\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"1653",leadTitle:null,fullTitle:"Hemodynamics - New Diagnostic and Therapeutic Approaches",title:"Hemodynamics",subtitle:"New Diagnostic and Therapeutic Approaches",reviewType:"peer-reviewed",abstract:'Hemodynamics is study of the mechanical and physiologic properties controlling blood pressure and flow through the body. The factors influencing hemodynamics are complex and extensive. In addition to systemic hemodynamic alterations, microvascular alterations are frequently observed in critically ill patients. The book "Hemodynamics: New Diagnostic and Therapeuric Approaches" is formed to present the up-to-date research under the scope of hemodynamics by scientists from different backgrounds.',isbn:null,printIsbn:"978-953-51-0559-6",pdfIsbn:"978-953-51-6981-9",doi:"10.5772/2113",price:119,priceEur:129,priceUsd:155,slug:"hemodynamics-new-diagnostic-and-therapeutic-approaches",numberOfPages:166,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"2cf4b686414a77f0c867007f5062914f",bookSignature:"A. 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Review and Recent Progress",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe biliary tract is the duct that carries bile from the liver to the duodenum and is anatomically divided into intrahepatic and extrahepatic bile ducts. The biliary tract is an important channel for bile transport, ensuring the normal bile metabolism and the functioning of all functional mechanisms of the body. However, the bile ducts cause diseases such as biliary stones, cholangitis, and obstructive jaundice due to structural malformations or bile abnormalities. Meanwhile, malignant tumors of the bile ducts, due to their high malignancy, are at an advanced stage once detected and lose the chance of radical treatment by surgery. The diagnosis and treatment of bile duct diseases are constantly updated with technological advances. Early screening helps to detect the disease at an earlier stage, and the development of minimally invasive surgery minimizes the trauma of surgery, and the rapid postoperative recovery enables patients to resume normal life earlier.
\r\n\r\n\t
\r\n\tThis book discusses the anatomy and pathophysiological characteristics of the biliary tract, the latest progress in the treatment of different diseases of the biliary tract, and the management of complications. We hope that this book will provide clinicians with evidence for clinical decision-making and provide scientists with a comprehensive overview of current developments in this vital area.
The stimulus-induced turnover of membrane lipids is an important event during cell signaling. The protein kinase C (PKC) family is a group of serine/threonine kinases that mediate intracellular signaling activated by growth factor receptors, G-protein-coupled receptors, and tyrosine kinase receptors through lipid-derived secondary messengers [1]. The PKC family members share a highly conserved carboxy-terminal kinase domain, and differences in their requirements for lipids and calcium for activation are attributed to structural differences in the amino-terminal regulatory domain [2]. In mammals, the PKC family is composed of the following three structurally and functionally distinct subgroups: conventional PKCs (cPKC; α, βI/II, and γ), novel PKCs (nPKC; δ, ε, η, and θ), and atypical PKCs (aPKC; ζ and ι/λ: λ in mice) (Figure 1) [2, 3]. The cPKCs have a prototypic regulatory domain consisting of the following two conserved regions: C1 and C2. The C1 region serves as a binding site for diacylglycerol (DAG) and phospholipids, whereas the C2 region serves as a binding site for calcium. The C1 domain also acts as a target for tumor-promoting phorbol esters [4]. The nPKCs are similarly activated by DAG, phospholipids, and phorbol esters, but are not activated by calcium because of the lack of calcium-binding loops in the C2-like region [2]. The aPKCs have an atypical C1 domain and do not depend on DAG or calcium for activation [5, 6]. The activity of aPKCs is primarily regulated by protein-protein interactions through a Phox/Bem1 (PB1) domain located at the amino-terminus, which interacts with other PB1 domain-containing proteins, such as PAR 6 (see below) [7, 8].
\nSchematic presentation of the PKC family. In mammals, the PKC family is composed of the following three structurally and functionally distinct subgroups: conventional PKCs (cPKCs; α, βI/II, and γ), novel PKCs (nPKCs; δ, ε, η, and θ), and atypical PKCs (aPKCs; ζ and ι/λ: λ in mice). aPKC (a regulator of epithelial cell polarity) lacks the prototypic regulatory domain composed of C1 and C2 regions.
Among the PKC family members, aPKCs play essential roles in establishing epithelial cell polarity by interacting with partition-defective (Par) proteins [9, 10]. The par genes were first identified in genetic screening for regulators of asymmetric division in the early embryo of
Although in mammalian simple epithelia, the aPKC-Par complex is located at tight junctions and regulates apicobasal epithelial polarity, in the stratified epidermis, tight junctions are present only in the stratum granulosum [19, 20]. The aPKCs are expressed in the multilayered epidermis; aPKCλ, a predominant aPKC isoform in the epidermis, is distributed throughout the epidermis, whereas aPKCζ is present in basal cells [21]. These distributions suggest that the aPKCs have unidentified functions in the stratified epidermis, where epithelial polarity is established across different cell layers, and proliferation and differentiation are strictly regulated.
\nTo clarify the functions of aPKCs in the stratified epidermis, two groups, including my group, have generated mutant mice harboring epidermis-specific deletion of aPKC [22, 23], using the transgenic mouse line expressing Cre recombinase under the control of the keratin 5 (K5) or keratin 14 (K14) promoter [24, 25]. These mice show essentially the same phenotypes: progressive hair loss, abnormal hair cycling, hyperplasia of the epidermis and sebaceous gland, loss of the hair follicle stem cell (HFSC) quiescence, and a gradual decrease in HFSC in population. In this article, I discuss how these various phenotypes are related with one another and present the mechanism of hair loss from the point of view of epidermal cell polarity.
\nWhole-body inactivation of aPKCλ results in embryonic lethality, which hampers further examination of the role of the aPKCλ-Par complex in epidermal homeostasis. To overcome this problem, two groups, including my group, generated mutant mice with epidermis-specific loss of aPKCλ using K5-Cre or K14-Cre mice [22, 23]. Although, in a strict sense, the distribution of K14-Cre transgene activity differs from that of K5-Cre transgene activity in the epidermis and hair follicle [25, 26], both mutant mice showed similar skin phenotypes. Thus, hereafter, when referring to findings common to both conditional knockout (cKO) mice, the term mutant mice or aPKCλ cKO mice is used, and when referring to findings obtained in the mutant mice associated with K5-Cre or K14-Cre individually, the term K5-cKO or K14-cKO mice is used, respectively.
\nAlthough aPKCλ cKO mice showed no gross anomalies at birth, they were easily distinguished from their control counterparts by the thinning of pledge hair from around postnatal day (P) 14 onward. The hair loss was progressive, and one-year-old mutant mice exhibited total alopecia (Figure 2) [22, 23]. The vibrissae were also shortened or were lost in the mutant mice [23].
