\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\\n\\n\\n\\n\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\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:"3761",leadTitle:null,fullTitle:"Theory and Novel Applications of Machine Learning",title:"Theory and Novel Applications of Machine Learning",subtitle:null,reviewType:"peer-reviewed",abstract:"Even since computers were invented, many researchers have been trying to understand how human beings learn and many interesting paradigms and approaches towards emulating human learning abilities have been proposed. The ability of learning is one of the central features of human intelligence, which makes it an important ingredient in both traditional Artificial Intelligence (AI) and emerging Cognitive Science. Machine Learning (ML) draws upon ideas from a diverse set of disciplines, including AI, Probability and Statistics, Computational Complexity, Information Theory, Psychology and Neurobiology, Control Theory and Philosophy. ML involves broad topics including Fuzzy Logic, Neural Networks (NNs), Evolutionary Algorithms (EAs), Probability and Statistics, Decision Trees, etc. Real-world applications of ML are widespread such as Pattern Recognition, Data Mining, Gaming, Bio-science, Telecommunications, Control and Robotics applications. This books reports the latest developments and futuristic trends in ML.",isbn:null,printIsbn:"978-3-902613-55-4",pdfIsbn:"978-953-51-5842-4",doi:"10.5772/56681",price:139,priceEur:155,priceUsd:179,slug:"theory_and_novel_applications_of_machine_learning",numberOfPages:388,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"2703f4beb52021731818c16292070f66",bookSignature:"Meng Joo Er and Yi Zhou",publishedDate:"January 1st 2009",coverURL:"https://cdn.intechopen.com/books/images_new/3761.jpg",numberOfDownloads:51601,numberOfWosCitations:25,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:null,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:25,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 22nd 2013",dateEndSecondStepPublish:"June 12th 2013",dateEndThirdStepPublish:"September 16th 2013",dateEndFourthStepPublish:"December 15th 2013",dateEndFifthStepPublish:"January 14th 2014",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"121367",title:"Dr.",name:"Er",middleName:null,surname:"Meng Joo",slug:"er-meng-joo",fullName:"Er Meng Joo",profilePictureURL:"https://mts.intechopen.com/storage/users/121367/images/system/121367.jpg",biography:"Professor Er Meng Joo is currently a Full Professor in Electrical and Electronic Engineering, Nanyang Technological University, Singapore. He served as the Founding Director of Renaissance Engineering Programme and an elected member of the NTU Advisory Board and from 2009 to 2012. He served as a member of the NTU Senate Steering Committee from 2010 to 2012.\n\nHe has authored five books entitled “Dynamic Fuzzy Neural Networks: Architectures, Algorithms and Applications” and “Engineering Mathematics with Real-World Applications” published by McGraw Hill in 2003 and 2005 respectively, and “Theory and Novel Applications of Machine Learning” published by In-Tech in 2009, “New Trends in Technology: Control, Management, Computational Intelligence and Network Systems” and “New Trends in Technology: Devices, Computer, Communication and Industrial Systems”, both published by SCIYO, 18 book chapters and more than 500 refereed journal and conference papers in his research areas of interest.\n\nProfessor Er was bestowed the Web of Science Top 1 % Best Cited Paper and the Elsevier Top 20 Best Cited Paper Award in 2007 and 2008 respectively. In recognition of the significant and impactful contributions to Singapore’s development by his research projects, Professor Er won the Institution of Engineers, Singapore (IES) Prestigious Engineering Achievement Award twice (2011 and 2015). He is also the only dual winner in Singapore IES Prestigious Publication Award in Application (1996) and IES Prestigious Publication Award in Theory (2001). Under his leadership, the NTU Team emerged first runner-up in the Freescale Technology Forum Design Challenge 2008. He received the Teacher of the Year Award for the School of EEE in 1999, School of EEE Year 2 Teaching Excellence Award in 2008, the Most Zealous Professor of the Year Award in 2009 and the Outstanding Mentor Award in 2014. He also received the Best Session Presentation Award at the World Congress on Computational Intelligence in 2006, Best Paper Award (First Prize) at the International Automatic Control Conference 2016 and Best Presentation Award at the IEEE International Conference on Intelligent Control, Power and Instrumentation (ICICPI) 2016. On top of this, he has more than 60 awards received at international and local competitions.\n\nCurrently, Professor Er serves as the Editor-in-Chief of 3 international journals, namely International Journal of Intelligent Autonomous Systems, Transactions on Machine Learning and Artificial Intelligence and the International Journal of Electrical and Electronic Engineering and Telecommunications. He also serves an Area Editor of International Journal of Intelligent Systems Science and an Associate Editor of 14 refereed international journals, namely IEEE Transaction on Cybernetics, Information Sciences, Neurocomputing, Asian Journal of Control, International Journal of Fuzzy Systems, ETRI Journal, International Journal of Humanoid Robots, International Journal of Modelling, Simulation and Scientific Computing, International Journal of Applied Computational Intelligence and Soft Computing, International Journal of Business Intelligence and Data Mining, International Journal of Fuzzy and Uncertain Systems, International Journal of Automation and Smart Technology, International Journal of Intelligent Information Processing and an editorial board member of the Open Automation and Control Systems Journal and the EE Times. \n\nProfessor Er has been invited to deliver more than 60 keynote speeches and invited talks overseas. He has also been active in professional bodies. Under his leadership, the IEEE CIS Singapore Chapter won the CIS Outstanding Chapter Award in 2012 (The Singapore Chapter is the first chapter in Asia to win the award). He was bestowed the IEEE Outstanding Volunteer Award (Singapore Section) and the IES Silver Medal in 2011. He is listed in Who’s Who in Engineering, Singapore, Edition 2013.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"252216",title:"Dr.",name:"Yi",middleName:null,surname:"Zhou",slug:"yi-zhou",fullName:"Yi Zhou",profilePictureURL:"https://mts.intechopen.com/storage/users/252216/images/system/252216.jpg",biography:"Research Areas:\nHuman-Machine Interfaces, Robotics, Automation & Control\nEducation\nPhD, Electrical & Electronics Engineering, Nanyang Technological University (NTU), Singapore, 2008\nB. Eng (First Class Hons.), Electrical and Electronic Engineering, Nanyang Technological University (NTU), Singapore, 2004\nAwards\nExcellent Teaching Journal Award, Singapore Polytechnic, 2011\n3rd Place of RoboCup World Champion Competition: Festo Logistics Competition, 2010.\nR&D Publication Award, School of Electrical and Electronic Engineering, Singapore Polytechnic, 2008.\nGold prize for the most popular research award in College of Engineering Exhibition (COE), NTU, 2006.\nBronze EEE Color Award, for excellent achievements in academe and activities NTU, 2004.\nCertificate of merit for publication award (student category, Institution of Engineers), Singapore, 2004.\n1st Class Freshman Award, Zhejiang University, China, 1999.\nResearch\nResearch Interests\n\nMachine learning\nFuzzy neural networks\nOptimization\nAutonomous and unmanned system\nRobotics\nMulti-agent system\nResearch Projects\n\nCollaborator/Co-PI for the RFID-based Autonomous Navigation of AGVs for Port Automation, MOE-TIF 2011-2013;\nPI for Tele-robotics system for education and assistive applications, Toteboard R&D model project, 2009-2011;\nCo-PI for Development of emotional expression system for social robots, Toteboard R&D model project, 2009-2011;\nCo-PI for Underwater robot swarm, Toteboard R&D model project, 2007-2010;\nPublications\nMeng Joo Er and Yi Zhou, Theory and novel applications of machine learning, book editors, published by Intechweb publisher, 2009.\nYi Zhou and Meng Joo Er: An evolutionary approach toward dynamic self-generated fuzzy inference systems, IEEE Transactions on Systems, Man, and Cybernetics, Part B, Vol. 38, No. 4, pp. 963-969, August, 2008.\nMeng Joo Er and Yi Zhou: Automatic generation of fuzzy inference systems via unsupervised learning, Neural Networks, Vol. 21, No. 10, pp. 1556-1566, December 2008.\nMeng Joo Er and Yi Zhou: A novel framework for automatic generation of fuzzy neural networks, Neurocomputing, Vol. 71, pp. 584-591, 2008.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"520",title:"Machine Learning",slug:"computer-and-information-science-artificial-intelligence-machine-learning"}],chapters:[{id:"6180",title:"A Drawing-Aid System using Supervised Learning",doi:"10.5772/6670",slug:"a_drawing-aid_system_using_supervised_learning",totalDownloads:1619,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Kei Eguchi",downloadPdfUrl:"/chapter/pdf-download/6180",previewPdfUrl:"/chapter/pdf-preview/6180",authors:[null],corrections:null},{id:"6181",title:"Supervised Learning with Hybrid Global Optimisation Methods. 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\r\n\tDue to their unique physicochemical features, metal nanoparticles are frequently used in various biomedical applications. The new and unique properties of gold nanoparticles (AuNPs) including, biocompatibility, low cytotoxicity, and optical properties, make them valuable for applications in biomedical fields, including biosensing, bioimaging, cancer therapy of cancer, and drug delivery. Radiation and photothermal therapy using AuNPs have developed a new platform for primary cancer diagnosis and treatment. Chemical functional groups and biological molecules, such as drug molecules, can be immobilised on gold surfaces owing to AuNPs' large surface area. Therefore, AuNPs are an applicable carrier for targeted drug delivery because of their surface functionalization.
\r\n\r\n\tThis book aims to provide an overview of gold nanoparticles extraction, processes, treatment, and coating with their mechanistic study and environmental and biological impacts. It will provide the most thorough and up-to-date information on the gold in both structures as nano and bulk and its metallurgical characteristics including physical, chemical, and biological properties.
",isbn:"978-1-80356-723-5",printIsbn:"978-1-80356-722-8",pdfIsbn:"978-1-80356-724-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"542a34c54bafa94c1da450b6e6f0901c",bookSignature:"Dr. Safaa Najah Saud Al-Humairi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11767.jpg",keywords:"Gold, Environmental Impacts, Structure, Morphology, Physical, Chemical, Bonding, Coating, Nano-Structure, Application, Biomaterials, Oxidation",numberOfDownloads:4,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 24th 2022",dateEndSecondStepPublish:"May 26th 2022",dateEndThirdStepPublish:"July 25th 2022",dateEndFourthStepPublish:"October 13th 2022",dateEndFifthStepPublish:"December 12th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Saud completed his postdoctoral and Ph.D. degrees in Mechanical Engineering from the Universiti Teknologi Malaysia, is registered in a number of engineering associations (ASME, IAENG), and has more than 10 years of experience in materials engineering, manufacturing, and design. 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Treatments for leukemia are complex, depending on the type of leukemia and other factors. At present, treatment may include some combination of chemotherapy, radiation therapy, targeted therapy, and hematopoietic stem cell transplantation, in addition to supportive care and palliative care as needed.
