexes binding to Fcγ receptors stimulate different neutrophil responses including phagocytosis, respiratory burst, cytokine and chemokine production, and antibody-dependent cellular cytotoxicity (ADCC) [7, 8, 33]. However, our understanding of what particular function is activated in a cell responding to an individual type of FcγR is still very limited. This lack of knowledge is due, in part, to the fact that each cell expresses several types of FcγRs and all receptors can bind to more than one type of IgG. Thus, it is not clear whether each receptor leads to a particular response or the average signaling from various receptors activates a predetermined cell response. Traditionally, it has been thought that each cell is set to activate a particular cell function after FcγR cross-linking. More recently, however, another interpretation has been considered: each FcγR activates a particular signaling pathway leading to a unique cell response. In the traditional view, each cell is already programmed to perform a particular cell function after FcγR cross-linking, independently of the receptor used. This idea is not really supported by experimental evidence. As indicated above, different IgG subclasses bind particular Fcγ receptors with different affinity, leading to unique cell functions
The idea that particular Fcγ receptors could activate unique cell functions was initially published more than 20 years ago. It was found that the neutrophil FcγRIIIb induced actin polymerization in a Ca2+-dependent manner, while FcγRIIa did not [87]. This initial report was not followed by similar reports and the idea of one receptor one response was forgotten. However, with time, other reports have provided new evidence that supports this idea. Some years later, it was reported that FcγRIIa, but not FcγRIIIb caused shedding of L-selectin expression [88] (Figure 6). Consequently, it was proposed that binding of antibodies to FcγRIIIb could induce a proadhesive phenotype of neutrophils [88]. More recently, new evidence supporting this idea was found. When each receptor was selectively activated with specific monoclonal antibodies, FcγRIIIb but not FcγRIIa, was able to activate β1 integrins [77] (Figure 7). This activation resulted from an increase in binding affinity to fibronectin [77]. Thus, after neutrophils leave the circulation, engagement of FcγRIIIb could lead to activation β1 integrins, allowing the cells to adhere to extracellular matrix proteins and migrate into tissues [89] (Figure 1). In contrast, for antibody-mediated phagocytosis [17], FcγRIIa was the main Fcγ receptor mediating this response, while FcγRIIIb contribution to phagocytosis was minimal [86]. Therefore, at least in human neutrophils, each Fcγ receptor initiates particular cell functions. FcγRIIa induces phagocytosis (Figure 6), while FcγRIIIb promotes an adhesive phenotype via activation of β1 integrins (Figure 7).
\nIn addition, it was also reported that FcγRIIIb signals to the neutrophil nucleus more efficiently than FcγRIIa. FcγRIIIb, but not FcγRIIa, induced a large increase in phosphorylated ERK in the nucleus, and also efficient phosphorylation of the nuclear factor Elk-1 [84] (Figure 7). Interestingly, FcγRIIa also induced phosphorylation of ERK in the cytosol [84, 90], but this active ERK seems to function mainly in enhancing phagocytosis and not in nuclear signaling [91] (Figure 4).
\nA recently discovered antimicrobial function of neutrophils is the formation of neutrophil extracellular traps (NETs) [92, 93]. NETs are induced by several pathogens, including virus, bacteria, fungi, and parasites [94]. Also, pro-inflammatory stimuli such as IL-8, TNF-α, and phorbol-12-myristate-13-acetate (PMA) are efficient inducers of NETs [95]. Because, antigen-antibody complexes are also capable of inducing NET formation [96]; it was clear that FcγRs were involved in NET formation. Recently, it was found that FcγRIIIb, but not FcγRIIa, is the receptor responsible for NET formation [78, 79, 80] (Figure 8).
\nTogether, all these reports strongly reinforce the modern view that each FcγR induces a particular signaling pathway that activates a single cellular function. Elucidating the conditions that engage a single type of FcγR to activate a particular cellular response would be very helpful in the future for controlling some of cellular functions in clinical settings. For example, in intense infections, it may be important to activate phagocytosis. Because IgG2 binds better to FcγRIIa than to FcγRIIIb [33, 35], it is likely that IgG2 antibodies would activate phagocytosis by neutrophils much better than other IgG subclass antibodies. In consequence, promoting IgG2 antibodies against certain pathogens would result in better phagocytosis against them.
\nFcγ receptors expressed in different immune cells are capable of activating different cellular responses important not only for controlling microbial infections but also for regulating immunity [71, 97]. Different subclasses of IgG antibodies bind the various Fcγ receptors with different affinities [33, 35] and can activate various cellular functions of great importance for host defense and for immune regulation. In the human neutrophil, it is clear that a specific Fcγ receptor activates particular cellular responses. FcγRIIa induces efficient phagocytosis [86], while FcγRIIIb signals to the nucleus for nuclear factor activation [84] and for NETs formation [78]. Therefore, in principle, a particular cell response could be induced or inhibited by engaging or blocking the corresponding FcγR. Information similar to the one described for neutrophil Fcγ receptors on other immune cells, such as monocytes or dendritic cells, is not available. Future research is needed in this area.
\nThis work was supported by Grant 254434 from Consejo Nacional de Ciencia y Tecnología, México.
\nIn the year 1996, the National institute of Health (NIH, USA) held a conference from which the NIH issued a pamphlet of clinical guidelines regarding temporomandibular disorders (TMD). In the NIH report as well as from the National Institute of Dental Research (NIDR) (NIH publication no. 94-3487), no distinction was made between temporomandibular disorders and myofascial pain dysfunction syndrome (MPDS). All potential etiological factors, clinical symptoms, the diagnoses and the treatment recommendations fell under the single term, “Temporomandibular Disorders” [1]. There was no clear distinction made between TMJ internal derangements and myofascial pain dysfunction syndrome. Additionally, the final report did not recommend any definitive treatment for temporomandibular disorders. Although the NIH meeting attendees claimed to have solved the “TMJ problem,” no consensus was reached making the conference a complete disappointment. However, later in 1999, Dr. Peter Dawson opposed the conference results in an article that was cosponsored by American Equilibration Society (AES, Chicago, IL, USA) [2]. After further numerous arguments, no consensus was found regarding the etiology or treatments that should be applied in TMD cases.
\nOf note is that 4 years before the release of the NIH report in 1991, Dr. Robert Barry Kerstein from Tufts University School of Dental Medicine in Boston Massachusetts had developed a T-Scan I time-based coronoplasty procedure, which focused on reducing excursive movement disclusion times [3]. According to this study, the length of disclusion time was correlated to high levels of masseter and temporalis excursive muscle activity levels [3] that were of diagnostic importance when evaluating differing etiologic factors of chronic MPDS [2]. These early studies were the beginning of a series of studies about this topic [3, 4]. As Dawson noted in his article, there had been found an evidence-based relationship between occlusion and MPDS. Often MPDS symptoms affected the chewing system mechanics because the symptoms had a close association with the dental occlusion and its relationship to the central nervous system (CNS).
\nMyofascial pain dysfunction syndrome is a common term that is used in other medical branches outside of Dentistry [5, 6, 7]. But in the last few decades, this term has been used in Dental Medicine to describe orofacial chronic pain [8, 9], often abbreviated in the literature as MPDS [3]. MPDS is a functional disease related to the masticatory muscles, the neural structures and the temporomandibular joint structures. MPDS syndrome can be a very uncomfortable condition for a patient. The patient can barely move their mandible, and often there is pain in the face and head area. Sometimes, the pain may extend to neck and dorsal area. Most typical symptoms are acute hypercontraction (spasm) of the muscles, and laxity of the TM joint ligaments. The symptoms of the MPDS are explained in detail later in this chapter [5, 10, 11, 12].
\nEtiologically, the MPDS muscle and TM joint symptoms have been linked primarily to the occlusion [2, 3, 13, 14]. Muscle spasm is caused by occlusal surface friction and prolonged disclusion time overcompressing the posterior tooth PDLs causing hyperfunction and ischemia in the muscles. This leads to muscle fatigue and then poor mandibular movements. This is what leads to deterioration of the movements.
\nMuscle spasm is usually caused by occlusal surface friction and prolonged disclusion time [15] overcompressing the posterior tooth periodontal ligament mechanoreceptors causing hyperfunction and ischemia in the muscles. This leads to muscle fatigue and then poor mandibular movements [16].
\nThe deterioration of mandibular movements can be accelerated by deterioration of the occlusion. A filling, crown, or a bridge will always cause the occlusion to deteriorate. Alternatively, ligament laxity affects the movements of the joint structures in the glenoid fossa and often occurs without patient awareness of the problem’s existence.
\nMyofascial pain dysfunction syndrome (MPDS) is one particular type of temporomandibular disorder (TMD) [12]. Historically, clinicians and researchers have subclassified TMDs into either intracapsular disorders or masticatory muscle disorders (such as local myalgia, myofascial pain, centrally mediated myalgia, myospasm, myositis, myofibrotic contracture, and masticatory muscle neoplastic disease). TMJ internal derangement may not be involved with MPDS. However, when a temporomandibular joint irregularity occurs along with the symptoms of MPDS, the complete problematic condition should be considered as temporomandibular joint disease [17, 18]. All masticatory organs participating in oral function may or may not be involved in MPDS.
\nBefore discussing about the etiologic factors and treatment techniques related to MPDS, it is necessary to properly understand the neural mechanisms of masticatory system.