\nK14-cKO mice showed impaired hair morphology. Scanning electron microscopy demonstrated that the regular cuticle pattern was lost in the mutant hair shafts. Consistent with this finding, the expressions of hair keratins in the inner root sheath (K28), cuticle (K35, K82, K85), cortex (K35, K81, K85), medulla (K28, K6, K75), and companion layer (K75, K6) were severely reduced [22].
\nHair loss phenotype of mutant mice. Macroscopic presentation of a one-year-old control (left) and a K5-cKO mouse (right). Note that the vibrissae were lost in the mutant mouse (arrows).
During postnatal morphogenesis stages (P0–P16), the hair cycling of mutant hair follicles appeared to proceed normally, although the mutant integument became histologically noticeable with a thickened interfollicular epidermis (IFE) and enlarged sebaceous glands [22, 23]. However, entry into the first postnatal telogen (resting phase, normally starts around P18) was delayed in the mutant hair follicles. At P28, when control hair follicles entered into the first anagen (growth phase), they still had a long epithelial strand, a characteristic structure of catagen (regression phase) [27], and were positive for placental cadherin (P-cadherin), a marker for the epithelial strand. As a result, the start of the first anagen was delayed until P37 in the K5-cKO mice. In the K14-KO mice, the percentages of hair follicles that properly entered into catagen, telogen, and anagen were significantly reduced.
\nMoreover, mutant hair follicles were morphologically abnormal. They exhibited hyperkeratotic plugs and cyst-like structures with an expanded infundibulum and isthmus. Strikingly, these severely deformed mutant hair follicles regrew and entered into the second anagen much later than the control hair follicles. However, the mutant hair follicles in anagen did not proceed further into the second catagen or telogen. Instead, they started to degenerate, as revealed by the shrinking hair bulbs and reduced expressions of Ki67 and Lef1 [23]. In one-year-old mutant mice, the number of hair follicles was severely diminished.
\nFibroblast growth factor 18 (Fgf18) is expressed in hair follicles and colocalized with keratin 15 (K15) and CD34 [28, 29], both of which are expressed in the bulge region at telogen. Fgf18 shows a cyclic expression pattern in hair follicles; its levels are low in anagen and high throughout telogen [29]. In mutant mice with epidermis-specific loss of Fgf18, the length of telogen was short, resulting in rapid succession of hair cycling [29]. Interestingly, the expression of Fgf18 was severely suppressed in the K5-cKO mice during hair morphogenesis and hair development [23]. Although precise molecular mechanisms associated with abnormal hair cycling in cKO mice remain to be elucidated, these results suggest that aPKCλ controls hair follicle cycling through Fgf18 signaling.
\nIn aPKCλ cKO mice, the IFE and sebaceous glands were affected [22, 23]. The thickness of the IFE of the dorsal skin increased in the mutant mice, as revealed by significant expansion of the expression domain for loricrin (a marker for terminal differentiation) and keratin 10 (K10, a marker for spinous cells). Moreover, the sebaceous glands were enlarged in the cKO mice. Accordingly, immunostaining for adipose differentiation-related protein (ADFP, a marker for the surface of lipid droplets) and stearoyl-CoA desaturase 1 (SCD1, a marker for mature sebocytes), and Nile red staining showed remarkable increases in the sebaceous glands of the mutant mice.
\nImportantly, the expression domain of Lrig1 was expanded in the mutant mice [22, 23]. Lrig1 marks the junctional zone between the infundibulum and the sebaceous gland, and Lrig1-expressing cells contribute to the IFE and sebaceous glands [30]. Thus, this bipotent activity of Lrig1 is thought to be implicated in hyperplasia of these tissues.
\nThe hair follicle at telogen is composed of several compartments, including the interfollicular epidermis, infundibulum, isthmus, bulge, and hair germ. Recent studies have identified multiple new stem cell and progenitor populations in each compartment, which exhibits unique marker expression profiles (Figure 3) [31, 32].
\nIn the skin, label-retaining cells (LRCs) having a highly proliferative activity reside in the bulge region of the hair follicle [33], and LRCs in the bulge are multipotent [34, 35]. Since the first identification of K15 as a bulge marker [36], several factors have been demonstrated to be expressed in the bulge region at telogen, such as CD34 [37], leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) [38], and transcriptional factors Sox9 [39, 40], Tcf3 [41], Lhx2 [42, 43], and nuclear factor of activated T cells c1 (Nfatc1) [44]. CD34, a hematopoietic stem and progenitor cell marker, colocalizes with LRCs and K15 expression in the bulge region [37]. Lgr5 marks the lower bulge and secondary hair germ during telogen, and contributes to all hair lineages, but not to the epidermis and sebaceous glands [38]. Sox9-expressing cells also contribute to all skin epithelial lineages [39, 40]. Tcf3 and Tcf4 are downstream targets of Wnt signaling, and in Tcf3/Tcf4-null mice, hair follicle formation was initiated, but further development was severely impaired [45]. Lhx2 maintains the HFSC character downstream of Wnt and Shh signaling [43]. Nfatc1 colocalizes with other bulge stem cell markers, including CD34, Sox9, Tcf3, and Lhx2 [44]. Nfatc1 mediates HFSC quiescence by transcriptionally suppressing cyclin-dependent kinase 4 (CDK4) expression upstream of BMP4 signaling [44].
\nDistinct stem cell populations in the hair follicle. The hair follicle is divided into the interfollicular epidermis (IFE), infundibulum, junctional zone (JZ)/isthmus, sebaceous gland, bulge, and hair germ. The expressions of proposed stem cell markers at telogen are indicated. Note that the expression domains of these markers dynamically change during hair cycling. A murine hair follicle in telogen is immunostained for keratin 10 (a marker for suprabasal cells, green) and keratin 15 (a marker for bulge stem cells, red). Nuclei are counterstained with 4′, 6-diamidino-2-phenylindole. The dotted area indicates the sebaceous gland.
Comparison of the expression profiles of these bulge stem cell markers between the early and late stages in mutant mice demonstrated that the expressions of these markers diminished at later stages or were mislocalized to areas outside the bulge [22, 23]. These results indicate that aPKCλ regulates the expression and localization of HFSCs.
\nMarkers that recognize distinct cell populations of the upper (junctional zone) and lower bulge regions have been identified. As mentioned above, Lrig1 is a marker for the junctional zone/isthmus, which is located between the sebaceous gland and the bulge [30]. Lrig1-expressing cells have a bipotent activity in the steady state, and give rise to the IFE and sebaceous glands [30]. The cell-surface glycoprotein MTS24 is another marker for the isthmus/junctional zone [46]. MTS24-expressing cells do not express CD34 or keratin 15, and LRCs are infrequently observed among them. Lgr6 is expressed in a distinct population between the upper K5- and CD34-expressing cells and lower MTS24- and Lrig1-expressing cells in the bulge region [47]. Although prenatal Lgr6-positive cells contribute to the IFE, sebaceous glands, and hair follicles, the contribution to the hair follicles diminishes with age. In mutant hair follicles, the expression domains for Lrig1 and MTS24 were considerably expanded.