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) and accounts for approximately 10–15% of all cases of AML in adults. Morphologically, it is identified as AML–M3 by the French–American–British classification. Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, generating a promyelocytic leukemia (PML)/retinoic acid receptor α (RARα) fusion gene, which is thought to play a central role in the initiation of leukemogenesis [1–4]. The oncogenic fusion protein PML-RARα has been demonstrated to recruit corepressor (CoR) complexes containing nuclear receptor CoRs, histone deacetylases (HDACs), resulting in myeloid differentiation arrest observed in APL [5, 6]. An introduction of all-
Arsenic and its compounds are widely distributed in the environment and exist in organic and inorganic forms. There are three inorganic forms of arsenic: yellow arsenic (As2S3, also known as orpiment and Cihuang “female yellow” in China); red arsenic (As2S2 or As4S4, also known as realgar and Xionghuang“male yellow” in China); and white arsenic or ATO (As2O3, AsIII), which is made by burning realgar or orpiment [6]. Although a well-known poison, arsenic has been used medicinally for over 2 000 years. Since the mid-1990s, investigators from China and the USA have demonstrated that treatment with ATO results in complete remission in 90% of relapsed APL patients [4, 13–15]. From then on, a dramatic clinical efficacy of ATO-based regimens against APL has been reported around the world. An impressive drug efficacy against APL led to its approval in the USA and in Europe under the brand name Trisenox for “the induction of remission and consolidation in patients with APL whose conditions are refractory to, or who have relapsed from retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15:17) translocation or PML-RARα gene expression” [13]. Moreover, As2S2 as another important arsenic compound has been gaining increasing attention and traditionally used to treat certain types of hematological disorders, including chronic myeloid leukemia (CML), AML, myelodysplastic syndrome (MDS) and MDS/AML in China [16–18]. Although realgar has not yet been approved by the U.S. Food and Drug Administration (FDA) and other major countries for clinical use, it has become another research for focus following ATO due to its good therapeutic efficacy and perceived low toxicity [19, 20].
In this chapter, we first highlight the pharmacokinetics of ATO and realgar in leukemia patients and/or a healthy volunteer. We will further summarize the detailed mechanisms underlying the cytocidal effects of these arsenic compounds. We also provide detailed insight into potential future clinical applications of those promising candidates endowed with potent antitumor activities in view of combination with arsenic compounds.
It has been established that biomethylation, which primarily occurred in the liver [21, 22], is a major metabolic pathway for inorganic arsenic in human and many animal species [23], by which arsenic undergoes metabolic conversion by the reduction of AsV to AsIII with subsequent methylation, yielding monomethylated and dimethylated metabolites [24, 25]. A postulated metabolic pathway is as follows: AsV → AsIII → methylarsonic acid (MAsV) → methylarsonous acid (MAsIII) → dimethylarsinic acid (DMAsV) → dimethylarsinous acid (DMAsIII) (Figure 1). It has been demonstrated that, following arsenic exposure, 40–60% of arsenic intake is eliminated through urine. The standard profile of urinary arsenic in human is comprised of 10–30% inorganic arsenic, 10–20% monomethylated arsenic (MAs: MAIII + MAV), and 60–80% dimethylated arsenic (DMAs: DMAIII + DMAV) [26, 27].
Postulated pathways of the biotransformation of arsenic in mammalian systems. Biomethylation, which primarily occurs in the liver, is a major metabolic pathway for inorganic arsenic in human and many animal species. In human, dimethylarsinous acid (DMAsIII) and dimethylarsinic acid (DMAsV) appear to be the end products of this pathway [
In order to provide an effective treatment protocol for individual APL patients, detailed studies have been conducted on the pharmacokinetics of AsIII in APL patients using biological samples such as peripheral blood (PB), cerebrospinal fluid (CSF), BM, and urine [14, 28–31]. Compared with a limited understanding of metabolic profiles of realgar and its pharmacokinetics, many detailed systematic analyses of the metabolites of ATO in blood cells and plasma of APL patients have been performed. In this regard, by using high-performance liquid chromatography (HPLC)/inductively coupled plasma mass spectrometry (ICP-MS), we have conducted studies on the total arsenic and speciation of ATO metabolites in an APL patient when 0.15 mg/kg/day was infused. Blood samples were obtained from the patient at various time points after remission induction therapy and during consolidation therapy [31]. Of note, biological samples, such as blood and urine, contain much higher concentrations of chloride ion, which interferes with arsenic detection at
We first demonstrated that, in all blood samples collected either after the remission induction therapy or during the consolidation therapy, approximately 80–90% of the total arsenic in the blood samples was observed in the blood cells, suggesting that most of the blood arsenic is bound to hemoglobin [31]. These results are in good agreement with a previous report showing that 90% of blood arsenic is bound to hemoglobin [33]. These findings suggest that careful attention should be paid to profiles of total arsenic in blood cells and consequently provide valuable insight into clinical applications of AsIII. We further clarified that, during the drug withdraw period, the amount of AsV in plasma was more readily eliminated among all arsenic metabolites [31], as reported by other groups [32, 34]. We also demonstrated that AsIII concentrations in plasma initially declined more quickly than those of MAsV and DMAsV [31]. These results suggest that methylated metabolites (MAsV and DMAsV) are major metabolites in plasma and are similar to those reported by other groups [23–25]. Furthermore, we demonstrated that the concentrations of methylated metabolites (MAsV and DMAsV) as well as inorganic arsenic (AsIII and AsV) in plasma increased with multiple administration during the consolidation therapy period [31]. In comparison, Fujisawa et al. demonstrated no increase in the maximum concentrations of inorganic arsenic (AsIII and AsV) despite multiple administrations, suggesting that inorganic arsenic plasma may reach a steady state after multiple administration [28]. It is noteworthy that only one of the 14 patients enrolled in the study of Fujisawa et al. was in the first relapse, and the remaining patients were in the second to fifth relapse [28]. In contrast, the patient in our study was in the first relapse [31]. Although the exact reason for the above-mentioned apparent differences in the profiles of the concentrations of inorganic arsenic (AsIII and AsV) in the plasma of APL patients is not clear, the differences in patient characteristics may explain the discrepancy in the concentrations of inorganic arsenic. These results also suggest that understanding the differences in metabolism among patients is very useful for providing an effective treatment protocol for individual patients with leukemia.
Although the central nervous system (CNS) relapse of APL occurs in 1–5% of patients, the optimal therapy for this case remains unclear [35, 36]. Fortunately, several clinical data have demonstrated that ATO seems to be capable of crossing the blood–brain barrier in humans and can be considered as an effective treatment strategy for the CNS relapse of APL [37–40]. We have recently determined the total arsenic and speciation of ATO metabolites in the CSF and PB plasma samples from three patients with APL who were treated with intravenous ATO as salvage therapy [0.15 mg/kg/day ATO + intrathecal chemotherapy (methotrexate + cytosine arabinoside + prednisolone)] [29]. In this study, PB was collected before and after the infusion, and the CSF was collected after the infusion, respectively. Furthermore, in order to prepare samples for arsenic speciation, the PB plasma was ultrafiltered with a 10-kDa molecular mass cutoff. The filtrates were thus defined as low-molecular-weight fraction (LMW-F) and subjected to arsenic speciation analysis. The remains trapped in filters were defined as high-molecular-weight fraction (HMW-F) and subjected to total arsenic determination [29]. We first demonstrated that not only inorganic arsenic (AsIII and AsV) but also methylated arsenic metabolites (MAsV and DMAsV) existed in the CSF and that the total CSF arsenic concentrations ranged from 148 nM to 250 nM (mean: 199 nM) [29]. It has been demonstrated that ATO exerts a dual effect on APL cells; that is, ATO induces apoptosis at relatively high concentrations, ranging from 1 μM to 2 μM, whereas trends to promote differentiation of APL cells at low concentrations range from 0.1 μM to 0.5 μM [4, 6, 41]. Therefore, the beneficial effects of arsenic on the CNS relapse of APL patients might be attributed to its differentiation induction, rather than apoptosis induction. Furthermore, we found that the total PB plasma arsenic concentration is about twice of the sum of the amount of each arsenic metabolite present in LMW-F [29]. We also demonstrated that the total arsenic concentration in HMW-F accounted for approximately 50% of the total PB plasma arsenic concentration, suggesting that considerable amounts of arsenic species exist in clinical samples as a protein-bound complex.
Similar to previous reports showing that arsenic concentrations in the CSF were about 10% of those in whole blood or plasma [38, 40], we also demonstrated that the arsenic concentrations of the CSF were 8–17% of the plasma levels [29]. Taken together, it is possible to use a combination of arsenic with other chemotherapeutics to achieve a favorable clinical outcome in APL patients with CNS relapse, although a further larger scale randomized study must be conducted to reach a firm conclusion. It is noteworthy that Meng et al. have developed a non-invasive method via a concomitant with 20% mannitol intravenous bolus injection to help ATO enter into the CNS [42]. Their regimens include 125 ml of 20% mannitol bolus through the medial cubital vein at the rate of 12 ± 30 ml/min, followed with 250 ml of mixed solution (including 20% mannitol and ATO 0.08 mg/kg/day) through intravenous infusion at the rate of 6 ml/min, followed by ATO 0.08 mg/kg/day + 5% glucose 250-ml infusion at the rate of 0.5 ml/min in the total dosage of ATO (0.16 mg/kg/day) [42]. Compared with the general ATO intravenous infusion, the mannitol-assisted ATO penetration followed by the slow-speed continuous ATO intravenous infusion can not only increase the elemental arsenic concentration in the CNS but also keep the plasma arsenic at prolonged effective therapeutic levels without remarkable plasma arsenic peak. Therefore, the non-invasive method was supposed to be more beneficial to the CNS relapse of APL and increase the prevention and treatment efficiency of APL marrow relapse, as well as less side effects to normal tissues [42]. The same group has recently extended the application of the non-invasive method to additional patients [43]. They demonstrated that, in 16 of the 17 patients examined, abnormal blasts/promyelocytes from the CSF were eliminated in 18 to 32 days (median: 24 days) after the start of induction treatment and that all the patients tolerated the induction well. Importantly, there were no complaints of side effects associated with the use of mannitol [43]. Of note, over the course of the entire induction treatment process, the concentrations of arsenic in the blood and CSF were fairly stable in each patient. For each individual, the arsenic level in the CSF was ~99.7% of those in the paired blood samples, although the arsenic levels in different individuals were highly variable in the blood and CSF [43].