\nMuscular pain is a typical and a decisive symptom of MPDS. Functional disorders that occur in the stomatognathic system are a cause of pain. If the functional disorders are not successfully treated, pain may be present for years. Pain minimization during function is the result of the protective mechanisms within the stomatognathic system.
\nThe most important stomatognathic function is chewing. There is a great relationship between impairment of chewing function and painful muscle problems [13, 16, 17, 19, 20, 21, 22, 23, 24]. During the chewing function, tooth contact occurs at the extreme end of the chewing cycle when occlusal force is applied to crush the food bolus. In this way, the resultant chewed food is readied for swallowing. For the chewed food product to be effectively prepared for swallowing, all related functions must occur in a harmonious order. Hence, the duration of chewing, the control of the mandibular movements, the masticatory muscle contractions, the level of force applied during the bolus crush, temporomandibular joint movements, the tooth-tooth interactions, and the neural feedback mechanisms all must interact synergistically (\nFigure 1\n).
\nA normal mastication pattern in three planes as recorded by a Jaw Tracker (3-D Electrognathograph, BioResearch Assoc., Milwaukee, WI, USA). Excellent chewing ability evolves in the developing human from youth into the adult years. An ideal chewing pattern requires harmony between all the masticatory functional organs.
The relationship between muscle malfunction and MPDS is a two-sided problem, where each affects the other. Muscle malfunction triggers MPDS, while MPDS causes impairment of masticatory movements. Stomatognathic system functions are the best diagnostic indicator of dysfunction. The main purpose of the stomatognathic system is to perform the best chewing possible, which requires a very well-coordinated system. As proper chewing evolves within the developmental period of human growth, it becomes optimal during the adult years. Deciduous, mixed, and permanent dentitions have their own chewing patterns [25], with the chewing pattern being closely linked to a person’s dental condition [24]. However, corruption of the chewing pattern indicates the beginnings of myofascial distortion [26, 27].
\nAs is the case with other body functions, the chewing pattern results from a complex integration of the neural and the myofascial structures. The resultant product of chewing is chewed food that is readied for swallowing. The most effective determining factor of a good chewing pattern is the dental occlusion [28], whereby the structural posture, the stretching of muscles and the chewing process itself are improved by upper and lower tooth contact. However, changes to the dental occlusion from tooth loss, orthodontic tooth movement, restorative dentistry, or mechanical trauma, all of which can alter the neurologic input significantly, may be the most important etiological factor leading to the impairment of chewing mechanism [19].
\nNervous system mechanoreceptors in and around the teeth transmit neural information to the central nervous system (CNS) regarding the nature of the masticatory function. This neural feedback mechanism is designed to protect the physiologic borders of the chewing pattern and controls the masticatory system mechanics. Neural sensors collect all the necessary neural input during chewing function as it is a sensory process. However, the mandibular functional and parafunctional movements are controlled by the motor function of the neural system. The neuromuscular mechanism of stomatognathic system collects the neural input that controls mandibular motion [29, 30].
\nMyofascial pain dysfunction syndrome (MPDS) can be used as general definition for one type musculoskeletal human disease state that consists of specific muscular symptoms. In a patient with temporomandibular disorders, MPDS often results from the hypercontraction of the masticatory elevator muscles. Spasm of one or more elevator muscles is a serious problem, which may cause pain, muscle tenderness, limitation of mandibular movements, and induce changes in the temporomandibular joint structural alignment. Muscle spasm usually emanates through the central nervous system (CNS) from the neural mechanoreceptors located in and around the teeth that hypercontract the elevator muscles. Along with muscle spasm, painful trigger points can also be a component of the MPDS condition. Some trigger points may be classified as latent [5, 6, 31, 32], in that they only occur when a muscle is pressed upon.
\nThe neuronal mechanism is a determining factor in the development of MPDS. The central nervous system (CNS) controls all activities of the masticatory system including the contraction of masticatory muscles, the sequence of contractions, the level of contraction, the posture of mandible, the mandibular movements, and the resultant occlusal force, all of which are influenced by the occlusal relationship of upper and lower teeth [33]. The control mechanism of the nervous system is based on environmental neural data input. Every function of the masticatory system has a characteristic pattern that occurs within certain physiologic limits. Any overreaching from a physiologic limit can lead to a symptom of a particular problem. For example, any deviation in the opening (or closing) movement of the mandible is often the result of a muscle spasm that occurs during the opening movement. Limited mouth opening mouth (or S-shaped masticatory movement) is also an indication there is a problem within the stomatognathic system. Functional movements that designed by central nervous system (CNS) are outside of their physiologic limits. Many pathological conditions can also be produced by the central nervous system (CNS). If there is a strong but problematic feedback mechanism present in stomatognathic system, certain pathological conditions may increase in frequency and intensity, unless the pathology is not removed. Every type of nonphysiological movement has its own specific characteristics.
\nThe neural system mechanics must be very well understood to ascertain the etiology of a stomatognathic system pathology.
\nThe stomatognathic system neural network is comprised of three basic parts:
\nPerception of the sensory inputs.
Evaluation of the gathered inputs.
Reaction to the inputs.
Sensory input collection is an ongoing function of the neural system that can be conscious or unconscious. There is a continuous data stream entering the CNS from the peripheral nervous system (PNS), which gathers environmental data that send impulses to the masticatory muscle fibers to establish postural tonus activity. This occurs even when there is no function, such that there is a slight tension in the muscles when at rest (\nFigure 2\n).
\nA resting EMG recording of the masseter and temporalis muscles. Note, there is slight electrical activity providing tension to these muscles when holding the mandible in the rest position.
The human body consists of billions of similarly constructed cells that contain the cytoplasm, a nucleus, some chromosomes, some mitochondria, and some ribosomes. But some cells are different from the ordinary cells, despite that they also have cytoplasm, a nucleus, and ribosomes, but also contain neurons. Neurons and muscle cells are an excitable type of cell because they can receive electrical impulses and transfer the environmental neurologic data biochemically. These special cells are known as inducible cells.
\nThe functional unit of the motor system, the motor unit, is composed of a motor neuron and a group of muscle fibers with similar, if not identical, structural and functional properties. These are inducible cells known as neurons and myocites (muscle cell).
\nThere is a static electrical balance between the outside and inside of a cell membrane. This steady state is called the “resting membrane potential,” which does not change unless there exists a stimulus. This steady-state electrical potential difference between the outside and inside of a cell membrane is between −50 mV and −100 mV. A stimulus changes this steady state to an action state, whereby the resting potential difference is turned into an action potential difference. The main cause of the potential difference results from the existence of anions and cations on both sides of the cell membrane. Outside the membrane are positively charged natrium cations. Positively charged natrium ions attach to negatively charged chlorine ions (Cl−) that are outside of the membrane. However, despite the presence of negative ions (such as chlorine and HCO3), the outer side of the membrane remains positively charged. Alternatively, the inside of the membrane is negatively charged because positively charged potassium (K+) ions diffuse “down” its steep concentration gradient to move out of a cell via leakage channels. This K+ ion movement to outside of the cell membrane makes the outside more positively charged than inside the cell membrane. Outside the positive ions side at the edge of the membrane, with the inside negative ions located at the inner edge of the membrane. Therefore, the electrical potential difference exists on both sides of the membrane. A change in the electrical activity within the cell membrane plays an important role in the character of sensory conduction.
\nAll masticatory system functions are governed by the central nervous system (CNS). In order to coordinate what function occurs, and when, how much, and how it should occur physiologically, the CNS gathers information about the environment in which the function is to take place. There is a continuous flow of information between the sensory and motor neurons within the stomatognathic system and the central nervous system (CNS). Physiologically, proper oral functions like mastication, swallowing, and speaking need a rhythmic process whereby all parts of the masticatory system are coordinated so that the activity of the jaw muscles, the tongue, the cheeks, and the lips work synergistically to achieve correct function.
\nThere are two basic neurologic components of mastication:
the central pattern generator (and the)
the peripheral control mechanisms
For controlling and managing oral function, the central nervous system (CNS) must initially sense the environmental data. This data collection process is provided to the CNS by the mechano and sensory receptors of the peripheral nervous structures (PNS). Data collected from these receptors are transferred to the other levels of central nervous system (CNS). These receptors are specialized neurons for gathering the environmental sensory data related to the many sensorimotor functions, involving the coordinated contraction and inhibition of the musculature located around the mouth, at the tongue, larynx, pharynx, and esophagus bilaterally [34]. Moreover, according to the localization of the function, there are many differing types of receptors present in the mouth. The data received from receptors are transferred electrochemically to differing levels of the central nervous system (CNS). In this way, the peripheral neural control modulates the output of the central pattern generator and associated motor neurons, so that most effective occlusal forces are developed during chewing, without overly damaging the masticatory organs.
\nTransmission of the peripheral neural data is provided to the CNS by a neuron’s axons and dendrites. Dendrites receive the potential from the previous neuron. If a nerve cell is stimulated, the transmembrane voltage is necessarily changed. The stimulation may be excitatory or inhibitory. If the membrane stimulus is insufficient to cause the transmembrane potential to reach the threshold, then the membrane will not activate. If the excitatory stimulus is strong enough, the transmembrane potential reaches the threshold, and the membrane produces a characteristic electric impulse, known as the
The membrane potential may reach the threshold by a short, strong stimulus, or by
A very tiny premature contact that is not removed for a long time will have a sufficient excitatory level for instigating a nerve impulse. When the total sum level of stimulus reaches the threshold level, an action potential can emerge. This is known as the All-or-None principle.