\nHFSCs can be identified as α6-integrin and CD34 double-positive cells with fluorescence-activated cell sorting (FACS) analysis [48]. Consistent with the decrease in the expression of the bulge stem cell markers at later stages, quantitative FACS analysis demonstrated that the number of α6-integrin/CD34 double-positive cells gradually decreased in aPKCλ cKO mice as the mice aged [22, 23]. Moreover, LRCs in BrdU pulse-chase labeling experiments were severely reduced in the bulge region of the mutant hair follicles [22, 23]. Conversely, the number of Lrig1- or MTS24-expressiong cells was gradually increased [22]. These results indicate that in aPKCλ cKO mice a decrease in quiescent HFSCs is accompanied by an increase of progenitor cells committed to the junctional zone/isthmus and infundibulum.
\nMutant mice analyses have identified intrinsic and paracrine mechanisms to clarify the loss of HFSC quiescence caused by epidermis-specific inactivation of aPKCλ.
\nOriented cell division is crucial for tissue morphogenesis and homeostasis [49, 50]. Basal cells in the epidermis show the following two types of cell division: symmetric cell division (SCD) and asymmetric cell division (ACD). SCD, in which alignment of the mitotic spindle is parallel to the basement membrane, results in two equivalent daughter cells, whereas ACD, in which alignment of the mitotic spindle is perpendicular to the basement membrane, results in two daughter cells with different fates (one basal cell and one more differentiation-committed suprabasal cell) (Figure 4).
\nIn the epidermis, a balance between SCD and ACD is important for coordinated proliferation and differentiation. A shift from SCD to ACD in basal cells of the developing epidermis coincides with the onset of stratification [51]. At embryonic day 12.5 (E12.5), most of the murine epidermis is single-layered, and the majority of cell divisions (>90%) are symmetric, whereas at E14.5–18.5, more than 70% of cell divisions are perpendicular to the basement membrane [51]. ACD promotes Notch signaling, leading to epidermal differentiation [52]. During SCD and ACD, the aPKC-Par complex localizes at the apical surface in a β1-integrin- and α-catenin-dependent manner [51]. Thus, in the β1-integrin KO and α-catenin KO epidermis, apical localization of the aPKC and Par3-LGN-inscuteable complex is abolished. Niessen et al. demonstrate that epidermal loss of aPKCλ induced a shift toward ACD not only in the IFE but also in the bulge stem cells and the junctional zone/isthmus region, leading to an expansion of progenitor cell populations committed to epidermal cell fate [22].
\nLocalization of aPKC in the simple epithelium and multilayered epidermis. (A) In the simple epithelium, aPKC forms a ternary complex with Par3 and Par6 and is localized to the apical surface of the cell and tight junctions (yellow circles). (B) In the stratified epidermis, tight junctions are only present in the granular layer. During symmetric cell division, in which alignment of the mitotic spindle is parallel to the basement membrane (gray), and during asymmetric cell division, in which alignment of the mitotic spindle is perpendicular to the basement membrane, aPKC (pink) is localized to the apical surface of the cell.
Lineage tracing analysis using Lgr5-Cre mice confirmed that epidermal loss of aPKCλ changes the fate of a bulge stem cell to an epidermal lineage [22]. In telogen, Lgr5-positive cells resided in the lower bulge and hair germ, as described above. During anagen, Lgr5 progeny exclusively contributed to down-growing hair follicles, whereas upon loss of aPKCλ, Lgr5-positive cells contributed to the upper junctional zone/isthmus and the IFE, as well as the lower-growing hair follicles. Consistent with this the expression domains for Lig1 and MTS24 increased. These findings indicate that aPKCλ regulates oriented cell division and thereby controls epidermal stem cell behavior and cell fate decisions.
\nHFSCs remain quiescent during telogen. Near the end of telogen, the HFSCs become activated to elicit the growth phase of the hair cycle. Basically, Bmp signaling induces quiescence and Wnt signaling activates HFSCs. However, the molecular mechanism underlying the cyclic inhibition and activation of HFSCs has recently started to be elucidated. Three types of Bmps from different sources induce quiescence in HFSCs: Bmp2 from subcutaneous adipocytes, Bmp4 from dermal fibroblasts [53], and Bmp6 from the inner layer of the bulge (Figure 5) [54]. Bmp antagonism is one of the key concepts to understand morphogenesis. In the telogen to anagen transition, the dermal papilla secretes HFSC-activating factors, Fgf7, Fgf10, Wnts, and Tgfβ2 [55], and Bmp inhibitors, such as noggin [53, 56], overcome the inhibitory effects of Bmps to activate HFSCs (Figure 5) [57].
\nCurrent model for the maintenance of HFSC quiescence. A hair follicle at telogen is presented. K6-positive cells mark the inner layer of the bulge, from which quiescence-inducing Bmp6 and Fgf18 are produced. The HFSCs are kept quiescent by Bmp2 from subcutaneous adipocytes and Bmp4 from dermal fibroblasts. At the telogen to anagen transition, HFSC-activating factors, such as Fgf7, Fgf10, Wnts, Noggin (Bmp antagonist), and Tgfβ2, antagonize the inhibitory effects of quiescence-inducing factors.
The inner layer of the bulge has attracted attention as a source of the quiescence-inducing factors Bmp6 and Fgf18 [54]. Although induction of K6 expression is closely associated with hyperproliferative conditions [58, 59], such as psoriasis and squamous cell carcinoma, a recent study has clarified that during telogen, K6 is strongly expressed in the inner layer of the bulge and K6-positive bulge cells secrete Bmp4 and Fgf18 to inhibit proliferation of the CD34-positive outer bulge stem cells [54]. Thus, upon the ablation of K6-positive bulge cells, HFSCs become prematurely activated and enter a new cycle of hair growth [54]. In the K5-cKO mice, K6 expression in the inner bulge cells was abolished, and the expressions of Bmp6 and Fgf18 were suppressed at the mRNA and protein levels [23], suggesting that aPKCλ regulates HFSC quiescence upstream of Bmp6 and Fgf18. Moreover, because K6-positive bulge cells are also involved in intercellular junctions that anchor the old hair shaft [54], a decrease in the expression of K6 in the inner layer of the mutant bulge may be involved in the falling-off of hair shafts in mutant hair follicles.