Although an initial report demonstrated that the total arsenic concentrations in the plasma of a BM sample from five relapsed APL patients were close to levels for differentiation induction, the analysis was conducted for the BM sample collected at only one collection time point [44]. Moreover, despite the fact that BM is a vital site for regulating the production of blood cells, no speciation analysis of arsenicals in the BM from APL patients undergoing long-term administration of ATO has been done before. In this regard, in order to gain more detailed information on the distribution of arsenic, we have recently investigated, for the first time, the arsenic speciation in the plasma of the BM and compared the arsenic speciation profiles between the PB and BM collected before and after the start of administration of 0.15-mg/kg/day ATO [30]. In this study, we first demonstrated a time-dependent increase of the total arsenic concentrations in the BM plasma, which was similar to that in the PB plasma. Furthermore, the total arsenic concentration levels tended to be higher in the BM plasma than those in the PB plasma, raising clinical concerns and inspiring us to unravel the detailed information on the distribution of arsenic as well as its speciation in these biological samples [30]. In this study, the concentrations of MAsV and DMAsV substantially increased after the start of administration, whereas those of AsIII were still kept at a low level until day 10, followed by a substantial increase from day 14 after the start of administration. As mentioned in Section 2.1, we have previously demonstrated that the PB plasma concentrations of both methylated arsenic metabolites (MAsV and DMAsV) and inorganic arsenic (AsIII and AsV) remarkably increased after the start of administration in a Japanese APL patient undergoing consolidation therapy [31]. Compared with the APL patient in our previous study [31], the patient enrolled in this study appeared to have relatively higher metabolic efficiency, probably due to her relatively young age or without clinical complications. Collectively, our findings suggest that the efficiency of drug metabolism is obviously different in individual patients with different backgrounds, such as age range, with or without organ failure or disseminated intravascular coagulation (DIC), which, in turn, affect clinical outcomes and appearance of side effects. Of note, a close similarity of the arsenic speciation profiles between the PB and BM plasma was observed throughout the remission induction therapy, suggesting for the first time that the arsenic speciation analysis of the PB plasma could be predicative for BM speciation without applying BM aspiration [30]. Investigation of the total amount of arsenic in HMW-F trapped in a 10-kDa molecular mass cutoff filters further demonstrated that arsenic concentrations were much higher in the BM plasma than those in the PB plasma. One important biological effect of arsenic has been suggested to be mediated by reaction with closely spaced cysteine residues on a critical cell protein [45]. Several proteins such as tubulin, thioredoxin reductase, human arsenic methyltransferase (AS3MT, responsible for arsenic methylation) with a high cysteine content, and accessible thiol group are candidates for interactions with arsenic [4, 46]. In fact, arsenic bound to high molecular weight proteins (MW > 10-kDa) has been detected in livers and kidneys in rats after an intravenous injection of arsenite [47]. In view of the vital role of the BM microenvironment in maintaining the homeostasis of hematopoietic system, we assumed that a higher amount of proteins (MW > 10-KDa)-bound arsenic complex contributes to the protection effect from the attack of free arsenic species. Likewise, patients with low-proteinemia besides liver and/or renal dysfunctions might frequently develop arsenic-mediated side effects. Understandably, further investigation of the detailed information about these proteins is needed.
The pharmacokinetic studies in APL patients have been well discussed by using urine samples [14, 28, 32, 48]. Previous studies on urinary arsenic excretion profiles demonstrated that there are large variations among individual patients with regard to the arsenic metabolic profiles and excretion patterns. For instance, an initial study demonstrated that urinary arsenic contents slightly increased during drug administration and the total amounts of arsenic excreted daily into the urine accounted for approximately 1–8% of the daily dose [14]. However, a previous report revealed that the mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of the daily dose on day 1 and remained at about 60% of the daily dose during subsequent weeks [28]. A clinical pharmacokinetic study performed in an APL patient showed that, in the urine sample collected for 24 h after administration of ATO, the total amount of inorganic arsenic and the methylated metabolites was almost 30% more of the daily dose [32]. Furthermore, Wang et al. [48] have demonstrated that there is an interindividual difference in excretion profiles and the relative concentrations of major arsenic species in the urine among four Chinese APL patients undergoing ATO treatment. In addition, other pathways of excretion, such as through the bile, have also been suggested to play a partial role in the elimination of arsenic [14, 48]. Therefore, systematic monitoring of the speciation of arsenic compounds in not only urine samples but also other biological samples such as the PB plasma has important implications for achieving favorable outcomes and minimizing side effects in leukemia patients treated with arsenic-based regimens.
Realgar has been widely used clinically in China [17, 18]. Moreover, an As2S2-containing formula, Qinghuang powder (QHP), was used as a folk medicine recorded in a famous traditional Chinese medicine (TCM) book, Shi Yi De Xiao Fang, published in 1345. Despite this, the systematic study on metabolic profiles of realgar and its pharmacokinetics have not yet been fully investigated. Compared with intravenous administration of ATO, oral administration of realgar is advantageous and would be more suitable for consolidation and maintenance therapy and consequently make better patient compliance and quality of life [16]. In this regard, Lu and colleagues designed a pilot study in which 129 APL patients with different disease stages were enrolled and received oral administration of highly purified crystalline realgar (As4S4) [19]. In this pilot study, encouraging responses such as high complete remission rate, long disease-free survival period, and tolerable side effects after oral administration of realgar alone were observed [19]. Furthermore, clinical pharmacokinetic studies on seven volunteers with APL and hematologic complete remission (HCR) by using 60 mg/kg oral As4S4 in a single dose demonstrated that arsenic could be detected in the blood 30 min after oral administration of As4S4. The peak time (Tpeak) was 3.4 ± 1.4 h, and the maximum concentration (Cmax) was 24.9 ± 8.0 μg/l. As expected, there was a wide interpatient variation in area under the concentration–time curve (AUC0-infinity) (899.01 ± 705.64 μg/h per liter) and elimination half-life (t1/2) (30.1 ± 11.1 h). These pharmacokinetic data revealed that rapid absorption of arsenic occurred after oral administration of As4S4 [19]. In addition, most urinary arsenic excretion occurred within the first 24 h. Measurement of blood arsenic levels in eight patients who were given oral As4S4 at a dosage of 50 mg/kg/day for 2 weeks followed by a break of 2 weeks during the first year of treatment demonstrated that blood arsenic levels declined during the drug withdraw period [19]. Arsenic concentrations in plasma and red cells were also measured in five patients with newly diagnosed APL and showed that the red-cell arsenic level was approximately two times higher than the plasma level, similar to the findings observed in an APL patient treated with ATO. Similar to the behavior of blood arsenic levels, urinary arsenic levels also quickly declined after discontinuation of As4S4. Of note, the arsenic level in the CSF in nine patients on the 10th day of treatment was 5.6–14.6 μg/l, a level similar to that in plasma, indicated that oral As4S4 is capable of penetrating into the CSF, suggesting the usefulness of As4S4 for the CNS relapse of APL [19]. These previous findings suggested that As4S4 treatment alone is highly effective and safe in both remission induction and maintenance therapy in patients with APL, regardless of disease stage.
Recently, the therapeutic effects of QHP have been evaluated in MDS patients with different karyotypes, including normal karyotype, trisomy 8 karyotype, and other cytogenetic abnormalities after receiving one to two 3-month courses of oral administration of QHP (containing realgar 0.16 g/capsule/day). Furthermore, the PB samples were collected 10–12 h after ingestion, and the total arsenic concentrations in the PB or PB plasma were determined using HPLC/ICP-MS. A positive correlation was found between the efficacy of QHP and total arsenic concentrations in the PB, but not in the PB plasma. Compared with patients with other cytogenetic abnormalities, much better clinical efficacy was observed in patients with normal or trisomy 8 karyotype, in agreement with our previous findings [49]. Surprisingly, no significant difference in the total arsenic concentrations in the PB was observed between the high-efficacy groups (patients with normal or trisomy 8 karyotype) and low-efficacy groups (patients with other cytogenetic abnormalities). Furthermore, no correlation between total arsenic concentrations in the PB or PB plasma and administration period was found in the study, suggesting that realgar might have a relatively low absorption/accumulation rate. Interestingly, compared with patients who did not receive oral administration of QHP, no apparent alteration in the mitochondria membrane potential (ΔΨm) was found in primary blasts from the BM in patients treated with QHP. Moreover, among 28 patients treated with QHP, no correlation between ΔΨm and total arsenic concentrations in the PB was observed, suggesting that the mitochondria might not be the main target for QHP, although further detailed studies are obviously needed.
Currently, as much as 49 items among approximately 500 TCMs contain realgar [16]. Furthermore, there are 22 registered oral formulae containing realgar in the
Koch and colleagues also evaluated arsenic concentrations and their speciation in urinary samples collected from a volunteer aged 70 years before and after ingestion of one pill of
Due to the poor bioaccessibility and/or bioavailability of realgar mentioned above, realgar nanoparticles (NPs) were designed to improve its pharmacological and toxicological profiles [16]. It has been demonstrated that, compared with commercially used coarse realgar powder, realgar NPs with a size less than 200 nm prepared even by different methods show much higher efficiency in cytotoxicity associated with apoptosis induction and differentiation induction in leukemic cells such as HL-60 and U937 [54–57]. Although the detailed pharmacokinetic studies on realgar NPs have not yet been investigated in human beings, an
It is well known that, besides administration of arsenic to patients in clinical practice, arsenic can also enter the body through food chains. The most common exposure to high levels of arsenic in food is through marine products in the form of arsenobetaine or plant products in the form of various arsenosugars [4]. Arsenobetaine, a trimethylarsenic compound, is one of the major organic arsenic in seafood and is not produced by the metabolism of AsIII in human [34, 60]. Once arsenobetaine is ingested during periods of arsenic-based therapy, it will be excreted from the body in the same form and consequently interrupt the accuracy of evaluation of the pharmacokinetics of arsenic species. Therefore, controlling the daily diet, in particular seafood, during the periods of remission induction therapy and/or consolidation therapy is very important to accurately monitor the metabolic profiles of arsenic.
The remarkable clinical results achieved with ATO and realgar in relapsed as well as newly diagnosed APL patients have promoted investigations to determine the mechanisms underlying their activity. Accumulating evidence has shown that ATO exerts dose-dependent dual effects in APL cells such as NB4, with preferential apoptosis at relatively high concentrations ranging from 0.5 μM to 2.0 μM and partial differentiation at relatively low concentrations ranging from 0.1 to 0.5 μM [4, 61, 62]. The apoptosis-inducing effect is primarily associated with the mitochondrial-mediated intrinsic apoptotic pathway, whereas the extrinsic pathway through death receptors, such as the tumor necrosis factor receptor (TNFR) and Fas, have also been reported to be implicated in ATO-induced apoptosis in human leukemia, lymphoma, as well as glioma cell lines [63–65]. Moreover, a third pathway involving endoplasmic reticulum and caspase-12 has been reported to associate with ATO-mediated apoptosis in the chronic myeloid leukemia cell line K562 [66].