A sudden nociceptive stimulus can cause a special type escape reflex known as the “jaw jerk reflex.” The jaw-jerk myotatic reflex is activated by the sudden stretching of the jaw-closing muscles spindles. The jaw jerk reflex is one of the most important neuronal patterns as it may or may not be nociceptive. The repetition of nociceptive stimuli that causes a reflex action early on during the development of dysfunction may after awhile cease to exist. This adaptation to the stimulus initiates the failure of the CNS to continue to respond to the stimulus. With the jaw jerk mechanism reflex over time, this insensitivity to further immediate noxious stimulation develops irritated neural tissue, which worsens from the intense and prolonged stimulation [7]. This worsening can lead to reduced mandibular vertical opening (\nFigure 4\n).
\nSpasm of the elevator muscles and limited maximum mouth opening of less than 25 mm indicates this women exhibits significant muscular dysfunction. This critical distance of healthy limited opening in men is 35–40 mm.
Information from the peripheral nervous system (PNS) tissues outside the CNS is continuously transferred into the CNS onto higher centers in the brain stem and cortex for interpretation and evaluation. All human functional and parafunctional movements are based on five major sensory systems:
Olfaction
Taste
Vision
Hearing
Touch
Touch sensory activity (Touch) is the critical neurologic control for the stomatognathic system’s functional and parafunctional movements.
\nNeural receptors perform two important tasks:
The gathering of sensory information
The transfer of the sensory response into the CNS and then back out to the muscles.
Mandibular functional movement sensory detection and the associated reflex responses are shaped by information gathered from the periodontal ligament mechanoreceptors in response to tooth compressions during chewing and from the temperature and touch receptors present in the pulp, the gingival tissues, and the mucobuccal tissues. One of the most important neural receptors is the pulpal mechanoreceptors, which together with periodontal mechanoreceptors carry tooth loading information to the CNS. These receptors transmit the intensity of force acting on a tooth as it contacts its opposing tooth counterpart, the changes of the force velocity at occlusal impact, a tooth’s movement direction during chewing, and the hardness of the food bolus. Moreover, the periodontal ligaments are also extremely important structures because their mechanoreceptors within the PDL are highly concentrated [34, 35, 36, 37, 38]. Receptors in the periodontal ligaments control and guide all functional and parafunctional movements because they relay information about the magnitude of tooth loads, which is described by the mean firing rate response of loaded periodontal receptors [34].
\nSeveral studies have indicated that the extracellular matrix collagens of the periodontal ligament have a high turnover and remodeling rate that are much higher than collagen turnover observed in the gingiva, skin, and bone [39]. The periodontal ligaments themselves are basically striated muscles with muscle spindles located within the fibers of the ligaments. These ligament fiber muscle spindles gather stretching and compression information when teeth are under tooth movement within the PDL space.
\nPeriodontal mechanoreceptors respond to the forces that are applied to teeth. They have been studied in histological and electrophysiological investigations that illustrated periodontal mechanoreceptors signal information about the degree of tooth loads because they have special force-encoding properties, which provides for functional control of human mastication. Microneurography recordings from single nerve fibers revealed that human periodontal receptors adapt slowly to maintained tooth loads. Most receptors are broadly tuned to the direction of force application, while about half respond to forces that are applied to more than one tooth at a time. Populations of periodontal receptors reliably encode information about both how the teeth are stimulated, and the direction that forces are applied to the individual teeth.
\nAnother important receptor type is “periodontal ligament integrins” [40], which are cell-surface receptors that connect cells to the collagen-rich and mechanically stressed periodontal ligament microenvironment. Mutations in integrin subunits have been found to cause clinical disorders in man that correlate well with mice, in which the same integrins are deleted [40]. Integrins are able to transduce signals intracellularly following ligand binding (“outside-in” signaling). However, unlike most other cell receptors, integrins can shift between high- and low-affinity conformations for ligand binding, whereby the signal direction is reversed (“inside-out” signaling). Depending on the cell type, integrins can be either basally activated, as is the case with most adherent cells that are attached to a basement membrane, or they can be basally inactive, like platelets or leukocytes that freely circulate until activated to undergo platelet aggregation or mediate an inflammatory response [41].
\nUltimately, all the collected load data from the pulp, the periodontal ligament receptors, and the mucosa are transmitted to the CNS via the trigeminal nerve (V) ganglions. Ganglions are the neurologic distribution center for both the afferent and efferent neural pathways.
\nBasically, there are two important ganglions involved in craniofacial area with neuroanatomic ties to the stomatognathic system:
Trigeminal ganglion
Mesencephalic nucleus
Living organisms need to be able to sense their immediate environment if they are to withdraw from or avoid potentially hazardous situations. One of the most typical examples of this protective mechanism is jaw jerk reflex. Sudden, strange matter that is perceived during chewing leads to the formation of this reflex. However, shortly after the identification of a hard substance, the central nervous system (CNS) reduces the reflex level to normal levels. Sometimes, the jaw jerk reflex may occur as a nociceptive reaction. For example, touching the pulp meter to the tooth surface can lead to a typical jaw jerk reflex.
\nReflexes are involuntary and relatively stereotyped responses to specific stimuli. Stimulated receptors send afferent impulses to the central nervous system (CNS), which are then transmitted through efferent nerve fibers to the cells, muscles, and organs that carry out the
A protective reflex is not continuous because the reflex stimulus is defined in the memory, and after few cycles, it does not cause the repeated reflex. Development of the multicellular structures in the nervous system evolves a specialized apparatus that detects and reacts to external stimuli, when combined together with the evolution of specific transduction proteins, and enables the CNS to accurately differentiate between innocuous and noxious stimuli. This early warning system, which is further elaborated, develops the capacity to increase its sensitivity following an exposure to an injurious stimulus, which is known as nociceptive sensitization. In mammals, the early warning protective pain that occurs in response to noxious stimuli (nociceptive pain) is mediated by specialized, high-threshold primary sensory neurons (nociceptors) [43].
\nPain management is one of the most important therapeutic interventions. Chronic pain is the main reason that patients seek out health care, while also being the most common reason for disability and addiction, and being the highest driver of health care costs. Most often, myopain conditions are the pain source. As such, it has been reported that in the United States, more than 100 million adults suffer from myofascial pain dysfunction syndrome. In dentistry, MPDS is defined as one type of masticatory system problem [32]. However, myofascial pain (MFP) is the most common cause of persistent regional back pain, headaches, and facial pain [10].
\nMyofascial pain is pain that arises from the muscles or the related fascia. The trigger point concept has been a widely studied aspect of myofascial pain dysfunction syndrome. Many hypotheses of how trigger points evolve are based on the opinions of experienced clinicians who treat and research trigger points. Trigger points are most often discussed as a component of myofascial pain syndromes where widespread or regional muscular pain is associated with hyperalgesia, psychological disturbance, and significant restriction of daily function [44]. Trigger points are 2–5 mm diameter points of increased hypersensitivity in palpable bands of the skeletal muscle, tendons, and ligaments with decreasing hypersensitivity as one palpates the band further away from the trigger point. As stated before, trigger points may be active or latent. An active trigger point causes spontaneous pain at rest, with an increase in pain on contraction or stretching of the involved muscle. There is often restricted muscular range of motion. Any pain on motion may cause “pseudo-muscle weakness” due to pin reflex inhibition. A latent trigger point is a focal area of tenderness and tightness in a muscle that does not result in spontaneous pain, but must be palpated to elicit the pain. However, a latent trigger point may restrict the range of motion and result in weakness of the muscle involved.
\nThe characteristic symptoms of a myofascial pain dysfunction syndrome trigger points have been previously described by R. Bennett as follows [5]:
A focal point of tenderness to palpation of the muscle involved,
Patient complaint from trigger point palpation,
Palpation reveals an induration of the adjacent muscle (the “taut band”),
A restricted range of motion in the muscle involved,
Pain is accompanied by pseudo-weakness of the muscle involved,
Referred pain can result with continuous applied pressure on the trigger point that lasts approximately 5 s in duration.
Pain perception is not simply determined by the intensity of nociceptive stimulation but also depends upon psychological factors such as the emotional and motivational state of the patient. The chronic pain threshold is divergent from the patient’s level of fear and/or anxiety [45]. Memory and pain, though two richly diverse fields, have many underlying commonalities. Both, for example, contain conscious and unconscious processes that allow for the acquisition of altered behavior in response to environmental stimuli [46]. After a very hot liquid is brought into the mouth, this warm sensation will be placed in the permanent memory to be remembered easily in later scenarios where the patient will drink a very hot liquid once again. However, if a new hot liquid experience is repeated a number of times over a long time frame, the patient’s reflex response to hot liquid will slowly disappear. As a learned function repeats, it becomes a reflex state.
\nA new complete denture adaptation process a patient must go through when receiving a different prosthesis than they are physically used to involves the development of a new denture chewing model. If the new prosthesis causes pain, the pain will be perceived as more prominent in the patients’ psyche, compared to the known chewing pattern of the old denture that was saved in the patient’s memory. The central nervous system (CNS) will develop a reflex protective mechanism against the pain, such that the protected pattern of chewing will take a very different shape from a healthy average chewing pattern (\nFigure 5\n).
\nIrregular masticatory pattern of a patient with new denture while the CNS tries to develop a new chewing pattern to accommodate the new denture. Chewing patterns are not similar to each other and irregular.
The electromyographic record of the same patient with the new denture shows that all four elevator muscles are in hyperactivity, exhibiting higher than the average values (\nFigure 6\n).