\nIn the epidermis, aPKCζ, another isoform of aPKC, localizes in the cytoplasm and nucleus of basal cells, although its expression level is much lower than that of aPKCλ in the skin of newborns and adults (40-fold and 10-fold, respectively) [21]. Although the activity of aPKCζ in epithelial polarity in vitro is distinguishable from that of aPKCλ, mice lacking aPKCζ at the whole-body level were viable and showed no obvious skin phenotypes [60]. This may be attributed to the low expression of aPKCζ in the epidermis, and aPKCλ may compensate for the loss of aPKCζ. However, these results do not exclude the possibility that aPKCλ and aPKCζ synergistically regulate epithelial cell polarity, oriented cell division, epidermal differentiation, and HFSC maintenance. Indeed, the combined deletion of the aPKCλ/ι and aPKCζ isoforms in podocytes leads to defective glomerular maturation with incomplete capillary formation and mesangiolysis, and causes severe proteinuria and perinatal death [61]. Thus, studies on mutant mice with simultaneous epidermal inactivation of aPKCλ and aPKCζ would help provide further information on the synergism between the two.
\nBecause aPKCs are localized to tight junctions, in aPKCλ cKO mice, the aPKCλ-Par6-Par3 complex at tight junctions was supposed to be absent or impaired in the granular layer. However, in the mutant mice, the overall multilayered architecture of the epidermis appeared to be normal, or rather hyperplasic [22, 23], suggesting that in contrast to simple epithelia, junctional aPKCλ is dispensable for establishing the polarity of the stratified epidermis, and that aPKCλ localized to the apical surface of basal cells during mitosis is more critical for maintaining epidermal homeostasis. Par6 and aPKCs form a stable heterodimer through their respective Phox/Bem1 (PB1) domains [7, 8], and aPKC-mediated phosphorylation is required for the dissociation of Par3 from the ternary complex. Thus, analysis of the dynamics of Par6 and Par3 or the Par6-Par3 complex in the absence of aPKCλ is helpful to understand the role of junctional aPKCλ.
\nThe difference between junctional and non-junctional aPKC has been demonstrated by two-step chemical skin carcinogenesis experiments using epidermis-specific Par3 knockouts [62]. The epidermal loss of Par3 reduced papilloma formation and promoted keratoacanthoma formation, indicating that Par3 acts as a tumor promoter for papilloma and as a tumor suppressor for keratoacanthoma. In the absence of Par3, the aPKC-Par6 complex localized to the cytoplasm [62]. These results imply that the junctional aPKC-Par6 complex with Par3 is involved in papilloma formation, whereas the non-junctional, cytoplasmic aPKC-Par6 complex without Par3 is involved in keratoacanthoma formation.
\nThe role of other components of the aPKC-Par complex (Par3 and Par6) in HFSC maintenance is unknown. Par3 is expressed throughout the interfollicular epidermis and the hair follicles, and it interacts with aPKCλ to colocalize at keratinocyte tight junctions [62]. However, no hair abnormalities were described in epidermis-specific Par3-deleted mice [62]. During SCD and ACD in the basal layer, Par3 was localized to the apical surface of the cell as a component of the Par3-LGN-inscuteable complex [51]. It would be useful to examine whether a shift from SCD to ACD in the hair follicle and subsequent HFSC depletion occurs in Par3-deficient mice as seen in aPKCλ cKO mice. Additionally, it would be interesting to investigate whether Par6 knockouts show similar phenotypes to those of aPKCλ knockouts. To the best of my knowledge, Par6 knockouts have not yet been reported. The presence of three isoforms of Par6 in mammals might make it difficult to reveal the phenotypes of Par6 inactivation.
\nIs alopecia observed in aPKCλ cKO mice relevant to human diseases? As few inflammatory cells were present around the hair follicles of mutant mice, the mutant mice model is unlikely to be a disease model for alopecia areata, which involves perifollicular T cell infiltration and autoimmune responses to hair antigens. Progressive hair loss in aPKCλ cKO mice was similar to alopecia observed in collagen XVII (COL17A1/BP180/BPAG2, a structural component of the hemidesmosome) knockout mice and aged mice. In humans, COL17A1 deficiency causes a subtype of congenital junctional epidermolysis bullosa [63]. The patients also show premature hair loss (alopecia) with hair follicle atrophy [64, 65], suggesting that COL17A1 plays a role in hair follicle homeostasis. Consistent with this finding,
A recent study clarified that accumulation of DNA damage in HFSCs leads to proteolysis of COL17A1 that triggers HFSC aging [68]. Importantly, aged HFSCs lose their stem cell signature and commit to epidermal differentiation, and they are finally eliminated from the epidermis [68]. The progressive depletion of HFSCs and the cell fate change observed in aPKC cKO mice are similar to aged mice. Thus, it would be interesting to examine whether the expression of Col17a1 is decreased in mutant mice and whether aPKCλ is involved in the induction and maintenance of Col17a1.
\nAnalyses of mutant mice with epidermal loss of aPKCλ have clarified a novel function of aPKCλ in HFSC maintenance. aPKCλ influences HFSC maintenance through the regulation of oriented cell division among HFSCs in the bulge (intrinsic mechanism) and the regulation of the expression of quiescence-inducing Fgf18 and Bmp6 (paracrine mechanism). Identification and evaluation of the downstream effectors of aPKCλ in HFSC maintenance will provide further insight into the mechanism of hair loss.
\nAs the population grows older, the prevalence of aortic valve disease, particularly aortic stenosis, is swelling, making it currently, the most prevalent form of valvular heart disease [1, 2, 3]. Surgery and percutaneous interventions of the aortic valve are frequently needed in patients with severe symptomatic aortic valve disease, the timing for these procedures’ conditional on a comprehensive evaluation of the dysfunctional aortic valve and the resultant repercussions on the rest of the heart, particularly the left ventricle (LV). Parameters used to predict favorable/unfavorable results from aortic valve surgery or intervention include LV ejection fraction (EF), presence and severity of left ventricular hypertrophy (LVH), LV end-systolic volume (LVESV), degree of leaflet calcification, and trans-aortic valve gradients. Because of the LV deformation indices potential to detect subclinical LV dysfunction, they are being used with increasing frequency in the management of patients with aortic valve disease [4] and advancing the timing for aortic valve surgery or intervention, before the LV is irreversibly damaged.
Our objective with this chapter is to describe the use of strain imaging, particularly global longitudinal strain in the assessment of cardiac function in patients with aortic valve disease. We review the current clinical applications of strain analysis in patients with aortic valve disease, highlighting strengths and weaknesses and emphasizing normal and abnormal findings in aortic stenosis (AS) aortic regurgitation (AR) and mixed aortic valve disease (ASAR); we summarize unresolved issues, potential future research priorities, and recommended indications for incorporating this technique into the clinical practice of patients with aortic valve disease.