It has become clear that oxidative damage is one of the main mechanisms by which arsenic induces apoptosis [4, 6, 55, 61, 62, 67]. This idea is consistent with the binding capacity of arsenite to adjacent sulfhydryl (SH) groups present in many vital biomolecules [4, 6, 61, 62, 67] and also strongly supported by clinical data that levels of 8-hydroxy-2’-deoxyguanosine (8-OH-dGuo), one of the most abundant oxidative products of DNA, are increased in plasma from APL patients after remission induction and consolidation therapy with ATO [68]. Similar to ATO, realgar NPs also caused elevated urinary 8-OH-dGuo excretion in rats from day 1 after oral administration [69]. ATO has been demonstrated to disrupt mitochondrial respiration through blockading of electron flow at complex III and IV to elevate the generation of oxygen free radicals [70]. It has also been reported that reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) are responsible for the susceptibility to arsenic cytotoxicity in leukemia cells [71, 72]. Furthermore, downregulation of the ROS elimination system, comprising glutathione (GSH), thioredoxin, and anti-oxidative enzymes including superoxide dismutase (SOD), catalase, as well as glutathione peroxidase (GPx), has been reported to be involved in cytocidal effects of arsenic compounds [73–78]. In line with these findings, GPx inhibitors such as mercaptosuccinic acid [79], catalase inhibitors such as 3-amino-1,2,4-trizaole [79], and SOD inhibitors such as 2-methoxyestradiol have been reported to potentiate the apoptosis-inducing activity of arsenic in NB4 cells as well as primary leukemia cells from patients with chronic lymphocytic leukemia [70, 73, 80]. Collectively, through not only enhancing the ROS production system but also impairing the ROS elimination system, arsenic compounds are able to induce intracellular ROS accumulation, which, in turn, activates apoptotic pathways in hematological cell lines including the APL cell line [41, 73, 74, 81–84].
It has been demonstrated that higher DNA methylation levels at a few CpG sites in some erythroid specific genes correlated with a decreased erythroid differentiation capacity of K562 cells, which has been proposed as a very useful
It is no doubt that PML-RARα plays a central role in the initiation of leukemogenesis, although there is evidence to suggest that the fusion gene expression is not the sole genetic event required for the development of APL [4–6]. It has been clarified that arsenic-mediated modulation/degradation of the PML-RARα oncoprotein is one of the major mechanisms responsible for the efficacy of arsenic compounds in APL [4–6, 93]. Furthermore, the PML moiety, but not the RARα moiety, of the PML-RARα chimera represents the target for arsenic treatment [6, 61]. It has been clarified that both PML and PML-RARα form high-molecular-weight conjugates with a small ubiquitin-related modifier (SUMO)-1 and are recruited from the nucleoplasm to the nuclear body (NB), followed by ubiquitin-mediated proteolysis [94–96]. Degradation of PML-RARα is closely associated with differentiation, growth inhibition associated with the induction of apoptosis, as well as cell cycle arrest in APL cells treated with arsenic compounds [4–6, 93]. In addition, degradation of the PML-RARα protein associated with its redistribution was also reported in fresh APL cells obtained from the PB and BM of APL patients after treatment with As4S4 [97]. More intriguingly, Tian and colleagues have recently investigated the effects of As4S4 on RA-resistant human APL NB4-R1 cells and found that treatment with As4S4 induced apoptosis in cells through the downregulation of expression of the SET gene, which is a natural inhibitor for protein phosphatase 2 (PP2A), a pro-apoptotic protein [93]. They further demonstrated that the addition of As4S4 strengthened the SET RNAi-induced upregulation of PP2A and the downregulation of PML-RARα, suggesting that As4S4 induces apoptosis through the downregulation of the SET protein expression, which, in turn, increases PP2A expression and reduces PML-RARα expression, consequently leading to the apoptosis of NB4-R1 cells [93].
An extensive body of literature has clearly demonstrated superiority in treating APL simultaneously with ATO and ATRA [4–6, 61, 98]. It has been demonstrated that ATRA synergizes ATO activity to provide superior efficacy of combination therapy in patients by promoting the effects of ATO on several signaling pathways such as apoptosis induction, differentiation, as well as the degradation of PML-RARα [4–6]. In this regard, we have recently investigated the effects of ATO, ATRA, and the granulocyte colony-stimulating factor (G-CSF), alone or in combination, on the APL cell line HT93A by focusing on differentiation, growth inhibition, as well as arsenic uptake [87]. Our experimental data demonstrated that ATRA induced greater differentiation in cells than ATO and that G-CSF promoted differentiation-inducing activities of both ATO and ATRA [87]. Similar to a previous report showing that ATRA induced aquaporin-9 (AQP-9), which is a member of the aquaporin superfamily and proposed to be responsible for arsenic uptake [99–101], in HL-60 cells, we also demonstrated that ATRA induced AQP9 expression in a time- and dose-dependent manner in HT93A cells [87]. However, probably due to its cytotoxicity, treatment with 1 μM ATRA decreased arsenic uptake compared with the control subject. Interestingly, the addition of G-CSF recovered the reduced arsenic uptake to the same level as that in controls by increasing the number of viable cells, although G-CSF itself did not affect the expression levels of AQP9 [87]. Collectively, our results indicate that G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO but also makes APL cells vulnerable to increased arsenic uptake, providing new insight into combination therapy using these three agents for the treatment of APL.
Since HDACs play a key role in the transcriptional regulation and pathogenesis of cancer [102, 103], its inhibitors (HDACi) are currently being developed for the therapy of several types of cancer, including leukemia [104]. Furthermore, aberrant recruitment of HDACs through the expression of PML-RARα has been implicated as an initiating tumorigenic event in APL [5–7]. Based on these previous findings, we hypothesized that treatment with ATRA in combination with HDACi could provide therapeutic benefit for patients with APL. In this regard, we investigated the effects of ATRA and valproic acid (VPA), alone and in combination, on the NB4 cells in view of differentiation induction and growth inhibition [105], since VPA is a member of class I HDACi and has shown potential anti-leukemic activities either alone or in combination with other anti-leukemic agents [102, 103, 106, 107]. In this study, we demonstrated that not only ATRA but also VPA induced differentiation in NB4 cells, and their combination further augmented the differentiation activity [105]. We further demonstrated that the upregulation of transcription factors, including CCAAT/enhancer-binding proteins (CEBPα, β, ε) and PU.1, which are known to be critical factors for normal myelopoiesis, granulocytic maturation, and being repressed in APL, concurred with the differentiation induction [105]. Given the importance of CEBPs and PU.1 in myeloid development, our results thus suggest that restoration of the normal function of the myeloid cell transcriptional machinery is a major molecular mechanism underlying the differentiation induction in NB4 cells [105]. It has been suggested that ATO/ATRA degrades the PML-RARα oncoprotein, resulting in the eradication of leukemia-initiating cells [108, 109]. Therefore, as a new therapeutic approach, a multi-target therapy based on a combination of ATRA, ATO, and VPA would be useful and worth evaluating further for its beneficial clinical effects.
Although advances in science and technology have replaced raw herbs and/or herbal compounds with powerful synthetic drugs, including molecular target-based drugs, in cancer therapy, the issue of concern is still resistance, disease relapse, and side effects of drugs in a clinical setting. In the case of arsenic compounds, side effects such as white blood cell count, QT prolongation, as well as liver dysfunction are still a serious concern and limit further clinical application, although the remarkable clinical efficacy of arsenic compound-based regimens against APL has been reported [4, 16]. Therefore, application of new arsenic-based therapies may require the generation of sensitizing strategies for improving the efficacy of arsenic compounds as well as minimizing their side effects. In order to optimize and/or maximize future clinical applications of arsenic compounds in patients with leukemia or even other malignancies, including solid tumors, combination therapy has attracted considerable interest as new therapeutic strategies. In this regard, we have been interested in the effects of naturally derived substances such as flavonoids on different kinds of cancerous cells, including leukemic cells [110–115]. Of these, Vitex, an extract from the ripe fruit of Vitex agnus-castus, has attracted great attention [112, 113, 115, 116]. We have investigated the effects of Vitex and its major component, casticin (Figure 2), on leukemia cell lines, HL-60 and U-937, and found that HL-60 cells were more sensitive to the cytotoxicity of Vitex/casticin compared with U-937 cells [112]. Furthermore, compared with unstimulated HL-60 cells, phorbol 12-myristate 13-acetate (PMA)- and 1,25-dihydroxyvitamin D3 (VD3)-differentiated HL-60 cells acquired resistance to Vitex/casticin. Based on the observation that the HL-60 cell line is more immature than the U-937 cell line, our results suggest that the levels of cytotoxicity of Vitex/casticin were largely attributed to the degree of differentiation of leukemia cells; that is, cell lines with less differentiated phenotype were more susceptible than the differentiated ones [112]. More importantly, much less cytotoxicity was observed in peripheral blood mononuclear cells (PBMNCs) from healthy volunteers when treated with concentrations of Vitex/casticin showing significant cytotoxicity in both leukemic cell lines [112]. Since recent studies have demonstrated that less differentiated cancer cells, referred to as leukemia stem cells (LSCs), acquired limitless self-renewal through oncogenic transformation and that the incomplete eradication of primary LSCs is closely linked to chemotherapy resistance and consequently contribute to eventual disease relapse [117], our findings thus provide fundamental insight into the clinical application of Vitex/casticin for hematopoietic malignancy in combination with arsenic compounds. We further demonstrated [113, 114] that Vitex/casticin-triggered cytotoxicity in HL-60 cells was implicated in histone H3 phosphorylation through the activation of the p38 MAPK pathway, which is a common signaling pathway involved in the mechanism underlying the cytocidal effects of arsenic compounds [4, 6, 16]. These findings suggest that Vitex/casticin could be promising candidates of adjunct therapeutic reagents for leukemia patients.
Chemical structures of casticin and delphinidin.
Delphinidin (Figure 2), a major anthocyanidin known to be present in pigmented fruits and vegetables, such as pomegranate, berries, dark grapes, eggplant, and red onion, is a diphenylpropane-based polyphenolic ring structure that carries a positive charge in its central ring [118]. Delphinidin has been gaining considerable attention, as it appears to possess a strong antioxidant/oxidant property as well as other potentially beneficial traits, such as anti-inflammatory, antimutagenesis, and antiangiogenesis activities [119, 120]. Furthermore, delphinidin and its glycosides have been demonstrated to trigger apoptosis in HL-60 cells through a ROS/JNK-mediated mitochondrial death pathway [121, 122]. We have recently demonstrated that delphinidin exhibited a dose- and time-dependent cytotoxic effect against NB4 cells, in which intrinsic/extrinsic pathway-mediated apoptosis, but not cell cycle arrest, was involved (Yuan et al, submitted). We further demonstrated that delphinidin exerted more potent cytotoxicity against NB4 cells than normal PBMNCs and that delphinidin in combination with arsenite achieved an enhanced cytocidal effect against NB4 cells, but lesser on PBMNCs (Yuan et al, submitted). These results suggest that delphinidin selectively sensitizes NB4 cells to arsenite, resulting in an enhancement of arsenite cytotoxicity by strengthening intrinsic/extrinsic pathway-mediated apoptosis induction. Our observations may offer a rationale for the use of delphinidin to improve the clinical efficacy of arsenite.