\nBoth the temporalis and masseter muscle electrical activity levels are higher than the physiological average resting values. This is not unexpected during the development of new prosthesis adaptation.
Chronic pain is a habitual pattern generated by the central nervous system (CNS) that must be broken before trying to treat myofascial pain dysfunction syndrome.
\nChronic pain is a nonphysiologic and extraordinary somatosensory process that can take place either in the peripheral or central nervous systems that is sustained beyond the normally expected time frame relative to the existence of a stimulus. This scenario, although somewhat explanatory, only provides for part of the story. Chronic pain is often clandestinely ambiguous and can be difficult to pinpoint its primary causative location. The perception of pain results from the summation and culmination of the nerve transduction process that arises from temporarily stimulated and affected peripheral nociceptors. Nociceptors may be specific for painful stimuli or they may be generally responsive to a wide range of mechanical, thermal, chemical, and/or electrical stimuli. Nociceptive responses are transmitted from peripheral sites into the CNS via myelinated (type A-delta) or unmyelinated (type C) nerve fibers [47].
\nMasticatory system myofascial pain constitutes one of the most important chronic problems that is encountered in clinical dental practice. Pain is a critical factor in evolving this chronic problem because pain increases muscle contraction, and more spasms from the excess contractions increase the level of pain. Elongation of the contraction time leads to the formation of trigger points.
\nWithin the literature, dental occlusion appears to be a key causative agent for MPDS because all kinds of treatment suggestions for MPDS are targeted on changing the occlusion in some way. In a study by Laskin et al. [48], the authors remarked that although many aspects of the MPDS are either controversial or unexplored, most investigators and clinicians seem to agree that the majority of patients with MPDS report relatively rapid improvement or symptom disappearances with splint therapy [48]. Splint therapy is a very effective occlusion determinant because when splint is placed between occluding teeth, the occlusion changes dramatically which can quickly break the pain generating pattern. However, all researchers agree that a splint therapy protocol must be provided by only skilled clinicians.
\nThere are many types of splints in dentistry such as custom splints, prefabric splints, posterior splints, anterior jig, hard splints, soft splints, etc. Each splint is described in detail by its advocate. The following factors should be taken into account during splint construction [44, 49]:
The treatment protocol must be provided by skilled clinicians
All masticatory activities can be changed by changing the occlusion
Splint therapy changes the tooth-to-tooth occlusal relationships, which then changes the neuromuscular activity accordingly
Prolonged hyperactivity of muscles can cause heightened synaptic transmission. Consequently, long contraction durations decrease action potential threshold levels and decrease the patient’s pain threshold.
During the use of a splint, there must be careful follow-up; if complications occur from splint treatment, the therapy should be terminated immediately.
If the splint is only used for a temporary occlusal correction, a 3–4 day use period should be sufficient. The best splints to be used for this purpose are either hydrostatic splints or hard splints because the surface of these designs does not allow teeth to engage and clash, which allows the masticatory muscles to freely exist in a harmonic balance.
After acquiring muscle balance and improved physiologic muscle contraction reestablishment, splint therapy must be stopped and an etiological treatment must be initiated.
Basically, splints are applied for a specific purpose [48, 50, 51, 52]. Therefore, it is very important to determine the type of splint, application period, and schedule, if applicable (\nFigure 7\n). Using a proper splint for a longer period of time may cause the patient to worsen in a variety of ways (worsening of MPDS symptoms; creating an open occlusion, intruding of teeth out of occlusal contact). Hence, splint treatment duration and its daily schedule are important to manage properly.
\nSplint therapy must be performed by a skilled clinician. Hard splints are very effective for changing the occlusal relationship between upper and lower jaws (maxillary splint; left pane). Hydrostatic soft splints (right pane) are helpful in creating muscular balance and physiologic harmonization. An etiologically based treatment for MPDS can be instituted after 3–5 days of successful splint therapy.
Removing of premature contacts with occlusal adjustment is one of the most important methods for breaking the neuromuscular cycle in myofascial pain dysfunction syndrome [53]. Changing the occlusal scheme and balancing of the occlusion are very effective methods for pinpointing and eliminating extraordinary neural firings. Hence, an occlusal analysis has always been an important diagnostic component of the treatment efforts to resolve MPDS symptoms. Several decades ago, dentists were performing occlusal analysis solely with mounted casts on semi-adjustable or fully adjustable dental articulators. There was no scientific method for performing intraoral occlusal analysis, and no real effective way to measure occlusal forces between all the contacting teeth.
\nThe very simple principal rule that was widely believed, purported is that proper occlusal function resulted from the close relationship between condylar movements and the occlusal contact relationships. To utilize this thinking clinically, most articulator systems were designed with the following requirements:
Some special equipment was built to detect condylar movements. The Lauritzen Hinge Axis Locator [54, 55] or Condylator Joint Tracer [56, 57] are examples of these types of condylar movement analysis tools. However, these devices are not easy to manage, often require repeated and difficult-to-make registrations, both intra- and extra-orally [58].
Completion of the condylar tracing procedure usually requests more than one visit.
Registration of centric relation location needs special devices and careful working.
Articulator-based diagnostic work is not repeatable and cannot be digitally stored. It is difficult to compare two different analyses on the same articulator, as one must be removed to mount another set of casts.
Two different registrations may be quite different, spatially. This difference can arise from making registrations at different times of the day for both the operator and the patient, from impression material setting distortion, registration material setting distortion, and from differing degress of poured stone setting contraction. Because many variables come into play with the articulating of dental casts, precision levels of the differing analyses may be quite inconsistent from one analysis to another.
Therefore, occlusal analysis performed on articulators for occlusal adjustment can be difficult and time-consuming; and once completed, it is not necessarily reliably to be accurate for diagnosis and treatment.
\nThe development of the computerized occlusal analysis method (T-Scan 9, with the Novus Recording Handle, and the HD Recording Sensor, Tekscan, Inc. S. Boston, MA, USA) has been removed from the making of occlusal analyses, the necessity of using inaccurate articulator-based methods, which present the clinician with many challengers that complicate their clinical usefulness.
\nComputer-based occlusal analyses have many clinical advantages over the articulator-based method:
Digital occlusal analysis is usually completed in one session. It can be repeated at another session, if there is a need.
Digital occlusal analysis data can be stored and recalled easily, so that many analyses of a single patient can be compared with each other, over time, to observe changes in the occlusal status as the patient ages.
The recording and data acquisition is quick to accomplish chairside, so that many occlusal analyses and corrective adjustments can be performed in same treatment session.
Adjustment results can be compared with the preoperative status of the occlusion to observe that occlusal force and timing improvements have been therapeutically obtained.
The cost of performing the occlusal analysis has decreased sharply.
As with every new method, the earliest T-Scan computer-based occlusal analyzing systems (T-Scan I, II, III; Tekscan Inc. S. Boston, MA, USA) were questioned as to their clinical reliability [59, 60]. However, the modern The T-Scan HD recording sensor (\nFigure 8a\n) has been shown to accurately measure 256 differing relative occlusal force levels [3, 4, 5, 6, 55, 61] with 95% of force reproduction capability [4]. Other recent T-Scan studies show the T-Scan accurately records occlusal contact time sequencing [62, 63]. Today’s T-Scan Novus System with the version 9 software is a highly advanced digital occlusal force and timing analyzer that can be used chairside to treat a wide range of commonly encountered occlusal force problems. Moreover, additional research and clinical publications have illustrated how the T-Scan occlusal analysis method can be used in many dental medicine disciplines (\nFigure 8a\n and \nb\n) [64, 65, 66, 67].
\n(a) The T-Scan Novus Definition (HD) sensor records 256 levels of relative occlusal force in 0.003 s time frames to reveal an occlusal playback video that illustrates changing occlusal force levels across time. (b) The T-Scan Novus recording handle with the HD sensor in place, connected directly to a computer with a USB plug.
The correction of orthodontic and prosthodontic occlusal problems has become much easier for clinicians who use computerized occlusal analysis. Prior to the development of the T-Scan, dentists could only “look at” the occlusion, and now with T-Scan sensor interposed between occluding teeth during mandibular functional movements, dentists are able to see occlusal force changes over time as occlusal contacts on opposing teeth engage and interact frictionally (\nFigure 9\n). Note in \nFigure 9\n how during the early part of a patient self-closure into MIP, tooth #18 rises quickly to high occlusal force (tall pink column; left pane #1), as all the other closure tooth contacts maintain a low force state (dark blue columns; left pane#1). Then later in the same T-Scan recording, when more of the patient’s teeth fully interdigitate closer to complete intercuspation, the #18 premature forceful contact lessens to a low force state, while other occluding teeth increased in force bilaterally (light green and yellow columns: right pane #2).
\nPremature contacts are contacts that rise to very high force well before the maximum intercuspal position (MIP) (pane 1) are visible with the T-Scan occlusal analysis system. Tooth #18 rises quickly to high occlusal force (tall pink column; left pane #1), as other closure contacts are low force (dark blue columns; left pane #1). Then later in the same T-Scan recording (pane 2), the #18 forceful contact lessens to low force while other occluding teeth increased in force bilaterally (pane #2).