Strain is defined as the fractional change in length of a myocardial segment relative to its baseline length, it is expressed as a percentage. Strain rate is the temporal derivative of strain, providing information on the speed at which the deformation occurs. Echocardiography, because of its dynamic nature, is ideally suited for the evaluation of cardiac mechanics through the application of deformation indices [5, 6]. Two echocardiographic techniques have dominated the clinical and research arena of deformation echocardiography: (1) tissue Doppler imaging, and (2) speckle tracking imaging. Both techniques lend to the derivation of multiple parameters of myocardial function. Tissue Doppler Imaging (TDI) was the first method used to measure myocardial deformation by echocardiography. The method is well validated and has been shown to provide valuable data in a wide range of conditions. Tissue Doppler is currently used mainly for evaluation of diastolic LV function, its use in aortic valve disease will not be discussed in this chapter. Speckle tracking, mainly through the use of global longitudinal strain (GLS), is increasingly used to identify subclinical myocardial dysfunction in patients with valvular heart disease and to identify optimal timing for surgery or intervention and prognosticate outcomes after surgery/intervention, and is the main focus of this review.
Aortic stenosis inflicts progressive pressure overload on the LV with compensatory concentric hypertrophy (Figure 1). Initially, the increased wall thickness and conservation of normal LV chamber dimensions offsets the increased LV pressure, maintaining a normal ejection fraction. If the aortic stenosis is not corrected it will inexorably lead to reduced myocardial perfusion, and eventual fibrosis with consequent drop in ejection fraction. It is well recognized that LV GLS is superior to LVEF in detecting perturbations in myocardial function. Compared with normal controls, severe aortic stenosis patients have impaired strain in all three layers of the LV myocardium. LV strain analysis in aortic stenosis has been evaluated in different settings as noted in the following sections.
Severe aortic stenosis: global longitudinal strain (GLS) in a patient with severe aortic stenosis with an aortic valve area (AVA) of 1.1 cm2 maximal velocity (AV V2) of 3.9 m/s and a mean gradient of 48 mm Hg. Left ventricular end-diastolic and end-systolic volumes (EDV, ESV) are normal as well as the LV ejection fraction (EF). The GLS is normal at −20% indicating absence of any LV dysfunction.
Measuring LV ejection fraction is crucial in the management of patients with asymptomatic severe aortic stenosis (AS). According to the current American Heart Association/American College of Cardiology and European Society of Cardiology guidelines there is a Class I indication (Level of Evidence: B) to perform aortic valve intervention in asymptomatic patients with severe AS when the LVEF becomes <50% [7, 8]. Predictors of poor outcome in aortic stenosis include advanced age, significant leaflet calcification, rapid disease progression and decreased left ventricular (LV) ejection fraction (EF). Patients can develop impaired LVEF due to afterload mismatch or from true depression of myocardial contractility due to myocardial fibrosis. Myocardial fibrosis occurs early in the natural history of aortic stenosis, affecting diastolic and systolic function and offering a substrate for ventricular arrhythmias, playing a role in the progression to heart failure and sudden cardiac death. These observations indicate that current echocardiographic assessment of LV function by measuring only the LVEF is insufficient and that new parameters detecting subtle myocardial impairment are needed to improve risk stratification and predict outcomes in patients with AS.
Several studies have defined the added value of global longitudinal strain over LVEF to characterize and prognosticate the clinical evolution of patients with aortic stenosis:
There is growing evidence suggesting the prognostic role of global longitudinal strain (GLS), in asymptomatic patients with AS. The American Society of Echocardiography (ASE) on cardiac chamber quantification acknowledged the incremental value of LV GLS over traditional LVEF measurements, and recommended its clinical use in patients [9].
Conventional measures of LVEF can be preserved until end-stage disease due to the compensatory development of concentric hypertrophy, and thus lacks accuracy in identifying subtle changes in myocardial contractility [2].
Subclinical myocardial dysfunction with impaired LV GLS is frequently seen in patients with severe AS with preserved LVEF and no symptoms. Left ventricular global longitudinal strain deteriorates over time and impaired LV GLS at baseline is associated with an increased risk for progression to the symptomatic stage and the need for aortic valve surgery or intervention [10].
A relationship between aortic stenosis severity and alterations in LV deformation indices has been demonstrated in the following studies:
Strain and strain rate parameters relate to LV function and aortic stenosis severity. Further, they appear to be superior to tissue velocity and conventional echocardiography in detecting subtle changes in myocardial function after AVR before LV mass and LV function show improvement [11].
Despite unchanged LVEF, GLS gradually decreased as severity of AS increases. GLS measured by 2D-speckle tracking imaging might be useful to assess subtle changes in LV function in AS patients [12].
LV strain analysis has been demonstrated to provide prognostic information in patients with aortic stenosis:
A recent met analysis, including 1067 asymptomatic patients, with AS and preserved LVEF, showed that LVGLS is strongly associated with mortality, with >2.5-fold increase in risk of death in patients with impaired LVGLS (−14.7% or less) [13].
GLS detects subclinical dysfunction and has incremental prognostic value over traditional risk markers including hemodynamic severity, symptom class, and LVEF in patients with AS. Incorporation of GLS into risk models can improve the identification of the optimal timing for AV replacement [14].
Kusunose et al. [15] demonstrated on 395 patients that Longitudinal strain (LS) is independently associated with death in patients with AS and preserved LVEF, in addition they made the point that the flow/gradient pattern should also be considered as an important parameter. In the management of AS patients the use apical 4 chamber LS should be considered a new parameter of evaluation of LV function and prognosis [16].
LV GLS is independently associated with all-cause mortality in AS patients. It can further risk stratify severe AS patients and may influence the optimal timing of aortic valve replacement [2].
GLS is an independent predictor of all-cause mortality in severe AS, irrespective of their type of treatment. GLS <9.7% indicates a significantly higher 1- and 5-year mortality in non-AVR patients. Therefore, GLS should be regularly assessed for enhanced risk stratification and clinical decision-making [17].
In normal LVEF patients with significant aortic stenosis, brain natriuretic peptide (BNP) and LV-GLS provide incremental prognostic information over established predictors, suggesting that both play a synergistic role in defining outcomes [18].
A drop in LVGLS in bicuspid aortic valve (BAV) with preserved LVEF is not infrequent and was independently associated with increased risk of events (mainly aortic valve replacement events), as found by Kong et al. [19] in 513 patients (68% men; mean age 44 ± 18 years) with BAV and preserved LVEF (>50%).
Subclinical coronary artery disease is common in moderate and severe aortic stenosis, and should be suspected when regional longitudinal dysfunction is predominant in the apical and mid ventricular segments [20].