Intriguingly, it has been revealed that flavonoids can inhibit the function of ATP-binding cassette transporters such as multidrug-resistance-associated proteins (MRPs) as well as P-glycoprotein (P-gp) [123, 124], which are known to be responsible for the efflux of arsenic and may consequently contribute to resistance to arsenic therapy [4, 125, 126]. In addition, we have recently demonstrated [101] that MRP2 and AQP9, which belongs to the aquaporin superfamily and is closely associated with arsenic uptake, contribute to the differential sensitivity of primary human-derived normal cells to arsenite using a unique
In traditional medicines, including TCM, formulae consisting of more than one active ingredients are actually much more frequently used, aiming to act on more than one pharmacological targets and thus exerting synergistic therapeutic effects. One of the most successful models is the realgar–indigo naturalis formula (RIF), in which arsenic sulfide (A), indirubin (I), and tanshinone IIA (T) are three major components, and has been found effective against APL in China [16]. In this regard, Wang and colleagues performed the dissection of mechanisms of RIF using an APL murine model and APL cells, including NB4, NB4-R2 (ATRA-resistant NB4-derived cell lines), and primary leukemic cells from APL patients [129]. Their results not only indicated the functions of each component, e.g., A acted as a principal component, whereas I and T served as adjuvant ones, but also demonstrated the generation of expected synergistic effects in view of prolongation of the life span of treated mice, the efficiency of terminal differentiation induction, and the upregulation of APQ9 expression associated with increment in intracellular arsenic accumulation, without apparent severe side effects [129]. This study provides new insight into exploring the value of traditional formulae on a larger scale and helping to bridge Western and Eastern medicines in the era of systems biology. Besides, we also focused on the effects of products derived from the human body, such as progesterone (Pg), and demonstrated that Pg induced a dose- and time-dependent cell growth inhibition in A3 and I9.2 cells, both of which are subclones of a T-cell-derived leukemic Jurkat cell line [130]. We further suggested that growth suppression accompanied with the induction of apoptosis by Pg in these cells was mediated through the mitochondrial membrane disruption, followed by the activation of the caspase cascade [130]. These results provide a novel insight into Pg actions toward its use for clinical application in patients with lymphocytic T-cell leukemia and raise the possibility of combination with arsenic compounds.
A striking global
This work was supported in part by grants to Bo Yuan from the Japan–China Medical Association.
Atrioventricular septal defects are a group of malformations involving the atrioventricular (AV) septum and common atrioventricular junction (Figure 1). Previously, referred to as atrioventricular canal or endocardial cushion defects, is now called AV septal defect (AVSD). For the purpose of this chapter, we will use the term AV septal defects. They are divided into complete, partial and variations of both of them based on the orifices and septal communications which will be discussed in detail in this chapter.
Atrioventricular septum in the normal heart. The atrioventricular septum (AVS) lies between the right atrium (RA) and the left ventricle (LV). LA, left atrium; RV, right ventricle; MV, mitral valve; TV, tricuspid valve. “From: Cetta F, Truong D, Minich LL, Maleszewski JJ, O’Leary PW, Dearani JA & Burkhart HM. Chapter 29: Atrioventricular Septal Defects. In: Allen HD, editor. Moss & Adams’ Heart Disease in Infants, Children, and Adolescents, Including the Fetus and Young Adult, 9th Edition. Philadelphia: Lippincott Williams & Wilkins, 2016; used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.”
Congenital heart disease (CHD) accounts for around 1–1.2% of live births both in the United States and globally [1, 2]. AVSDs account for around 4–5% of all CHDs, with 5.38 cases per 10,000 live births, an increase from prior reports [1, 3]. It is the most common fetal cardiac anomaly detected on prenatal screening (Figure 2). Around half of the patients with AVSD have Down syndrome. However, approximately 45% of CHD patients with Down syndrome have AVSD [4, 5]. Most of these cases are isolated, although some may have pulmonary stenosis or atresia. There is an association with other anomalies like heterotaxy and Ellis-Van Creveld syndrome [6].
Fetal echocardiogram four-chamber view: Complete AVSD. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle. *Primum atrial septal defect and inlet ventricular septal defect.
In a normal heart, tricuspid and mitral valve annuli are positioned at different levels because of the atrioventricular septum. In AV septal defects, tricuspid valve annulus is located more apically in relation to mitral valve. The portion of the offset between tricuspid and mitral valve is the location of atrioventricular septum. It has overlapping atrial and ventricular walls [7]. Aortic valve is located anterior and superior between tricuspid and mitral valve, what is referred to as wedged between these valves. This makes the subaortic outflow region placed in between tricuspid and mitral valves. The papillary muscles in the left ventricle are located antero-superior and postero-inferior region. Another feature of importance to this topic, the distance from mitral valve to apex of left ventricle is same as the distance from left ventricular apex to aortic valve (Figure 3).
2D echocardiogram parasternal long axis view: A. In normal cardiac anatomy, distance from the mitral valve to left ventricular (LV) apex and from LV apex to aortic valve is same. B. In AVSD, LVOT is elongated and distance from LV apex to left AV valve annulus is shorter. LA, left atrium; RV, right ventricle; Ao, aorta.
In patients with AV septal defect, the fundamental abnormality is absence of the atrioventricular septum or having a common atrioventricular junction. This results in a cascade of features that are different from normal hearts. The common features shared by all forms of atrioventricular septal defects are:
Presence of common atrioventricular valve
Elongation of the left ventricular outflow tract
Clockwise rotation of papillary muscles
Cleft in the left AV valve
There are two major types of AV septal defects: complete and partial AVSDs. Two sub-types are described: intermediate and transitional, which are variations of complete and partial AV septal defects, respectively (Figure 4). It is preferable to describe the features of these subtypes rather than identifying them as an entity. Different combinations of shunting across atria and ventricles could happen based on the attachments and relationship of the bridging leaflets to septal structures. In general, we would see ostium primum defect and ventricular septal defect (VSD). If the bridging leaflets are attached to the atrial septum, there could be only a ventricular level shunt (Figure 5). When the bridging leaflets are attached to the crest of ventricular septum, it results in an atrial level shunt with an ostium primum defect. In rare instances, where the bridging leaflets close the septal defect(s), we will still see features of the common atrioventricular valve [8, 9, 10]. Complete AVSDs are classified further into three types based on the morphology of anterior bridging leaflet and is named after Giancarlo Rastelli who made significant contributions in his short career and life span:
Type A: In this type, anterior bridging leaflet (ABL) is divided and attached to the crest of the interventricular septum. It is the most common defect and is associated with Down syndrome.
Type B: ABL is partly divided and is not attached to the crest of the septum. Chordae attach usually to papillary muscle in the right ventricle (RV), on the septal surface. It is the least common of all types.
Type C: ABL is not attached or divided and is termed “free-floating”. There are chordal attachments to RV free wall. This type is seen in Down syndrome patients with Tetralogy of Fallot; double outlet right ventricle, complete transposition of the great arteries, and heterotaxy syndromes.
Summary of AVSD. Anatomic and physiologic similarities between the different forms of atrioventricular septal defect (AVSD) are illustrated. Complete AVSDs have one orifice with large interatrial and interventricular communications. Intermediate defects (two orifices) are a subtype of complete AVSD. Complete AVSDs have physiology of VSDs and atrial septal defects (ASDs). In contrast, partial AVSDs have physiology of ASDs. Transitional defects are a form of partial AVSD in which a small inlet VSD is present or the ventricular level shunt has been obliterated by chordal tissue. Partial AVSDs and the intermediate form of complete AVSD share a similar anatomic feature: A tongue of tissue divides the common atrioventricular valve into distinct right and left orifices. LA, left atrium; LPV, left pulmonary vein; LV, left ventricle; RA, right atrium; RPV, right pulmonary vein; RV, right ventricle. “From: Cetta F, Truong D, Minich LL, Maleszewski JJ, O’Leary PW, Dearani JA & Burkhart HM. Chapter 29: Atrioventricular Septal Defects. In: Allen HD, editor. Moss & Adams’ Heart Disease in Infants, Children, and Adolescents, Including the Fetus and Young Adult, 9th Edition. Philadelphia: Lippincott Williams & Wilkins, 2016; used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.”
2D echocardiogram apical four-chamber view: A rare form of AVSD with large inlet ventricular septal defect (*) without a primum atrial septal defect. Note that AV valves are at same level. RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.
In normal hearts, mitral valve has two leaflets, anterior and posterior with a zone of opposition in one plane. In hearts with AV septal defects, the left AV valve closes in tri-foliate fashion with zones of opposition between posterior, superior and inferior bridging leaflets. This characteristic feature of the left AV valve in AV septal defects will never achieve a mitral valve as in normal hearts. Usually, jet of LAVV cleft is directed to the ventricular septum when compared to isolated mitral valve clefts which are directed anteriorly towards the aortic valve [11]. Rarely, a fusion of the leaflets within the left AV valve (bridging and posterior leaflet) would lead to a double orifice valve. The combined area of the double orifice valve is always less than the single left AV valve area.
As described earlier, LVOT is wedged anteriorly and is narrow when compared to the aortic valve, irrespective of the type of AV septal defect. In partial form, where the superior bridging leaflet is attached to the crest of the septum, it is markedly narrow (Figure 6). This abnormality has been described as goose-neck deformity.
A. Diagram in a normal heart showing aortic valve (AoV) wedged between tricuspid valve (TV) and mitral valve (MV). B. In AVSD, aorta is not wedged between these valves, termed “sprung aortic valve”. PV, pulmonary valve; RAVV/LAVV, right and left atrioventricular valve. A. by Dr. Johannes Sobotta - Sobotta's atlas and text-book of human anatomy 1906, public domain,
Depending on the overall flow from the atrioventricular orifices to respective ventricles, the chambers are usually the same size which is termed as ‘balanced AVSD’. When a common AV valve opens more into the right ventricle or to the left ventricle, it would cause decreased growth of the contralateral ventricle and its great artery, leading to the term ‘unbalanced AVSD’. In right ventricle dominant atrioventricular septal defect, left ventricle and aorta are hypoplastic depending on the amount of blood flow, but usually, the atrial and ventricular septal alignment is maintained. In left ventricular dominance, there will be hypoplasia of the right ventricle and pulmonary artery, typically with septal malalignment. This chamber dominance when it involves the atrium would give rise to double outlet atrium (Figure 7).
2D echocardiogram showing right ventricle (RV) dominant AVSD with severely hypoplastic left AV valve and ventricle (LV). Moderately dilated right atrium (RA) and RV with large primum ASD. LA, left atrium.
In partial atrioventricular septal defects, the most common associated malformation includes secundum ASD, patent ductus arteriosus and persistent left superior vena cava to coronary sinus [12].
Tetralogy of Fallot with pulmonary stenosis is found in one-tenth of the patients with common atrioventricular septal defect and in these patients, Rastelli type C is common. Among others, common atrium, double outlet right atrium, double inlet ventricle with discordant ventriculoarterial connections can be seen.
In normal hearts, AV node is located in the triangle of Koch which is formed by Tendon of Todaro, coronary sinus ostium and septal leaflet of the tricuspid valve [13, 14, 15]. In patients with AVSDs, because of deficient AV septum, the atria will meet the ventricle at the crux of the heart, shifting the AV node more posteriorly and inferiorly.