Changing occlusal relationships between the upper and lower teeth breaks sharply the neuromuscular loop that causes acute muscle spasm. There are many studies that have shown the effect periodontal receptors have on functional and parafunctional occlusal excursions [34, 35, 36, 37, 38, 68]. An occlusal movement is modeled within the central nervous system (CNS), but the main trigger of action potential firing is the excitation of peripheral neurons from the peripheral nervous system (PNS) [33]. Continuous peripheral neuronal firing causes ongoing muscle contractions that lead to muscle fatigue and ischemia from toxic lactic acid buildup, which all ultimately leads to muscle spasms that rise and repeatedly peak, unless the continuous neuronal firing stopped.
\nThis neurologic mechanism is the main reason why adjusting the dental occlusion with T-Scan time-based occlusal surface modifications has been highly effective MPDS therapy [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 59, 69, 70, 71]. Applying occlusal splints, local anesthetic injections, botox injections, and similar nonocclusal treatment methods are temporary and symptomatic. Orthodontic treatment, restorative dentistry that changes the occlusal relationship, and occlusal coronoplasty are treatments aimed at the neurologic etiologically and are permanent treatment methods.
\nIt has long been advocated that to achieve a balanced occlusal relationship, the acute spasm must be eliminated before commencing definitive occlusal changes. Occlusal splints are the most common method for eliminating the acute symptoms of MPDS. However, since 1991, a new T-Scan-based “Disocclusion Time Reduction Therapy (DTR)” method has been developed by Dr. Robert B. Kerstein, for changing and breaking of the firing-reaction-spasm in the neuromuscular loop. The treatment itself requires no pretreatment splint therapy and has been shown in multiple studies performed over the past 26 years to rapidly lessen muscle activity levels and improve human chewing function in 7 days following initial treatment because the therapy works from within the CNS [69, 70, 72, 73, 74]. According to Dr. Kerstein, “Disocclusion Time Reduction Therapy” reduces the Disocclusion Time [15], which lessens the time posterior teeth frictionally engage during excursions, which thereby stops the neuronal action potentials from hyperfunctioning the masticatory muscles. To accomplish this, the Disocclusion time must be less than 0.4 s per excursion. However, this particular time of 0.4 s cannot be accurately calculated without using the T-Scan occlusal analysis system. Disocclusion time reduction therapy is one of the most important, etiologically directed treatment methods available because it drastically lessens the volume of PDL mechanoreceptor compressions thereby disrupting the neuronal trigger for occlusally induced MPDS symptoms. However, there are still many disagreements on the reliability of the “Disocclusion Time Reduction Therapy”, despite it being repeatedly shown in multiple studies to affect positive physiologic changes within the stomatognathic system. As DTR is usually performed as a coronoplasty (known as immediate complete anterior guidance development (ICAGD)), [9] these disagreements about DTR’s patient benefits are founded in that prior, unmeasured occlusal adjustment studies where no T-Scan measurements of the occlusion were involved in the rendered treatment have shown limited occlusal equilibration effectiveness in treating MPDS symptoms. Occlusal equilibration procedurally lacks precision and treats positionally eliminating the prematurity from CR-CO, while only adjusting nonworking side interferences [75, 76, 77, 78]. Periodontal neuronal mechanoreceptors surround all teeth on all sides of the roots. By leaving the working side teeth untreated meant occlusal equilibration to CR did not alter the CNS input enough to obtain predictable therapeutic MPDS results.
\nICAGD is very different occlusal adjustment procedure from occlusal equilibration [79], in that ICAGD is an excursively focused coronoplasty performed from the maximum intercuspal position (MIP) without mandibular manipulation to centric relation. ICAGD is a measurement-driven, computer-guided occlusal adjustment procedure that shortens prolonged excursive movement occlusal surface contact frictional durations. The main objective of ICAGD is to shorten the posterior disclusion time to ≤0.5 s per excursion because 0.41 was the first studied, physiologic mean disclusion time. ICAGD is always performed today with the T-Scan synchronized to the BioEMG III Electromyography system (T-Scan 9/BioEMG III, Tekscan Inc. S. Boston, MA, USA; Bioresearch Assoc., Milwaukee, WI, USA). The patient wears electromyography electrodes upon the masseter and temporalis muscles throughout the entire occlusal adjustment process to ensure that changes in muscle hyperactivity can be properly observed post treatment.
\nMost importantly, ICAGD treats both the working and nonworking sides including all premolars involved in excursive contacts, thereby greatly reducing the PDL and pulpal mechanoreceptor CNS input from all fictionally engaged posterior occlusal surfaces. All these procedural differences are published in occlusal adjustment studies, ICAGD has been shown to be far more effective than Occlusal Equilibration in treating MPDS.
\nAn example of disocclusion time reduction therapy performed with the immediate complete anterior guidance development coronoplasty is presented below.
\nA 30-year-old female airline flight attendant presented with a Class I anterior relationship post orthodontics that was completed in her teenage years. A number of posterior teeth demonstrated cuspal wear and appear slightly sanded away. All third molars were previously extracted (\nFigures 10\n and \n11a\n, \nb\n).
\nFrontal view of an MPDS female patient showing a Class I anterior relationship with average vertical overlap and available canine guidance contacts bilaterally.
(a) 1 mm into the right excursion as the canine teeth began to engage. Note the complete buccal posterior group function and excursive friction visible. (b) Early in the left lateral movement, opposing posterior teeth frictionally engage both buccally and lingually (unseen). The posterior group function visible is worsened by the nonvertical opposing tooth orientation.
For 1.5 years before consultation, the patient had experienced chronic bilateral masseter tension, with regular morning jaw soreness that worsened during stressful periods. The patient reported clenching during the day and bruxing to some degree during the nighttime. Most of her discomfort was in the masseter region bilaterally, with some temporal headache component present, as well. Her symptoms came on after having two fillings placed in her two upper premolar teeth #s 14 and 15. Muscular pain ensued shortly after the fillings were done as they changed her occlusal contact comfort. Since then, further occlusal adjusting to the teeth involved did not resolve her MPDS symptoms.
\nThe patient reported wearing an appliance for 10 months nightly, but also reported symptom worsening with his attempted regular appliance use. She felt it made her clench more than if it was not worn. As such, she stopped wearing the appliance some months before consultation. Anti-inflammatory and pain medication gave her some marginal relief that would last only for a few hours.
\nThe following figures (\nFigures 12\n–\n15\n) detail the patients in preoperative occlusal and muscle physiology status, as well as her post-ICAGD disclusion time reduction changes. For brevity, only the right and left excursions were illustrated, and protrusive excursions were not described.
\n(a) The preoperative right excursive T-Scan/BioEMG data showed (in the T-Scan left pane) prolonged disclusion time with mostly working and minimal balancing excursive frictional occlusal contacts present in the 2D and 3D ForceViews. Between C and D (in the EMG data right pane), there was very high muscle contractions visible in the two masseter MM-R MM-L and right temporalis muscles TA-R, as the patient moved laterally across their teeth toward the right canine. The nonworking (left temporalis TA-L) does not fire in the right excursion. The right disclusion time pretreatment was 3.58 s long, causing this high muscle firing and the MPDS symptoms the patient has been forced to live with since her bite changed after the upper premolar fillings were done. (b) The preoperative left excursive T-Scan/BioEMG data showed (in the T-Scan left pane) prolonged disclusion time with only working side excursive frictional occlusal contacts present in the 2D and 3D ForceViews the total force (black) line “step downs,” indicating sharp force drops as the patient’s posterior teeth frequently stopped the mandible from moving freely laterally. Between C and D (in the EMG data right pane), there was very high muscle contractions left temporalis TA-L muscle with right temporalis TA-R spasm visible for the same duration the left temporalis hyperfunctions. The right and left masseters MM-R and MM-L both fired excursively well above rest. The left disclusion time pretreatment was 1.37 s long causing the visible high muscle firing and the MPDS symptoms the patient has been forced to live with since her bite changed after the upper premolar fillings were done.
(a) The post-ICAGD right excursion showing slight space between the group function teeth that was not there before performing of the ICAGD coronoplasty. (b) The right excursion after ICAGD. The disclusion time equaled 0.45 s duration, which reduced the right temporalis and right and left masseter excursive hyperactivity dramatically compared to pretreatment. (c) Right excursive EMG improvements from pretreatment (left pane) to after ICAGD (right pane), where there is markedly lowered muscle activity levels post treatment at rest (before A), and in the excursion (to the right of C). With lessened excursive muscular hyperactivity, the muscle physiology can heal and MPDS symptoms can then abate.
(a) The post ICAGD left excursion showing slight space between the group function teeth that was not there before performing of the ICAGD coronoplasty. (b) The left excursion after ICAGD when the disclusion time equaled to 0.34 s. The excursive EMG improvements show markedly lowered muscle activity levels post-treatment at rest (before A), and in the excursion (to the right of C). (c) The left excursive EMG improvements from pretreatment (left pane) to after ICAGD (right pane), where there is markedly lowered muscle activity levels present at rest (before A), and in the excursion post-treatment (to the right of C). With lessened excursive muscular hyperactivity, the muscle physiology can heal and MPDS symptoms can then abate.