Sublayer strain analysis may add additional information in the characterization of LV function in patients with aortic stenosis. The following studies address this issue:
In severe AS, longitudinal strain impairment affects all three myocardial layers but is more noticeable in the endocardial layer. This becomes more manifest in the advanced phases of the disease when symptoms appear [21].
Bilayer strain ratio (subendocardial and subepicardial) can reliably differentiate patients with varying degrees of AS severity and is a sensitive marker of LV function. These findings suggest that the evaluation of subendocardial and subepicardial radial strain might be a novel method for assessing LV mechanics in patients with AS [22].
Medically treated patients with AS have worsening of GLS despite preserved LVEF, first appearing in the subendocardial layer. Global circumferential strain (GCS) becomes progressively impaired in moderate and severe AS. Improvement in LV strain after AVR is seen earlier with GLS than with GCS [23].
There is differential impairment in LV systolic strain in all three cardiac axes in patients with AS. Left ventricular longitudinal strain impairment is proportional to AS severity. Subendocardial longitudinal strain correlates better with AS severity than subepicardial longitudinal strain while correlations between circumferential and radial strain and AS severity are weak [24].
Compared with normal controls, severe aortic stenosis patients have impaired strain in all three layers of the LV myocardium [25].
Several studies have characterized the LV deformation indices in patients with low gradient aortic stenosis:
GLS is depressed in patients with paradoxic low flow (PLF) AS. This implies that subclinical myocardial dysfunction may be more prominent in PLF AS compared with normal-flow AS and suggests the possible diagnostic and prognostic value of two-dimensional global strain in identifying PLF AS [26].
In patients with low flow-low gradient aortic stenosis, 2-dimensional strain parameters are strong predictors of outcome. Peak longitudinal strain rate may add incremental prognostic value beyond what is obtained from N-terminal pro-B-type natriuretic peptide and peak stress left ventricular ejection fraction [27].
Sato et al. [28] demonstrated in 204 patients that longitudinal LV function is severely impaired in patients with paradoxical low-flow, low-gradient (LFLPG) AS and they have a poor prognosis. GLS could stratify the high-risk group for future adverse outcomes.
Patients with paradoxical low-flow severe aortic stenosis (PLF-AS) reportedly have higher left ventricular hydraulic load and more systolic strain dysfunction than patients with normal-flow aortic stenosis. Holmes et al. [29] investigated the relationship of systolic loading and strain to PLF-AS in 120 patients. Patients with PLF-AS were found to have more valvular load, lower energy loss coefficient, more arterial load and increased systemic vascular resistance and more total hydraulic load. They concluded that Increased hydraulic load, from more severe valvular stenosis and increased vascular resistance, and longitudinal strain impairment are associated with PLF-AS and their interplay is likely fundamental to its pathophysiology.
Dahou et al. [30] examined the impact of left ventricular (LV) global longitudinal strain (GLS) measured at rest and at dobutamine stress echocardiography on the outcome of 202 patients with low LV ejection fraction and low-gradient aortic stenosis. GLS was found to be independently associated with mortality in patients with low LV ejection fraction, low-gradient aortic stenosis. Stress GLS measured during dobutamine stress echocardiography provided incremental prognostic value beyond GLS measured at rest in these patients. Hence, these authors concluded that measurement of GLS at rest and during dobutamine stress echocardiography may be helpful to enhance risk stratification in low LV ejection fraction, low-gradient aortic stenosis.
In patients with LF-LG AS and low LVEF, reduced right ventricular longitudinal strain (RVLS) was found by Dahou et al. [31] to be independently associated with increased risk of mortality. Furthermore, stress RVLS provided incremental prognostic value beyond that obtained from rest RVLS. Thus, RVLS measurement at rest and with dobutamine stress may be helpful to enhance risk stratification in this high-risk population.
The added effect of hypertension in deformation indices abnormalities has been defined in the following studies:
Hypertension has significant negative effect on LV mechanics in patients with aortic stenosis. Blood pressure is associated with deterioration of LV global longitudinal and circumferential strains in aortic stenosis patients independently of clinical and demographic characteristics [32].
In AS, both the AS severity and concomitant hypertension attenuate radial tissue Doppler imaging strain in the inferior LV wall. The subendocardial radial strain is mainly influenced by AS severity, while midmyocardial radial strain is attenuated by both hypertension and AS severity [33].
The contributions of LV strain analysis in the surgical or interventional management of patients with aortic stenosis has been extensively documented. The following statements summarize the conclusions of several studies addressing the use of strain imaging as it relates to valve replacement or intervention in patients with aortic stenosis.
LV longitudinal systolic strain is depressed despite preserved LV ejection fraction and fractional shortening in AS. A significant association exists among natriuretic peptides, myocardial longitudinal contractility, and the degree of symptoms. Reverse LV remodeling after aortic valve replacement with regression of myocardial hypertrophy results in improvement of LV longitudinal myocardial strain and decrease of Nt-pro-BNP plasma levels. LV strain analysis has the potential to identify patients with asymptomatic AS who might benefit from earlier surgical intervention to preserve overall LV function [34].
In patients with symptomatic severe aortic stenosis undergoing aortic valve replacement, reduced GLS (Particularly in the setting of normal LVEF) provides important prognostic information beyond standard risk factors [35].
Shortly after balloon valvuloplasty for severe congenital AS, there is an improvement in systolic myocardial deformation. However, two-dimensional speckle-tracking echocardiographic parameters do not return to normal at 3-year follow-up. These abnormalities in systolic deformation cannot be fully attributed to residual stenosis or aortic regurgitation [36].
Marcus et al. [36] showed in 37 children that shortly after balloon valvuloplasty for severe congenital AS, there is an improvement in systolic myocardial deformation. However, two-dimensional speckle tracking echocardiography parameters do not return to normal at 3-year follow-up. These abnormalities in systolic deformation cannot be fully attributed to residual stenosis or aortic regurgitation.
Kafa et al. [37] evaluated 208 patients that underwent AVR for severe AS, measuring GLS pre and 12–24 months post AVR and found that in patients with severe aortic stenosis, approximately 20% of patients who survived more than 1 year after aortic valve replacement had an abnormal LV-GLS value on postoperative echocardiography, despite a preserved postoperative LVEF and demonstrable left ventricular mass regression. This finding was independently associated with adverse events, concluding that appropriately timed aortic valve replacement relieves left ventricular wall stress and prevents a decline in LVEF.
In asymptomatic/minimally symptomatic patients with severe bioprosthetic AS undergoing redo aortic valve replacement (AVR), baseline LV-GLS provides incremental prognostic value over established predictors and could potentially aid in surgical timing and risk stratification [38].
AVR reverses LA abnormalities and regains normal atrial function, a behavior which is directly related to the severity of preoperative LV outflow tract obstruction. Early identification of LA size enlargement and functional disturbances might contribute to better patient’s recruitment for AVR [39].