In the past, failure of the fusion of endocardial cushions was thought to be the only reason for AV septal defects [16]. It could be the first step in the formation of these hearts, but not in entirety. Delamination of valve leaflets occurs late in development, with its formation occurring by undermining of the ventricular myocardium [17]. When the endocardial cushions fail to meet, subaortic outflow tract will not be normally wedged and there will be abnormal development of ventricular mass. Additionally, mesenchymal tissues surrounding the primum ostial foramen play a role in these defects [18, 19].
In patients with complete AVSD, there is one common AV valve with large atrial and inlet VSD (Figure 8). In intermediate form, there are two AV valve orifices, which are formed by a tongue of tissue between superior and inferior bridging leaflets. It has similar physiology as the complete form with large ASD and VSD. In partial AV septal defects, where there are two AV valve orifices with the bridging leaflet attached to ventricular septal crest, giving rise to only interatrial communication (Figure 9A). In some instances, there could be communication at the ventricular level from the chordal attachments which is described as a transitional type (Figure 9B). In all forms of AV septal defects, the left AV valve invariably has a cleft. Rarely there will be no septal communications seen with other common features of AVSD [8].
2D echocardiogram apical 4-chamber view: Complete balanced AVSD. A. When AV valve is closed, there is large primum atrial septal defect (ASD, *) and large inlet ventricular septal defect (VSD, +). Common AV valve and single orifice. B. with valve open. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.
Transesophageal echocardiogram, four-chamber view. A. Partial AVSD with large primum atrial septal defect (ASD) (*). Note the valvar attachments to crest of the septum. B. Transitional AVSD with small primum ASD and inlet ventricular septal defect (+) covered by right AVV chordal attachments to the crest of ventricular septum. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.
Usually, patients with partial AV septal defect (also called primum ASD) remain asymptomatic until early childhood. They rarely present early with failure to thrive depending on the size of the defect and severity of AV valve regurgitation. Patients with primum ASDs usually present earlier and with symptoms when compared with secundum ASDs. Auscultatory findings include widely split and fixed second heart sound, crescendo- decrescendo systolic ejection murmur at the left upper sternal border from the increased flow across pulmonary valve, and holosystolic murmur at the apex from LAVV regurgitation. A mid-diastolic murmur may be heard at the apex if there is significant mitral regurgitation or at the left lower sternal border if there is a large atrial shunt.
Patients with complete AV septal defects present in the neonatal period after first few days/weeks of life when pulmonary vascular resistance falls. This is attributed to the large atrial and ventricular level shunts leading to pulmonary over circulation. There will be tachypnea, increased work of breathing, failure to gain weight. More often, they would require high-calorie nutrition, diuretics to decrease the preload. On exam, there will be accentuated first heart sound, with S1- coincident holosystolic murmur from LAVV regurgitation, widely split and fixed S2, crescendo- decrescendo systolic ejection murmur at the left upper sternal border from the increased flow across pulmonary valve and sometimes mid-diastolic murmur at apex.
As previously described, AV node is displaced posteriorly and inferiorly in these defects; this may result in prolongation of the PR interval. There will be a left superior deviation of the mean frontal plane vector. Biventricular hypertrophy is seen in complete and intermediate forms. Right ventricular hypertrophy is seen in the partial form. If there is moderate to severe mitral insufficiency, left ventricular hypertrophy may be seen. Other abnormalities which might be seen are prolongation of PR interval (Figure 10) [20].
12-lead EKG in patient with CAVSD showing left superior axis deviation and right ventricular hypertrophy.
Chest roentgenogram shows cardiomegaly with increased pulmonary vascular markings. Features of pulmonary edema may be seen in subjects with congestive heart failure.
Echocardiography is the primary diagnostic modality for the evaluation of atrioventricular septal AV defects [21]. Assessment of the ASD can be best done from a subcostal coronal and sagittal view. VSD could be best evaluated in the parasternal short axis. En-face view of the common AV valves is best achieved with a modified subcostal left anterior oblique view (Figure 11). This view also demonstrates the bridging leaflets, their attachments and helps with the Rastelli classification in patients with complete AVSDs. Subcostal short axis view would assess atrial or ventricular level unbalance. An Apical four-chamber view would augment the information on previously mentioned variables along with AV valve inflow and regurgitation. Overall, all the views complement each other to get comprehensive information, as in any other heart. Associated malformations like tetralogy of Fallot, coarctation, patent ductus arteriosus, arch sidedness should be evaluated using modified subcostal right anterior oblique/parasternal long axis and high parasternal/suprasternal views [22]. 3D echocardiography demonstrates a comprehensive and accurate assessment of the size and extent of the septal defects, size, number, and abnormalities of AV valve leaflets and their attachment sites, as well as the relation of the valvular structures to the great vessels [23]. Other findings such as double orifice left AV-valve, single papillary muscle should be evaluated.
Echocardiogam left anterior oblique (LAO) view. 1. Rastelli type a with attachments of the anterior/superior bridging leaflet (SBL) to crest of venticular septum; B. when valve is closed, notice the cleft in LAVV valve; C. Rastelli type C with “free floating” anterior bridging leaflet (<−>) and chordal attachments to right ventricular (RV) free wall (−>); D. 3D image showing tri-foliate cleft LAVV. IBL, inferior bridging leaflet; ML, mural leaflet; RAL, right anterior leaflet; RPL, right posterior leaflet; ML, left mural leaflet; LV, left ventricle.
In determining the balance of ventricles, a quantitative approach was proposed by Cohen et al. [24] using a subcostal sagittal view. In this view, they measured the area of AV valve over each ventricle and calculated a left/right ventricular ratio, also known as AV valve index (AVVI). Based on the index, patients were stratified either to single-ventricle or bi-ventricular repair pathways. Patients with an AVVI <0.67 and a large VSD would be considered for the single-ventricle pathway. This was modified to the left AV valve area/total area. An AVVI >0.6 is considered left ventricular dominant whereas AVVI <0.4 was considered right ventricular dominant. It is important after surgical repair to assess for residual defects, progressive LVOT obstruction, AVV stenosis and regurgitation, systolic function.
Cardiac catheterization is not frequently performed in AVSDs. However, it is helpful in assessing the hemodynamic information like the degree of shunting, pulmonary vascular resistance. One would see the characteristic “gooseneck appearance” from elongated LVOT on angiography. Patients with severely elevated PVR are poor candidates for full repair and may eventually be candidates for lung transplantation [25].
Cardiac computed tomography (CT) is particularly helpful to assess for any extracardiac defects or associated anomalies in these patients. Retrospective gated approach is useful for the evaluation of ventricular function and ventricular sizes, allows volumetric measurements, and also allows evaluation of ventricular function and wall motion. This may be of particular relevance in patients with hypoplastic ventricles and unbalanced AVSDs [26]. Cardiac magnetic resonance imaging (MRI) is an important tool to assess the degree of unbalance and guide for future surgical planning. These modalities have proven to decrease the amount of radiation exposure during cardiac catheterization [27].
Patients with complete defects present early with signs and symptoms of pulmonary over circulation such as tachypnea, increased work of breathing. In the neonatal period, when the pulmonary vascular resistance decreases, they require diuretics to help with pulmonary congestion and control heart failure along with optimizing nutrition. Occasionally they require afterload reducing agents if there is significant AV valve regurgitation and rarely inotropes. If heart failure or failure to thrive persists despite maximizing medical management, they would be referred for surgery. Based on the corrected gestational age, weight, type of atrioventricular septal defect and associated anomalies, surgical options vary which will be discussed below. As mentioned earlier, patients with partial atrioventricular septal defects usually show symptoms in childhood.
The goals of the surgery are to close the septal defect(s), repair the AV valve, construct two separate and competent AV valves, and avoid injury to conduction tissue.
Balanced atrioventricular septal defects
Surgical Palliation
Palliation with main pulmonary artery band (PAB) is performed in babies less than 5 Kg who failed medical management. In the recent era, complete repair is done even in this weight range. Palliation is considered in patients who are premature, those deemed ineligible for definitive repair or with other co-morbidities. A recent study showed that PAB in complete AVSDs as a bridge to biventricular repair has similar survival as those for primary biventricular repair [28].
Surgical Correction
Patients with complete AVSDs frequently require surgical repair in early infancy with a median age of 3.6 months at the time of repair [29]. Surgical repair is achieved by singe-patch, modified single-patch (Australian/Nunn) or two-patch techniques. A meta-analysis, which compared modified single-patch and two patch techniques showed no significant difference between two groups, but modified single-patch performed when there is small VSD had shorter cardiopulmonary bypass and aortic cross-clamp time [30]. Several other studies showed similar findings [31, 32, 33, 34, 35]. The main advantages of the two-patch technique are maintaining planar alignment of AV valves, lower chances of narrowing of LVOT, not compromising ventricular volumes and preserving the integrity of bridging leaflets [36]. In the Pediatric Heart Network (PHN) study, earlier complete repair showed increased resource utilization with longer intensive care unit stay but no association with incidence of residual VSD or significant left AV valve regurgitation at six months of age (Figure 12). Moderate or greater left AV valve regurgitation was found in 22% at six months with the strongest predictor being moderate or greater left AV valve regurgitation at one month [32]. In the majority of the cases, cleft was closed, 93% in this study [37], it was partially closed, or left open in remaining cases.
A, B: Intra-operative transesophageal echocardiogram, color compare deep transgastric view of left AV valve. A. Pre-operative image showing moderate regurgitation. B. Postoperative after left AVV repair. Note cleft is completely closed without any regurgitation. C. Transthoracic apical 4-chamber view of another patient with severe left AVV regurgitation in multiple jets.
Associated anomalies like patent ductus arteriosus, double orifice left AV valve parachute left AV valve should be addressed. Patients with complete AVSDs and tetralogy of Fallot associated with Down syndrome may need initial palliation with systemic to pulmonary artery shunt or right ventricular outflow tract (RVOT) stent placement and full repair at a later age. In a retrospective study [38], RVOT stenting showed a significant increase in median Z-score for both branch pulmonary arteries at a median follow-up of 255 days. Four patients out of 26 patients died during follow- up period, but none after the initial intervention. Another meta-analysis found no significant difference in the 6-year survival between staged palliation and primary repair, with higher rate of reintervention for RVOT who underwent staged repair [39].
In patients with partial and transitional AVSDs, there has been controversy regarding the age of surgical correction. A PHN study in 2010, showed good results at a median age of 1.8 years, with left AV valve regurgitation being most common and more frequently in children repaired after 4 years of age [12, 40, 41]. One patient out of 87 died in the hospital. Another review showed excellent results at median age of 1.5 years with LV outflow tract obstruction being most common reason for reoperation at their center [42]. Several other studies showed good long-term outcomes with 30-day and 5-, 10-, 20-, and 40-year survivals at 98%, 94%, 93%, 87%, and 76%, respectively. Approximately 3% of the patients in the Mayo group required permanent pacemaker [40, 41]. A minimally invasive right axillary approach has also been performed with good results in partial AVSD patients [43].
Unbalanced atrioventricular septal defects
Surgical techniques in patients with unbalanced AVSDs include single ventricle palliation, biventricular repair and 1.5 ventricular repair.