(a) Opposing occlusal surfaces with many pre-ICAGD articulating paper ink lines that describe that long disclusion time friction is present on all upper and lower posterior opposing occlusal surfaces (teeth #s 28–24 and #s 38–34). Note the very long red ink line visible on #37 distolingual occlusal incline. Its counterpart frictionally prolonged contact is the #27 distopalatol black ink line. (b) Post-ICAGD articulating paper markings showing 1–2 short disclusion time red and black pinpoint closure contacts per tooth, present on the opposing posterior occlusal surfaces (teeth #s 28–24 and #38–34). There are anterior guidance ink tracks visible across the occluding canine surfaces (#s 23 and 33). The small posterior closure contacts allow for the minimum posterior excursive contact, which are indicative of a disclusion time of <0.4 s. This small overall volume of tooth contact posteriorly is how the ICAGD coronoplasty controls the repetitive PDL mechanoreceptor neuronal action potential from heading into the CNS. Without the neural input, muscle contractions are dramatically lessened (
With the pretreatment T-Scan/BioEMG data showing prolonged disclusion times and very high levels of excursive muscular hyperactivity, the patient was a good candidate to undergo the ICAGD coronoplasty. She was a Class I MPDS patient with adequate bilateral canine contact present to be safely treated with ICAGD.
\nIt is through the measurement of the occlusion and muscles together using the T-Scan 9/BioEMG III synchronized occlusal measurement technologies so that these diagnostic and treatment improvements demonstrated within this case can become clinically predictable in managing MPDS patient. By quantifying occlusal function and muscle function together, the therapeutic effectiveness the ICAGD measured occlusal adjustment procedure has a dramatic effect on the central nervous system (CNS) that greatly reduces muscle activity levels and quickly lessens many common MPDS symptoms.
\nThis chapter describes in detail how the peripheral neural receptors that are located in and around the posterior teeth periodontal ligaments and in the dental pulp create ongoing masticatory muscle hyperactivity that can lead to the clinical appearance of myofascial pain dysfunction syndrome symptoms. MPDS commonly afflicts the masticatory musculature with chronic muscular pain, frequent temporal headaches, chewing pain and weakness, opening limitations, and frequent clenching and bruxing of teeth. Because unmeasured, published Occlusal Equilibration studies did not predictably treat the MPDS condition, conventional MPDS treatments have focused on lessening MPDS symptoms without treating the occlusion directly. The use of occlusal splints, physical therapy, and trigger point injections has been predominant. However, since the development of the T-Scan system in the 1980s, and the discovery of prolonged posterior disclusion time, a computer-guided alternative coronoplasty to occlusal equilibration, has evolved to treat MPDS (known as disclusion time reduction (DTR) with the ICAGD coronoplasty).
\nDTR is an etiologically based treatment aimed at reducing prolonged occlusal surface friction, which drastically limits the tooth socket compressions and pulpal occlusal contact impacts that the posterior teeth sustain multiple times on a daily basis (and nightly, if there is parafunction). By cutting down the volume of socket compressions and impacts, the molar and premolar peripheral action potential response to the occlusal contacts is drastically lessened, which remove the stimulus that the occlusion inputs into the central nervous system (CNS) to fire muscles and create ischemia. This limiting neurophysiologic change allows the masticatory muscles to calm down and relax physiologically, because the ischemia reverses intramuscularly from within the CNS, requiring the patient to not wear an occlusal splint. In short order following the ICAGD coronoplasty, studies repeatedly show the MPDS symptoms, then abate, and lessen in severity and frequency.
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structure that can exert beneficial effects on human health above and beyond their expected nutritional value. Among many types of food-derived peptides, peptides with antihypertensive activity have received the most significant attention due to the prevalence of hypertension and its associated complications with pharmacological interventions. One strategy for the selection of potential food-derived antihypertensive peptides is to search for in vitro renin inhibitory activity. Thus far, various food protein-derived peptides and protein hydrolysates have shown in vitro renin inhibitory capacity. Many of these peptides have induced antihypertensive effects when orally administered to spontaneously hypertensive rats, and also, antihypertensive effects in hypertensive humans have been reported. Indeed, the results indicate that antihypertensive food protein-derived peptides may be acting at the same time via multiple pathways at the protein level as well as at the gene level modulating the renin-angiotensin system. Important knowledge on structure-function parameters of peptides is increasing constantly, which can greatly enhance the production and processing of peptides with high physiological efficacy. By means of novel nutrigenomic approaches, it is possible and, in future, perhaps essential to investigate the impact of peptides on the expression of genes and hence endeavor to optimize the nutritional and health effects delivered by peptides. Novel technologies are available to standardize and stabilize the concentrations of active peptides in the products in down-stream processing. The existing data provide strong potential for developing new added-value products with scientifically approved health effects for consumers. This review provides an overview of food-derived peptides that may mediate the antihypertensive activities through inhibiting renin, one of the key enzymes in renin-angiotensin system, and reviews also the safety and applicability aspects of the these peptides.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Anne Pihlanto and Sari Mäkinen",authors:[{id:"191941",title:"Ph.D.",name:"Anne",middleName:null,surname:"Pihlanto",slug:"anne-pihlanto",fullName:"Anne Pihlanto"},{id:"192566",title:"Dr.",name:"Sari",middleName:null,surname:"Mäkinen",slug:"sari-makinen",fullName:"Sari Mäkinen"}]},{id:"53100",doi:"10.5772/66076",title:"Signaling Pathways of Cardiac Remodeling Related to Angiotensin II",slug:"signaling-pathways-of-cardiac-remodeling-related-to-angiotensin-ii",totalDownloads:1799,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Heart failure affects more than 23 million people worldwide, and its prognosis remains poor. Hypertension is one of the most prominent human health problem and places individuals at a higher risk for heart failure. Several factors interplay the development of hypertension contributing for decompensated heart hypertrophy. The renin-angiotensin system (RAS) has been shown to be the foremost regulator of blood pressure. Many evidences have pointed out the importance of RAS and its key mediator, angiotensin II (Ang II), on signaling pathways involved in cardiac remodeling. The Ang II-induced hypertrophic effects seem to be related to increased reactive oxygen species (ROS). Under oxidative stress conditions, as those observed in hypertension and heart failure, the matrix metalloproteinases (MMP) is activated. Ang II is connected with TNF-α and TGF-β by ROS-NF-κB-MMP mechanisms, which are involved in heart failure. The rationale of the present chapter is structured on the progression of heart failure related to Ang II, TNF-α and TGF-β by common signaling pathways. Pharmacotherapeutics approaches to the heart failure abound, but the mortality rates remain high. This chapter will also describe molecular mechanisms involved in heart failure highlighting that TGF-β and/or TNF-α inhibitors could contribute to treatment to this serious clinical condition.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Carolina Baraldi Araujo Restini, Arthur F. Engracia Garcia, Henrique\nMelo Natalin, Guilherme Melo Natalin and Elen Rizzi",authors:[{id:"178144",title:"Dr.",name:"Carolina",middleName:null,surname:"Baraldi A. Restini",slug:"carolina-baraldi-a.-restini",fullName:"Carolina Baraldi A. Restini"},{id:"193457",title:"Dr.",name:"Henrique",middleName:null,surname:"Melo Natalin",slug:"henrique-melo-natalin",fullName:"Henrique Melo Natalin"},{id:"193458",title:"Dr.",name:"Arthur",middleName:null,surname:"Feierabend Engracia Garcia",slug:"arthur-feierabend-engracia-garcia",fullName:"Arthur Feierabend Engracia Garcia"},{id:"193459",title:"Dr.",name:"Guilherme",middleName:null,surname:"Melo Natalin",slug:"guilherme-melo-natalin",fullName:"Guilherme Melo Natalin"},{id:"193460",title:"Dr.",name:"Elen",middleName:null,surname:"Rizzi",slug:"elen-rizzi",fullName:"Elen Rizzi"}]},{id:"54072",doi:"10.5772/65919",title:"Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases",slug:"local-renin-angiotensin-system-at-liver-and-crosstalk-with-hepatic-diseases",totalDownloads:1821,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"The systemic renin-angiotensin system mainly regulates blood pressure and maintains kidney function. Recent studies have realized that renin-angiotensin system (RAS) has been found in many tissues, such as heart, liver, and kidney. Although RAS in heart and kidney has been well documented, the RAS in the liver has been evaluated in a few studies. Therefore, this chapter will be assessed it. Based on findings, RAS in the liver has presented almost all of its components, such as angiotensin-I (Ang-I), angiotensin-II (Ang-II), angiotensin-converting enzyme (ACE), angiotensin type-1 receptor (AT1), angiotensin type-2 receptor (AT2), named as classical RAS. Expect these components, the local RAS has had alternative pathway components, including angiotensin-converting enzyme 2 (ACE2) and chymase. Classical RAS has an opposite effect of alternative RAS. Although these local RAS might not be such a crucial for the tissue, it could be a more vital function under pathophysiologic conditions. The chapter the local RAS in the liver the under both physiologic and pathophysiologic conditions is highlighted.