Speckle echocardiography analysis of left atrial (LA) myocardial deformation is considered a promising tool for the evaluation of LA subclinical dysfunction in patients undergoing AVR, giving a potentially better risk stratification for the occurrence of postoperative atrial fibrillation [40].
Gelsomino et al. [41] explored the influence of global longitudinal strain measured with two-dimensional speckle-tracking echocardiography on left ventricular mass regression (LVMR) in 83 patients with pure aortic stenosis (AS) and normal left ventricular function undergoing aortic valve replacement (AVR) and found that global longitudinal strain accurately predicts LV mass regression in patients with pure AS undergoing AVR.
In summary LV GLS can detect subclinical myocardial dysfunction in patients with severe aortic stenosis, and progressively worsens with increasing aortic stenosis severity. Impaired LV GLS is independently associated with increased mortality in high-gradient aortic stenosis, in low-flow, low-gradient severe aortic stenosis with preserved LVEF, and in low-flow, low-gradient severe aortic stenosis with reduced LVEF. Strain analysis of specific myocardial sublayers may add value to the evaluation of strain in aortic stenosis. Coronary artery disease and hypertension produce additional variables in strain analysis that need to be considered. Finally, there is increasing support for the use of strain imaging to determine the need and timing for aortic valve surgery or intervention in patients with aortic stenosis.
In contrast to aortic stenosis, aortic regurgitation (AR) generates LV volume overload with progressive LV dilatation, initially with preservation of LVEF and wall thickness (eccentric LV hypertrophy), but eventually with the development of LV systolic dysfunction expressed by a drop in LVEF (Figure 2). Several studies have described the value of strain imaging in the management of patients with aortic regurgitation. The results and conclusion statement of these studies are summarized in the following paragraphs:
In patient with AR, LV strain analysis can detect early subclinical myocardial dysfunction before the development of impaired LVEF. Using tissue Doppler imaging, Marciniak et al. [42] demonstrated that patients with severe AR had significant impairment of LV longitudinal strain, in contrast to patients with moderate AR where there was no difference with controls.
Smedsrud et al. [43] evaluated 47 AR patients and 31 controls with Longitudinal peak systolic strain rate and found they were significantly decreased in the patient’s population (P < 0.001). Global longitudinal peak systolic strain rate was also significantly decreased in aortic stenosis and regurgitation compared to the control group (−1 ± 0.5, −0.9 ± 0.3, and −1.6 ± 0.3, P = 0.001). As far as the comparison between patients with aortic stenosis and aortic regurgitation, neither global strain rate nor strain rate for each wall was found to be different. They concluded that there was reduced global longitudinal strain in patients with chronic AR with preserved LV ejection fractions. Global longitudinal strain might therefore disclose incipient myocardial dysfunction with a consequent potential for improved timing of aortic valve surgery.
Di Salvo et al. [44] evaluated 26 young patients (3-16 years) with asymptomatic AR and found LV average longitudinal strain to be significantly reduced in patients with progressive AR compared to those with stable AR (−17.8 ± 3.9% vs. −22.7 ± 2.7%, p = 0.001). On multivariate analysis, the only significant risk factor for progressive AR was average LV longitudinal strain (p = 0.04, cut-off value > −19.5%, sensitivity 77.8%, specificity 94.1%, area under the curve 0.889). These authors concluded that two-dimensional strain imaging can discriminate young asymptomatic patients with progressive AR. This could allow young patients with AR to have a better definition of surgical timing before the occurrence of irreversible myocardial damage.
Kaneko et al. [45] evaluated 36 chronic AR patients undergoing surgical correction and found, with the use of speckle-tracking strain imaging, that LV subendocardial dysfunction was present in patients with chronic severe AR and preserved EF, this improved after surgical correction.
Park et al. [46] evaluated 60 patients with chronic AR with LV global strain rate on apical four chamber image (GS-4CH). During 64 months follow-up duration, 16 patients (26.7%) were deceased and 38 patients (63.3%) underwent aortic valve replacement (AVR). Deceased group had lower longitudinal strain (−12.05 ± 3.72% vs. -15.66 ± 4.35%, p = 0.005). On multivariate analysis by cox proportional hazard model adjusting for age, sex, body surface area, history of atrial fibrillation, blood urea nitrogen, LV dilatation, LV ejection fraction and AVR, decreased GS-4CH proved to be an independent predictor of mortality in patients with chronic AR (hazard ratio 1.313, 95% confidence interval 1.010–1.706, p = 0.042). They concluded that GS-4CH may be a useful predictor of mortality in patient with chronic AR.
Alashi et al. [47] evaluated 1063 patients with asymptomatic severe chronic AR and preserved LVEF to examine the prognostic utility of left ventricular (LV) global longitudinal strain (GLS). A significantly higher proportion (log-rank p = 0.01) of patients with LV-GLS worse than median (−19.5%) died versus those with an LV-GLS better than median [86 of 513 (17%) vs. 60 of 550 (11%)]. The risk of death at 5 years significantly increased with an LV-GLS of worse than −19%. They concluded that in asymptomatic patients with ≥III+ chronic AR and preserved LVEF, worsening LV-GLS was associated with longer term mortality, providing incremental prognostic value and improved reclassification.
Alashi et al. [48] evaluated 865 patients with ≥3+ chronic AR and preserved LVEF undergoing AV surgery, a baseline LV-GLS value worse than −19% was associated with reduced survival. In a subgroup of patients who returned for 3- and 12-month postoperative follow-up examinations, persistently impaired LV-GLS was associated with increased mortality.
Severe aortic regurgitation: this patient had severe aortic regurgitation with normal LV end-diastolic and end-systolic volumes (EDV, ESV) and preserved systolic function as estimated by a normal LV ejection fraction (EF) of 68%; however, there is already evidence of insipient LV dysfunction as demonstrated by a mild drop in global longitudinal strain at −14%.
In summary, in patients with severe AR LV strain analysis detects early subclinical myocardial. Dysfunction before there is a drop in LVEF. This provides the potential for improving AVR/intervention timing. In addition GLS may be a useful predictor of mortality in AR patients by providing incremental prognostic value and improved reclassification. Finally, persistently impaired LVGLS in AR is associated with increased mortality.
Very little information has been published on the use of strain imaging in the management of patients with mixed aortic valve disease (Figure 3). The next paragraph summarizes the findings and conclusions in one study:
Longitudinal LV function is reduced in both pressure and volume overload, and both of this overload patterns are equally harmful to the ventricle. Gorgulu et al. [49] evaluated a total of 27 subjects with mixed aortic valve disease (53 ± 15 years). Fifteen healthy subjects (mean age 50 ± 6 years) were enrolled as the control group. Longitudinal peak systolic strain rate values of each segment derived from analysis of a total of 804 segments were significantly decreased in this patient population (P < 0.001). Global longitudinal peak systolic strain rate was also significantly decreased in aortic stenosis and regurgitation compared to the control group (−1 ± 0.5, −0.9 ± 0.3, and −1.6 ± 0.3, P = 0.001). As far as the comparison between patients with aortic stenosis and aortic regurgitation, neither global strain rate nor strain rate for each myocardial segment was found to be different.