Single Ventricle Palliation
Patients with severely hypoplastic right/left ventricle would be managed using staged single ventricle palliation. Initially, they are palliated with PAB and later undergo bidirectional Glenn around four to six months of age, if the pulmonary artery pressures are favorable. Around 2 to 3 years of age, extracardiac Fontan completion with or without fenestration is performed [44].
One and half or bi-ventricular repair (BVR)
There are no clear selection criteria to stratify patients into either single or bi-ventricular pathways. Several factors are taken into consideration such as hypoplastic ventricle end-diastolic volume (EDV) of >30 mL/m2, normal ventricular function, adequate AV valve size and function, and low end-diastolic pressures on cardiac catheterization [45].
In select patients with right ventricular dominant AVSD, a staged left ventricular recruitment approach is considered, especially in patients with trisomy 21. It includes ASD closure or restriction, without VSD closure, septation of the common AV valve and banding of the main pulmonary artery [45, 46]. This strategy allows rehabilitation of the left ventricle. With this approach, patient would not be committed at an early age to either a single or bi-ventricular approach and it would give an opportunity to monitor for LV growth [45].
On the other hand, in patients with LV dominant AVSD with inadequate RV size, one and a half ventricular repair has been proposed with primary AVSD repair along with a bidirectional Glenn procedure [47]. This would allow growth of the hypoplastic right ventricle for future biventricular conversion. In some institutions, routine 3-D printing is done for all complex AVSD for pre-surgical planning which permitted biventricular repair in some patients who were previously deemed to be candidates for single ventricle palliation [48, 49].
Even though the outcomes for partial AVSDs are excellent, approximately 10–15% of patients require additional operations. It is well known that pre-operative left AV valve regurgitation predicts the post-operative severity of regurgitation. Other factors are severely dysplastic valve, failure to close the cleft, age of initial surgery, left AV valve stenosis and LVOT obstruction [41]. A technical performance score (TPS) was proposed to grade residual lesions after partial and transitional AVSD repair. In that study, left AV valve regurgitation was the strongest predictor of in-hospital outcomes and unplanned reinterventions after discharge [50]. When compared to complete AVSD, LVOT obstruction occurs more frequently after repair of partial AVSD. Several technical strategies were proposed to decrease the likelihood of subaortic stenosis [51, 52, 53].
In complete AVSDs, late reoperation occurs in around 11–20% of patients with most common reason being left AV valve regurgitation [54, 55]. In these studies, freedom from further reoperation after the first reoperation was 63%, 48%, and 42% at 5, 10, and 15 years, respectively. On later follow-up (median 10.7 years, maximum 30 years), actuarial overall survival was 91%, 91%, and 86% at 5, 10, and 15 years, respectively [55]. A recent study showed improved outcomes with overall survival at 10, 15 and 20 years was 91.7%, 90.7% and 88.7%, respectively and freedom from reoperation was 82.7%, 81.1% and 77%, respectively [56].
Around 36.5–66% of Down patients have pulmonary hypertension with congenital heart disease less than six months of age [5, 57]. There has been controversy about the extent of pulmonary vascular changes with Down and non-Down syndrome patients. There are studies which showed earlier development of pulmonary parenchymal hypoplasia and pulmonary vascular obstructive disease (PVOD) in this patient population [58, 59, 60]. In children with Down syndrome, Rastelli type A is most common. But when associated with tetralogy of Fallot, Rastelli type C is common. In unbalanced AVSDs, left ventricular dominance is more common [6]. It’s known that this patient population tolerates single ventricle physiology poorly [61]. Nevertheless, surgical outcomes are not different for biventricular repair when compared with non-Down syndrome patients. Survival at 30 years was 85.6% for complete AVSD, in patients with trisomy 21 [62].
AVSDs are a group of disorders with deficient AV septum and abnormal AV valve morphology. It is the most common defect in Down syndrome. The definitive surgical repair has excellent outcomes in balanced AVSDs. For unbalanced AVSDs, it is a complex decision-making process and their repairs are usually categorized to single, one and half or bi- ventricular repair. For a select subset of patients, ventricular recruitment procedures improve the candidacy for future bi-ventricular circulation. Patients with Down syndrome should have similar surgical strategies as that of non-Down syndrome patients. The most common reason for reoperation is left AV valve regurgitation.
The authors declare no conflict of interest.
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A crucial characteristic for this group of bacteria is that they can easily acquire mechanisms of antibiotic resistance for a plethora of antibiotics currently in use for human and animal therapies. Therefore, there is a great need to find novel, non-antibiotic chemotherapeutics with marked antistaphylococcal activity. Promising but still underestimated group of potential antistaphylococcal chemotherapeutics constitute bee products: honey, pollen, royal jelly, fermented pollen and especially propolis. Another group of natural products that exhibit promising antibacterial activity is essential oils. Usefulness of bee products and essential oils in the treatment of infections caused by S. aureus has been confirmed by results of many investigations carried out by researches in different regions of the world. In this chapter, we have presented the review of publication in this area as well as perspectives and limitations of future applications of these two groups of natural products.",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Piotr Szweda and Barbara Kot",authors:[{id:"117528",title:"Dr.",name:"Szweda",middleName:null,surname:"Piotr",slug:"szweda-piotr",fullName:"Szweda Piotr"},{id:"189685",title:"Associate Prof.",name:"Barbara",middleName:null,surname:"Kot",slug:"barbara-kot",fullName:"Barbara Kot"},{id:"195004",title:"Dr.",name:"Barbara",middleName:null,surname:"Kot",slug:"barbara-kot",fullName:"Barbara Kot"}]},{id:"52875",doi:"10.5772/65761",title:"Bacteriophage Therapy: An Alternative for the Treatment of Staphylococcus aureus Infections in Animals and Animal Models",slug:"bacteriophage-therapy-an-alternative-for-the-treatment-of-staphylococcus-aureus-infections-in-animal",totalDownloads:1996,totalCrossrefCites:4,totalDimensionsCites:7,abstract:"Staphylococcus aureus causes hospital-acquired (HA), community-acquired (CA) and companion animal and livestock-associated (LA) infections. Molecular epidemiology studies suggest that although host specificity may be associated with specific genetic lineages, recent human-to-animal and animal-to-human transmissions related to mobile genetic elements have been described. Gene transfers include virulence and antibiotic resistance genes, thus making it difficult to control multidrug resistance S. aureus infections. Bacteriophages (phages) and endolysins, the enzymes responsible for bacterial lysis by phages, are alternatives to the use of antibiotics for the control of S. aureus infections. In this work, we review current advances in the development of phage therapy and the study and design of recombinant endolysins to treat S. aureus infections. Preliminary results of bacteriophage isolation based on molecular epidemiology knowledge show that bacteriophages are specific of genetic lineages and that this strategy may be used as an approach to isolate and evaluate new bacteriophages for therapy.",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Claudia I. Barrera-Rivas, Norma A. Valle-Hurtado, Graciela M.\nGonzález-Lugo, Víctor M. Baizabal-Aguirre, Alejandro Bravo-Patiño,\nMarcos Cajero-Juárez and Juan J. Valdez-Alarcón",authors:[{id:"191123",title:"Dr.",name:"Juan José",middleName:null,surname:"Valdez-Alarcón",slug:"juan-jose-valdez-alarcon",fullName:"Juan José Valdez-Alarcón"},{id:"195005",title:"Mrs.",name:"Claudia Ibeth",middleName:null,surname:"Barrera-Rivas",slug:"claudia-ibeth-barrera-rivas",fullName:"Claudia Ibeth Barrera-Rivas"},{id:"195006",title:"MSc.",name:"Norma Anahí",middleName:null,surname:"Valle-Hurtado",slug:"norma-anahi-valle-hurtado",fullName:"Norma Anahí Valle-Hurtado"},{id:"195007",title:"MSc.",name:"Graciela M.",middleName:null,surname:"González-Lugo",slug:"graciela-m.-gonzalez-lugo",fullName:"Graciela M. González-Lugo"},{id:"195008",title:"Dr.",name:"Víctor Manuel",middleName:null,surname:"Baizabal-Aguirre",slug:"victor-manuel-baizabal-aguirre",fullName:"Víctor Manuel Baizabal-Aguirre"},{id:"195009",title:"Dr.",name:"Alejandro",middleName:null,surname:"Bravo-Patiño",slug:"alejandro-bravo-patino",fullName:"Alejandro Bravo-Patiño"},{id:"195010",title:"Dr.",name:"Marcos",middleName:null,surname:"Cajero-Juárez",slug:"marcos-cajero-juarez",fullName:"Marcos Cajero-Juárez"}]},{id:"53377",doi:"10.5772/66225",title:"Staphylococcus aureus Bacteremia in Adults",slug:"staphylococcus-aureus-bacteremia-in-adults",totalDownloads:2113,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Staphylococcus aureus is an important cause of bacteremia, and S. aureus bacteremia constitutes a serious condition with high morbidity and mortality, secondary to multiple complications including infective endocarditis and embolization. The incidence of bacteremia with S. aureus is increasing with more frequent use of medications that lower immune system response, and with the utilization of more invasive medical procedures. In addition, the emergence of resistant S. aureus isolates is becoming more common and can negatively affect the outcome of an individual if not diagnosed and managed properly. Health care workers encounter S. aureus bloodstream infections on a routine basis, and in certain situations, it becomes a very challenging infection to control. Because of the impact this entity has on health care costs and the increased use of resources, it is necessary to highlight the causes, clinical presentation, associated complications, and treatment measures. In this chapter, we will cover each of these points, with somewhat more emphasis on methicillin‐resistant S. aureus that is prevalent in both community and hospital settings and is more commonly associated with worsening prognosis and higher mortality.",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Dima Youssef and Kate Molony",authors:[{id:"190397",title:"Dr.",name:"Dima",middleName:null,surname:"Youssef",slug:"dima-youssef",fullName:"Dima Youssef"},{id:"195814",title:"Dr.",name:"Kate",middleName:null,surname:"Molony",slug:"kate-molony",fullName:"Kate Molony"}]}],mostDownloadedChaptersLast30Days:[{id:"54154",title:"Staphylococcus aureus: Overview of Bacteriology, Clinical Diseases, Epidemiology, Antibiotic Resistance and Therapeutic Approach",slug:"staphylococcus-aureus-overview-of-bacteriology-clinical-diseases-epidemiology-antibiotic-resistance-",totalDownloads:7218,totalCrossrefCites:14,totalDimensionsCites:27,abstract:"Staphylococcus aureus is an important human pathogen that causes wide range of infectious conditions both in nosocomial and community settings. The Gram-positive pathogen is armed with battery of virulence factors that facilitate to establish infections in the hosts. The organism is well known for its ability to acquire resistance to various antibiotic classes. The emergence and spread of methicillin-resistant S. aureus (MRSA) strains which are often multi-drug resistant in hospitals and subsequently in community resulted in significant mortality and morbidity. The epidemiology of MRSA has been evolving since its initial outbreak which necessitates a comprehensive medical approach to tackle this pathogen. Vancomycin has been the drug of choice for years but its utility was challenged by the emergence of resistance. In the last 10 years or so, newer anti-MRSA antibiotics were approved for clinical use. However, being notorious for developing antibiotic resistance, there is a continuous need for exploring novel anti-MRSA agents from various sources including plants and evaluation of non-antibiotic approaches.",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Arumugam