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Eylem Taskin and Celal Guven",authors:[{id:"192567",title:"Prof.",name:"Eylem",middleName:null,surname:"Taskin",slug:"eylem-taskin",fullName:"Eylem Taskin"},{id:"195229",title:"Dr.",name:"Celal",middleName:null,surname:"Guven",slug:"celal-guven",fullName:"Celal Guven"}]},{id:"54082",doi:"10.5772/67016",title:"Regulation of the Renin-Angiotensin-Aldosterone System by Reactive Oxygen Species",slug:"regulation-of-the-renin-angiotensin-aldosterone-system-by-reactive-oxygen-species",totalDownloads:1921,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Angiotensin II (Ang II), the major effector of the renin-angiotensin-aldosterone system (RAAS), stimulates the production of reactive oxygen species (ROS) which are critically involved in Ang II-induced effects. Noteworthy, accumulating evidence indicates that ROS also regulate the activation of RAAS, contributing to the fine-tuning of this system under physiological conditions or to the amplification of the deleterious signaling in several pathologies. This chapter aims at giving an overview of the role of ROS in the regulation of expression, secretion and/or activity of several RAAS components.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Manuela Morato, Marta Reina-Couto, Dora Pinho, António Albino-\nTeixeira and Teresa Sousa",authors:[{id:"140800",title:"Prof.",name:"António",middleName:null,surname:"Albino-Teixeira",slug:"antonio-albino-teixeira",fullName:"António Albino-Teixeira"},{id:"142410",title:"Prof.",name:"Teresa",middleName:null,surname:"Sousa",slug:"teresa-sousa",fullName:"Teresa Sousa"},{id:"193340",title:"Prof.",name:"Manuela",middleName:null,surname:"Morato",slug:"manuela-morato",fullName:"Manuela Morato"},{id:"193341",title:"M.D.",name:"Marta",middleName:null,surname:"Reina-Couto",slug:"marta-reina-couto",fullName:"Marta Reina-Couto"},{id:"193342",title:"Prof.",name:"Dora",middleName:null,surname:"Pinho",slug:"dora-pinho",fullName:"Dora Pinho"}]},{id:"53588",doi:"10.5772/66997",title:"Renin-Angiotensin System on Reproductive Biology",slug:"renin-angiotensin-system-on-reproductive-biology",totalDownloads:1375,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"In the female reproductive system, angiotensin II (ANG II) is a potential signaling molecule involved in ovarian follicle development, which acts through two transmembrane receptors. Within the ovarian follicle, there appear to be species differences in the precise pattern of localization of AGTR2 protein and it has an important role in in vitro maturation of oocytes in mammals. The infusion of ANG II induced ovulation in rabbits and the use of ANG II antagonists inhibited ovulation in rabbits, rats, and cattle. In fetal ovaries, AGTR2 protein was detected in ovigerous cords and preantral follicles throughout porcine and bovine gestation. In the oviduct, ANG II is responsible for the orchestration of the transport of gametes. In the male reproductive system, there is considerable evidence for the local synthesis of components of renin-angiotensin system (RAS) in male reproductive tissues. The roles of RAS in local processes at these sites are still uncertain, although there is evidence for involvement in tubular contractility, spermatogenesis, sperm maturation, capacitation, acrosomal exocytosis, and fertilization.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Anthony C.S. Castilho, Patrícia K. Fontes, Fernanda F. Franchi,\nPriscila H. Santos and Eduardo M. Razza",authors:[{id:"191450",title:"Associate Prof.",name:"Anthony",middleName:"César Souza",surname:"Castilho",slug:"anthony-castilho",fullName:"Anthony Castilho"},{id:"191848",title:"M.Sc.",name:"Patricia",middleName:"Kubo",surname:"Fontes",slug:"patricia-fontes",fullName:"Patricia Fontes"},{id:"191860",title:"MSc.",name:"Fernanda",middleName:null,surname:"Franchi",slug:"fernanda-franchi",fullName:"Fernanda Franchi"},{id:"191862",title:"MSc.",name:"Priscila",middleName:null,surname:"Santos",slug:"priscila-santos",fullName:"Priscila Santos"},{id:"191906",title:"MSc.",name:"Eduardo",middleName:null,surname:"Razza",slug:"eduardo-razza",fullName:"Eduardo Razza"}]}],mostDownloadedChaptersLast30Days:[{id:"53100",title:"Signaling Pathways of Cardiac Remodeling Related to Angiotensin II",slug:"signaling-pathways-of-cardiac-remodeling-related-to-angiotensin-ii",totalDownloads:1799,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Heart failure affects more than 23 million people worldwide, and its prognosis remains poor. Hypertension is one of the most prominent human health problem and places individuals at a higher risk for heart failure. Several factors interplay the development of hypertension contributing for decompensated heart hypertrophy. The renin-angiotensin system (RAS) has been shown to be the foremost regulator of blood pressure. Many evidences have pointed out the importance of RAS and its key mediator, angiotensin II (Ang II), on signaling pathways involved in cardiac remodeling. The Ang II-induced hypertrophic effects seem to be related to increased reactive oxygen species (ROS). Under oxidative stress conditions, as those observed in hypertension and heart failure, the matrix metalloproteinases (MMP) is activated. Ang II is connected with TNF-α and TGF-β by ROS-NF-κB-MMP mechanisms, which are involved in heart failure. The rationale of the present chapter is structured on the progression of heart failure related to Ang II, TNF-α and TGF-β by common signaling pathways. Pharmacotherapeutics approaches to the heart failure abound, but the mortality rates remain high. This chapter will also describe molecular mechanisms involved in heart failure highlighting that TGF-β and/or TNF-α inhibitors could contribute to treatment to this serious clinical condition.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Carolina Baraldi Araujo Restini, Arthur F. Engracia Garcia, Henrique\nMelo Natalin, Guilherme Melo Natalin and Elen Rizzi",authors:[{id:"178144",title:"Dr.",name:"Carolina",middleName:null,surname:"Baraldi A. Restini",slug:"carolina-baraldi-a.-restini",fullName:"Carolina Baraldi A. Restini"},{id:"193457",title:"Dr.",name:"Henrique",middleName:null,surname:"Melo Natalin",slug:"henrique-melo-natalin",fullName:"Henrique Melo Natalin"},{id:"193458",title:"Dr.",name:"Arthur",middleName:null,surname:"Feierabend Engracia Garcia",slug:"arthur-feierabend-engracia-garcia",fullName:"Arthur Feierabend Engracia Garcia"},{id:"193459",title:"Dr.",name:"Guilherme",middleName:null,surname:"Melo Natalin",slug:"guilherme-melo-natalin",fullName:"Guilherme Melo Natalin"},{id:"193460",title:"Dr.",name:"Elen",middleName:null,surname:"Rizzi",slug:"elen-rizzi",fullName:"Elen Rizzi"}]},{id:"54072",title:"Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases",slug:"local-renin-angiotensin-system-at-liver-and-crosstalk-with-hepatic-diseases",totalDownloads:1816,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"The systemic renin-angiotensin system mainly regulates blood pressure and maintains kidney function. Recent studies have realized that renin-angiotensin system (RAS) has been found in many tissues, such as heart, liver, and kidney. Although RAS in heart and kidney has been well documented, the RAS in the liver has been evaluated in a few studies. Therefore, this chapter will be assessed it. Based on findings, RAS in the liver has presented almost all of its components, such as angiotensin-I (Ang-I), angiotensin-II (Ang-II), angiotensin-converting enzyme (ACE), angiotensin type-1 receptor (AT1), angiotensin type-2 receptor (AT2), named as classical RAS. Expect these components, the local RAS has had alternative pathway components, including angiotensin-converting enzyme 2 (ACE2) and chymase. Classical RAS has an opposite effect of alternative RAS. Although these local RAS might not be such a crucial for the tissue, it could be a more vital function under pathophysiologic conditions. The chapter the local RAS in the liver the under both physiologic and pathophysiologic conditions is highlighted.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Eylem Taskin and Celal Guven",authors:[{id:"192567",title:"Prof.",name:"Eylem",middleName:null,surname:"Taskin",slug:"eylem-taskin",fullName:"Eylem Taskin"},{id:"195229",title:"Dr.",name:"Celal",middleName:null,surname:"Guven",slug:"celal-guven",fullName:"Celal Guven"}]},{id:"54082",title:"Regulation of the Renin-Angiotensin-Aldosterone System by Reactive Oxygen Species",slug:"regulation-of-the-renin-angiotensin-aldosterone-system-by-reactive-oxygen-species",totalDownloads:1921,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Angiotensin II (Ang II), the major effector of the renin-angiotensin-aldosterone system (RAAS), stimulates the production of reactive oxygen species (ROS) which are critically involved in Ang II-induced effects. Noteworthy, accumulating evidence indicates that ROS also regulate the activation of RAAS, contributing to the fine-tuning of this system under physiological conditions or to the amplification of the deleterious signaling in several pathologies. This chapter aims at giving an overview of the role of ROS in the regulation of expression, secretion and/or activity of several RAAS components.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Manuela Morato, Marta Reina-Couto, Dora Pinho, António Albino-\nTeixeira and Teresa Sousa",authors:[{id:"140800",title:"Prof.",name:"António",middleName:null,surname:"Albino-Teixeira",slug:"antonio-albino-teixeira",fullName:"António Albino-Teixeira"},{id:"142410",title:"Prof.",name:"Teresa",middleName:null,surname:"Sousa",slug:"teresa-sousa",fullName:"Teresa Sousa"},{id:"193340",title:"Prof.",name:"Manuela",middleName:null,surname:"Morato",slug:"manuela-morato",fullName:"Manuela Morato"},{id:"193341",title:"M.D.",name:"Marta",middleName:null,surname:"Reina-Couto",slug:"marta-reina-couto",fullName:"Marta Reina-Couto"},{id:"193342",title:"Prof.",name:"Dora",middleName:null,surname:"Pinho",slug:"dora-pinho",fullName:"Dora Pinho"}]},{id:"54743",title:"Role of the Renin-Angiotensin System in Healthy and Pathological Pregnancies",slug:"role-of-the-renin-angiotensin-system-in-healthy-and-pathological-pregnancies",totalDownloads:1384,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Introduction: Pregnancy is a physiological process that necessitates many cardiovascular and hemodynamic adaptations to ensure the survival of the foetus and well‐being of the mother. The renin‐angiotensin system (RAS) has been suggested as key player in many of these changes as it is critical for blood pressure control as well as fluid and salt homeostasis in the non‐pregnant state.