Severe aortic stenosis and regurgitation: this example illustrates the presence of severe LV dysfunction as demonstrated by a marked drop of GLS to −6% despite a borderline drop of LV ejection fraction to 50%. The combination of severe aortic stenosis and regurgitation likely produces significant volume and pressure overload of the LV with significant LV dysfunction that is unmasked by strain analysis.
Although strain analysis is been used with increasing frequency for the evaluation of cardiac function, there are still issues with reproducibility of deformation analysis data, particularly when different echocardiography machines or analysis software is used. Until this issue is resolved the current recommendation is to use the same machine and software when obtaining comparative studies.
The fidelity of the strain data sets is dependent on the quality of the echocardiographic data, unfortunately endocardial contrast enhancing agents cannot be used during strain analysis, therefore strain analysis sometimes has to be obtained with substandard images. The current recommendation is not to report strain values if the echocardiographic images are of poor quality. Hopefully work-around solutions will be found to permit strain analysis with endocardial enhancement agents use.
The current literature supports actionable interventions according to fairly well-defined values of decreased LV ejection fraction, this is not as developed on the characterization of LV dysfunction according to levels of decreased strain values.
Although the literature on strain is fairly robust in aortic stenosis, it is only moderately developed in aortic regurgitation and almost not existent in mixed aortic valve disease.
Despite some of the shortcomings of strain analysis in aortic valve disease we have reviewed, we feel the added value this technique provides, justifies its use in the day to day imaging management of patients with diseases of the aortic valve. Our practice and recommendation is to characterize and sequentially follow global longitudinal strain in patients with moderate and severe aortic stenosis and/or moderate and severe aortic regurgitation. In asymptomatic patients with severe AS or AR and normal EF, the presence of an abnormal GLS should alert the clinician for the need of closer follow up or possibly aortic valve replacement/intervention.
The following studies highlight areas of study with high potential for development in the area of strain analysis in patients with aortic valve disease.
Broch et al. [50] studied, 31 patients with moderate to severe AR, 15 elite endurance athletes, and 17 healthy control subjects using three-dimensional speckle-tracking echocardiography. Global circumferential strain (GCS), global longitudinal strain (GLS), end-systolic circumferential wall stress (ESSc), end-systolic meridional wall stress (ESSm), and the wall stress ratio (ESSc/ESSm) were measured. LV end-diastolic volumes were similar in athletes and patients with AR and significantly larger than in healthy control subjects. Values of GLS in control subjects, athletes, and patients with AR were −18.8 ± 1.9%, −17.3 ± 2.0%, and −16.4± 2.0%, respectively (control subjects vs. athletes and patients, P < .05), whereas values of GCS were −16.9 ± 2.0%, −15.5 ± 1.9%, and −17.9 ± 2.6%, respectively (athletes vs. control subjects and patients, P < .01). The authors concluded that in compensated AR, relatively high GCS compensates for reduced GLS in a manner consistent with the preserved ejection fractions observed in these patients.
Uncovering post-exercise myocardial dysfunction in patients with asymptomatic AS with preserved left ventricular function can aid in risk assessment of these patients [51].
Left ventricular myocardial strain gradient using a novel multi-layer transthoracic echocardiography technique positively correlates with severity of aortic stenosis [23].
Early diastolic strain rate in relation to systolic and diastolic function and prognosis in aortic stenosis [52].
Preoperative left atrial strain predicts postoperative atrial fibrillation in patients undergoing aortic valve replacement for aortic stenosis [40].
Deformation imaging, particularly in the form of global longitudinal strain, has evolved as a powerful tool in the evaluation of ventricular function in patients with aortic valve disease. GLS is particularly suited to detect subclinical LV dysfunction, before a drop in LV ejection fraction, providing the opportunity to intervene earlier to prevent serious and permanent LV dysfunction. The role of GLS in the management of aortic stenosis is quite robust, illuminating nuances of LV dysfunction in aortic valve disease such as impact in severity of AS, prognosis, timing for surgery and interventions, low gradient aortic stenosis and presence of associated coronary artery disease, among others. Similar added value has been demonstrated in the application of GLS in the detection of subclinical LV dysfunction in patients with aortic regurgitation. Very little information exists in the use of GLS in patients with mixed aortic valve disease providing an opportunity for future research in this important group of patients with aortic valve disease.
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\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
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\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
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\n\nLast updated: 2020-11-27
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Very young children are regular users of smartphones and tablet, so their early digital engagement poses new challenges to parent-child relationships and parental role. First, the chapter introduces the “digital parenting” construct, moving through the literature from “traditional” parenting styles to more recent studies on “parental mediation,” that is, the different behaviors parents adopt to regulate children’s engagement with the Internet and digital media. Second, the chapter reviews empirical researches on different parental mediation practices (active or restrictive behaviors) and how they are adjusted according to the child’s characteristics (age, digital competences, etc.) or parent’s media competence and beliefs. Finally, from a bidirectional perspective of parent-child relationships, the chapter discusses the role of youths’ social involvement, communication, self-disclosure, and digital skills on parent’s beliefs and practices. 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Very young children are regular users of smartphones and tablet, so their early digital engagement poses new challenges to parent-child relationships and parental role. First, the chapter introduces the “digital parenting” construct, moving through the literature from “traditional” parenting styles to more recent studies on “parental mediation,” that is, the different behaviors parents adopt to regulate children’s engagement with the Internet and digital media. Second, the chapter reviews empirical researches on different parental mediation practices (active or restrictive behaviors) and how they are adjusted according to the child’s characteristics (age, digital competences, etc.) or parent’s media competence and beliefs. Finally, from a bidirectional perspective of parent-child relationships, the chapter discusses the role of youths’ social involvement, communication, self-disclosure, and digital skills on parent’s beliefs and practices. 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The chapter highlights the associated aspects of childhood and adolescence, raised by helicopter parenting. As parents have their own concern about raising their children in certain manner, it is important to understand the underlying mechanism of parenting style. Therefore, this chapter also describes the theoretical framework. The associated mental health issues and supportive psychological intervention to be also discussed.",book:{id:"9043",slug:"parenting-studies-by-an-ecocultural-and-transactional-perspective",title:"Parenting",fullTitle:"Parenting - Studies by an Ecocultural and Transactional Perspective"},signatures:"Deepika Srivastav and M.N. 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. 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After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. 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