Gnanamani, Periasamy Hariharan and Maneesh Paul-\nSatyaseela",authors:[{id:"192829",title:"Dr.",name:"Arumugam",middleName:null,surname:"Gnanamani",slug:"arumugam-gnanamani",fullName:"Arumugam Gnanamani"},{id:"204388",title:"Dr.",name:"Periasamy",middleName:null,surname:"Hariharan",slug:"periasamy-hariharan",fullName:"Periasamy Hariharan"},{id:"204389",title:"Dr.",name:"Maneesh",middleName:null,surname:"Paul-Satyaseela",slug:"maneesh-paul-satyaseela",fullName:"Maneesh Paul-Satyaseela"}]},{id:"53377",title:"Staphylococcus aureus Bacteremia in Adults",slug:"staphylococcus-aureus-bacteremia-in-adults",totalDownloads:2115,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Staphylococcus aureus is an important cause of bacteremia, and S. aureus bacteremia constitutes a serious condition with high morbidity and mortality, secondary to multiple complications including infective endocarditis and embolization. The incidence of bacteremia with S. aureus is increasing with more frequent use of medications that lower immune system response, and with the utilization of more invasive medical procedures. In addition, the emergence of resistant S. aureus isolates is becoming more common and can negatively affect the outcome of an individual if not diagnosed and managed properly. Health care workers encounter S. aureus bloodstream infections on a routine basis, and in certain situations, it becomes a very challenging infection to control. Because of the impact this entity has on health care costs and the increased use of resources, it is necessary to highlight the causes, clinical presentation, associated complications, and treatment measures. In this chapter, we will cover each of these points, with somewhat more emphasis on methicillin‐resistant S. aureus that is prevalent in both community and hospital settings and is more commonly associated with worsening prognosis and higher mortality.",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Dima Youssef and Kate Molony",authors:[{id:"190397",title:"Dr.",name:"Dima",middleName:null,surname:"Youssef",slug:"dima-youssef",fullName:"Dima Youssef"},{id:"195814",title:"Dr.",name:"Kate",middleName:null,surname:"Molony",slug:"kate-molony",fullName:"Kate Molony"}]},{id:"55253",title:"Clostridium difficile Infection Diagnosis by Biological Molecular Methods",slug:"clostridium-difficile-infection-diagnosis-by-biological-molecular-methods",totalDownloads:2001,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In the past 15 years, the incidence of Clostridium difficile infection has emerged especially because of the new highly virulent strains. The classical diagnosis methods used to diagnose C. difficile infection take time and the enzyme immunoassay (EIA) test has demonstrated the lack of sensitivity. Even though new modern molecular methods have become available, the diagnosis of C. difficile in patients or healthy carriers remains a big challenge for both clinicians and laboratory staff. In the present chapter, we will list the main genotyping methods, stressing their advantages and disadvantages, as well. A brief presentation of the most useful kit (principle, sensitivity, specificity, benefits and disadvantages) to assess the impact of molecular methods in comparison with classical methods will offer support for future research in the present context of an increasing prevalence of C. difficile infection that represents worldwide, a real public health problem. To improve the patients’ quality of life, to limit hospital transmission, and to save money, we have tried to identify the best diagnosis algorithm as tool in C. difficile diagnosis and surveillance. This algorithm may differ depending on the capacities of the laboratories and on the socioeconomic level of the countries in question.",book:{id:"5831",slug:"clostridium-difficile-a-comprehensive-overview",title:"Clostridium Difficile",fullTitle:"Clostridium Difficile - A Comprehensive Overview"},signatures:"Luminiţa Smaranda Iancu, Andrei Florin Cârlan and Ramona\nGabriela Ursu",authors:[{id:"197809",title:"Prof.",name:"Luminiţa Smaranda",middleName:null,surname:"Iancu",slug:"luminita-smaranda-iancu",fullName:"Luminiţa Smaranda Iancu"},{id:"205531",title:"Dr.",name:"Andrei",middleName:null,surname:"Cârlan",slug:"andrei-carlan",fullName:"Andrei Cârlan"},{id:"205532",title:"Dr.",name:"Ramona Gabriela",middleName:null,surname:"Ursu",slug:"ramona-gabriela-ursu",fullName:"Ramona Gabriela Ursu"}]},{id:"53782",title:"Methicillin-Resistant Staphylococcus aureus (MRSA) in Food- Producing and Companion Animals and Food Products",slug:"methicillin-resistant-staphylococcus-aureus-mrsa-in-food-producing-and-companion-animals-and-food-pr",totalDownloads:2765,totalCrossrefCites:8,totalDimensionsCites:16,abstract:"Methicillin-resistant Staphylococcus aureus (MRSA) has become a growing concern in companion and food-producing animals. The presence of multidrug-resistance with a wide range of extracellular enterotoxin genes, virulence factors, and Panton-Valentine leukocidin (pvl) cytotoxin genes confer life-threatening traits on MRSA and makes them highly pathogenic and difficult to treat. Clonal complex 398 (CC398), a predominant clonal lineage of livestock-associated-MRSA in domestic animals and retail meat, is capable of infecting humans. In order to monitor and prevent MRSA contamination, it is critical to understand its source and transmission dynamics. In this review, we describe MRSA in food-producing animals (pig, cattle, chicken), horses, pet animals (dogs, cats), and food products (pork, beef, chicken, milk, and fish).",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Jungwhan Chon, Kidon Sung and Saeed Khan",authors:[{id:"189634",title:"Dr.",name:"Kidon",middleName:null,surname:"Sung",slug:"kidon-sung",fullName:"Kidon Sung"},{id:"190400",title:"Dr.",name:"Jungwhan",middleName:null,surname:"Chon",slug:"jungwhan-chon",fullName:"Jungwhan Chon"},{id:"190401",title:"Dr.",name:"Saeed",middleName:null,surname:"Khan",slug:"saeed-khan",fullName:"Saeed Khan"}]},{id:"55751",title:"Overview of Clostridium difficile Infection: Life Cycle, Epidemiology, Antimicrobial Resistance and Treatment",slug:"overview-of-clostridium-difficile-infection-life-cycle-epidemiology-antimicrobial-resistance-and-tre",totalDownloads:2759,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"The use of antimicrobial agents and acquired resistances explains in part the emergence and spreading of epidemic strains of Clostridium difficile. Continued use of antimicrobial therapy still represents an acute danger in triggering the emergence and spreading of new resistant and multiresistant strains including against first-line antibiotics. We examine the pathway of peptidoglycan synthesis in this organism and associated resistances, as well as resistance to other classes of antibiotics. The life cycle of C. difficile involves growth, spore formation and germination. Spores endow the organism with a formidable capacity of persistence in the environment and in the host, resistance, dissemination and infectious potential. Highly resistant spores produced by antibiotic-resistant/multiresistant strains may be one of the most serious challenges we face in what concerns the containment of C. difficile. Finally, we review recent developments in the treatment and prevention of C. difficile infection.",book:{id:"5831",slug:"clostridium-difficile-a-comprehensive-overview",title:"Clostridium Difficile",fullTitle:"Clostridium Difficile - A Comprehensive Overview"},signatures:"Joana Isidro, Aristides L. Mendes, Mónica Serrano, Adriano O.\nHenriques and Mónica Oleastro",authors:[{id:"164933",title:"Prof.",name:"Mónica Alexandra",middleName:null,surname:"Sousa Oleastro",slug:"monica-alexandra-sousa-oleastro",fullName:"Mónica Alexandra Sousa Oleastro"},{id:"200015",title:"Dr.",name:"Joana",middleName:null,surname:"Isidro",slug:"joana-isidro",fullName:"Joana Isidro"},{id:"200016",title:"MSc.",name:"Aristides",middleName:null,surname:"Mendes",slug:"aristides-mendes",fullName:"Aristides Mendes"},{id:"200017",title:"Prof.",name:"Mónica",middleName:null,surname:"Serrano",slug:"monica-serrano",fullName:"Mónica Serrano"},{id:"200019",title:"Prof.",name:"Adriano",middleName:null,surname:"Henriques",slug:"adriano-henriques",fullName:"Adriano Henriques"}]}],onlineFirstChaptersFilter:{topicId:"906",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:107,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:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,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:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,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:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. 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He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. 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She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education. She also has the experience of participating in five Erasmus+ projects.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorThree:null},{id:"90",title:"Human Development",coverUrl:"https://cdn.intechopen.com/series_topics/covers/90.jpg",isOpenForSubmission:!0,annualVolume:11974,editor:{id:"191040",title:"Dr.",name:"Tal",middleName:null,surname:"Dotan Ben-Soussan",slug:"tal-dotan-ben-soussan",fullName:"Tal Dotan Ben-Soussan",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBf1QAG/Profile_Picture_2022-03-18T07:56:11.jpg",biography:"Tal Dotan Ben-Soussan, Ph.D., is the director of the Research Institute for Neuroscience, Education and Didactics (RINED) – Paoletti Foundation. Ben-Soussan leads international studies on training and neuroplasticity from neurophysiological and psychobiological perspectives. As a neuroscientist and bio-psychologist, she has published numerous articles on neuroplasticity, movement and meditation. She acts as an editor and reviewer in several renowned journals and coordinates international conferences integrating theoretical, methodological and practical approaches on various topics, such as silence, logics and neuro-education. She lives in Assisi, Italy.",institutionString:"Research Institute for Neuroscience, Education and Didactics, Patrizio Paoletti Foundation",institution:null},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:9,paginationItems:[{id:"82936",title:"Soil Degradation Processes Linked to Long-Term Forest-Type Damage",doi:"10.5772/intechopen.106390",signatures:"Pavel Samec, Aleš Kučera and Gabriela Tomášová",slug:"soil-degradation-processes-linked-to-long-term-forest-type-damage",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Forest Degradation Under Global Change",coverURL:"https://cdn.intechopen.com/books/images_new/11457.jpg",subseries:{id:"94",title:"Climate Change and Environmental Sustainability"}}},{id:"82777",title:"Sustainability and Social Investment: Community Microhydropower Systems in the Dominican Republic",doi:"10.5772/intechopen.105995",signatures:"Michela Izzo, Alberto Sánchez and Rafael Fonseca",slug:"sustainability-and-social-investment-community-microhydropower-systems-in-the-dominican-republic",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Globalization and Sustainability - Recent Advances, New Perspectives and Emerging Issues",coverURL:"https://cdn.intechopen.com/books/images_new/11476.jpg",subseries:{id:"91",title:"Sustainable Economy and Fair Society"}}},{id:"82387",title:"Kept Promises? 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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:"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:{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:"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.\r\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.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{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:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University 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:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul 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:"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:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. 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. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"23",type:"subseries",title:"Computational Neuroscience",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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