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Émilie Pepin, Shahin Shabanipour Dehboneh, Nozha Raguema,\nMaedeh Talebi Esfandarani and Julie L. Lavoie",authors:[{id:"191471",title:"Dr.",name:"Julie",middleName:"L.",surname:"Lavoie",slug:"julie-lavoie",fullName:"Julie Lavoie"},{id:"197626",title:"Dr.",name:"Émilie",middleName:null,surname:"Pépin",slug:"emilie-pepin",fullName:"Émilie Pépin"},{id:"197627",title:"MSc.",name:"Shahin",middleName:null,surname:"Shabanipour Dehboneh",slug:"shahin-shabanipour-dehboneh",fullName:"Shahin Shabanipour Dehboneh"},{id:"197628",title:"MSc.",name:"Nozha",middleName:null,surname:"Raguema",slug:"nozha-raguema",fullName:"Nozha Raguema"},{id:"197629",title:"MSc.",name:"Maedeh",middleName:null,surname:"Talebi Esfandarani",slug:"maedeh-talebi-esfandarani",fullName:"Maedeh Talebi Esfandarani"}]},{id:"53588",title:"Renin-Angiotensin System on Reproductive Biology",slug:"renin-angiotensin-system-on-reproductive-biology",totalDownloads:1374,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"In the female reproductive system, angiotensin II (ANG II) is a potential signaling molecule involved in ovarian follicle development, which acts through two transmembrane receptors. Within the ovarian follicle, there appear to be species differences in the precise pattern of localization of AGTR2 protein and it has an important role in in vitro maturation of oocytes in mammals. The infusion of ANG II induced ovulation in rabbits and the use of ANG II antagonists inhibited ovulation in rabbits, rats, and cattle. In fetal ovaries, AGTR2 protein was detected in ovigerous cords and preantral follicles throughout porcine and bovine gestation. In the oviduct, ANG II is responsible for the orchestration of the transport of gametes. In the male reproductive system, there is considerable evidence for the local synthesis of components of renin-angiotensin system (RAS) in male reproductive tissues. The roles of RAS in local processes at these sites are still uncertain, although there is evidence for involvement in tubular contractility, spermatogenesis, sperm maturation, capacitation, acrosomal exocytosis, and fertilization.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Anthony C.S. Castilho, Patrícia K. Fontes, Fernanda F. Franchi,\nPriscila H. Santos and Eduardo M. Razza",authors:[{id:"191450",title:"Associate Prof.",name:"Anthony",middleName:"César Souza",surname:"Castilho",slug:"anthony-castilho",fullName:"Anthony Castilho"},{id:"191848",title:"M.Sc.",name:"Patricia",middleName:"Kubo",surname:"Fontes",slug:"patricia-fontes",fullName:"Patricia Fontes"},{id:"191860",title:"MSc.",name:"Fernanda",middleName:null,surname:"Franchi",slug:"fernanda-franchi",fullName:"Fernanda Franchi"},{id:"191862",title:"MSc.",name:"Priscila",middleName:null,surname:"Santos",slug:"priscila-santos",fullName:"Priscila Santos"},{id:"191906",title:"MSc.",name:"Eduardo",middleName:null,surname:"Razza",slug:"eduardo-razza",fullName:"Eduardo Razza"}]}],onlineFirstChaptersFilter:{topicId:"988",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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",coverUrl:"https://cdn.intechopen.com/series/covers/3.jpg",latestPublicationDate:"August 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:2,paginationItems:[{id:"1",title:"Oral Health",coverUrl:"https://cdn.intechopen.com/series_topics/covers/1.jpg",isOpenForSubmission:!0,editor:{id:"173955",title:"Prof.",name:"Sandra",middleName:null,surname:"Marinho",slug:"sandra-marinho",fullName:"Sandra Marinho",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGYMQA4/Profile_Picture_2022-06-01T13:22:41.png",biography:"Dr. Sandra A. Marinho is an Associate Professor and Brazilian researcher at the State University of Paraíba (Universidade Estadual da Paraíba- UEPB), Campus VIII, located in Araruna, state of Paraíba since 2011. She holds a degree in Dentistry from the Federal University of Alfenas (UNIFAL), while her specialization and professional improvement in Stomatology took place at Hospital Heliopolis (São Paulo, SP). Her qualifications are: a specialist in Dental Imaging and Radiology, Master in Dentistry (Periodontics) from the University of São Paulo (FORP-USP, Ribeirão Preto, SP), and Doctor (Ph.D.) in Dentistry (Stomatology Clinic) from Hospital São Lucas of the Pontifical Catholic University of Rio Grande do Sul (HSL-PUCRS, Porto Alegre, RS). She held a postdoctoral internship at the Federal University from Jequitinhonha and Mucuri Valleys (UFVJM, Diamantina, MG). She is currently a member of the Brazilian Society for Dental Research (SBPqO) and the Brazilian Society of Stomatology and Pathology (SOBEP). Dr. Marinho's experience in Dentistry mainly covers the following subjects: oral diagnosis, oral radiology; oral medicine; lesions and oral infections; oral pathology, laser therapy and epidemiological studies.",institutionString:null,institution:{name:"State University of Paraíba",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"2",title:"Prosthodontics and Implant Dentistry",coverUrl:"https://cdn.intechopen.com/series_topics/covers/2.jpg",isOpenForSubmission:!0,editor:{id:"179568",title:"Associate Prof.",name:"Wen Lin",middleName:null,surname:"Chai",slug:"wen-lin-chai",fullName:"Wen Lin Chai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHGAQA4/Profile_Picture_2022-05-23T14:31:12.png",biography:"Professor Dr. Chai Wen Lin is currently a lecturer at the Department of Restorative Dentistry, Faculty of Dentistry of the University of Malaya. She obtained a Master of Dental Science in 2006 and a Ph.D. in 2011. Her Ph.D. research work on the soft tissue-implant interface at the University of Sheffield has yielded several important publications in the key implant journals. She was awarded an Excellent Exchange Award by the University of Sheffield which gave her the opportunity to work at the famous Faculty of Dentistry of the University of Gothenburg, Sweden, under the tutelage of Prof. Peter Thomsen. In 2016, she was appointed as a visiting scholar at UCLA, USA, with attachment in Hospital Dentistry, and involvement in research work related to zirconia implant. In 2016, her contribution to dentistry was recognized by the Royal College of Surgeon of Edinburgh with her being awarded a Fellowship in Dental Surgery. She has authored numerous papers published both in local and international journals. She was the Editor of the Malaysian Dental Journal for several years. Her main research interests are implant-soft tissue interface, zirconia implant, photofunctionalization, 3D-oral mucosal model and pulpal regeneration.",institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},editorTwo:{id:"479686",title:"Dr.",name:"Ghee Seong",middleName:null,surname:"Lim",slug:"ghee-seong-lim",fullName:"Ghee Seong Lim",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003ScjLZQAZ/Profile_Picture_2022-06-08T14:17:06.png",biography:"Assoc. Prof Dr. Lim Ghee Seong graduated with a Bachelor of Dental Surgery from University of Malaya, Kuala Lumpur in 2008. He then pursued his Master in Clinical Dentistry, specializing in Restorative Dentistry at Newcastle University, Newcastle, UK, where he graduated with distinction. He has also been awarded the International Training Fellowship (Restorative Dentistry) from the Royal College of Surgeons. His passion for teaching then led him to join the faculty of dentistry at University Malaya and he has since became a valuable lecturer and clinical specialist in the Department of Restorative Dentistry. He is currently the removable prosthodontic undergraduate year 3 coordinator, head of the undergraduate module on occlusion and a member of the multidisciplinary team for the TMD clinic. He has previous membership in the British Society for Restorative Dentistry, the Malaysian Association of Aesthetic Dentistry and he is currently a lifetime member of the Malaysian Association for Prosthodontics. Currently, he is also the examiner for the Restorative Specialty Membership Examinations, Royal College of Surgeons, England. He has authored and co-authored handful of both local and international journal articles. His main interest is in prosthodontics, dental material, TMD and regenerative dentistry.",institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"83087",title:"Role of Cellular Responses in Periodontal Tissue Destruction",doi:"10.5772/intechopen.106645",signatures:"Nam Cong-Nhat Huynh",slug:"role-of-cellular-responses-in-periodontal-tissue-destruction",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:null,authors:null,book:{title:"Periodontology - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11566.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"83073",title:"Dental and Orofacial Trauma Impacts on Oral-Health-Related—Quality of Life in Children: Low- and Middle-Income Countries",doi:"10.5772/intechopen.105845",signatures:"Yolanda Malele-Kolisa, Nazia Khan, Mpho P. Molete, Maphefo D. 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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. 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He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. Aljaser",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"428600",title:"MSc.",name:"Adriana",middleName:null,surname:"García-Alarcón",slug:"adriana-garcia-alarcon",fullName:"Adriana García-Alarcón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428599",title:"MSc.",name:"Gabino",middleName:null,surname:"De La Rosa-Cruz",slug:"gabino-de-la-rosa-cruz",fullName:"Gabino De La Rosa-Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428601",title:"MSc.",name:"Juan Carlos",middleName:null,surname:"Campuzano-Caballero",slug:"juan-carlos-campuzano-caballero",fullName:"Juan Carlos Campuzano-Caballero",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}}]}},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:"