",isbn:"978-1-83881-119-8",printIsbn:"978-1-83881-118-1",pdfIsbn:"978-1-83881-120-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8bd4f03c89e63ef15984ee1b7f1485c4",bookSignature:"Prof. Andrew James Manning",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10407.jpg",keywords:"Hydrodynamics, Suspension/Saltation/Bedload, Numerical Modeling / CFD, Deposition, Flocculation, Sediment Types, Regional/Temporal Variability, Turbidity Currents, Dust Storms, Socio-Economic Effects, Contaminants, Storm / Severe Weather Effects",numberOfDownloads:205,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 27th 2020",dateEndSecondStepPublish:"September 11th 2020",dateEndThirdStepPublish:"November 10th 2020",dateEndFourthStepPublish:"January 29th 2021",dateEndFifthStepPublish:"March 30th 2021",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Manning is a highly published and world-renowned scientist in the field of depositional sedimentary flocculation processes.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"23008",title:"Prof.",name:"Andrew James",middleName:null,surname:"Manning",slug:"andrew-james-manning",fullName:"Andrew James Manning",profilePictureURL:"https://mts.intechopen.com/storage/users/23008/images/system/23008.jpeg",biography:"Professor Andrew J. Manning is a Principal Scientist (Rank Grade 9) in the Coasts & Oceans Group at HR Wallingford (UK) and has over 23 years of scientific research experience (in both industry and academia) examining natural turbulent flow dynamics, fine-grained sediment transport processes, and assessing how these interact, (including both field studies and controlled laboratory flume simulations). Andrew also lectures in Coastal & Shelf Physical Oceanography at the University of Plymouth (UK). Internationally, Andrew has been appointed Visiting / Guest / Adjunct Professor at five Universities (Hull, UK; Delaware, USA; Florida, USA; Stanford, USA; TU Delft, Netherlands), and is a highly published and world-renowned scientist in the field of depositional sedimentary flocculation processes. Andrew has contributed to more than 100 peer-reviewed publications in marine science, of which more than 60 have been published in international scientific journals, plus over 180 articles in refereed international conference proceedings, and currently has an H-index of 24. He supervises graduates, postgraduates and doctoral students focusing on a range of research topics in marine science. Andrew has led numerous research projects investigating sediment dynamics in aquatic environments around the world with locations including: estuaries, tidal lagoons, river deltas, salt marshes, intertidal, coastal waters, and shelf seas.",institutionString:"HR Wallingford",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"HR Wallingford",institutionURL:null,country:{name:"United Kingdom"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"10",title:"Earth and Planetary Sciences",slug:"earth-and-planetary-sciences"}],chapters:[{id:"74115",title:"Formulae of Sediment Transport in Unsteady Flows (Part 2)",slug:"formulae-of-sediment-transport-in-unsteady-flows-part-2",totalDownloads:91,totalCrossrefCites:0,authors:[{id:"75062",title:"Prof.",name:"Shu-Qing",surname:"Yang",slug:"shu-qing-yang",fullName:"Shu-Qing Yang"}]},{id:"74481",title:"Study of Water and Sediment Quality in the Bay of Dakhla, Morocco: Physico-Chemical Quality and Metallic Contamination",slug:"study-of-water-and-sediment-quality-in-the-bay-of-dakhla-morocco-physico-chemical-quality-and-metall",totalDownloads:20,totalCrossrefCites:0,authors:[null]},{id:"74483",title:"Activated Flooded Jets and Immiscible Layer Technology Help to Remove and Prevent the Formation of Bottom Sediments in the Oil Storage Tanks",slug:"activated-flooded-jets-and-immiscible-layer-technology-help-to-remove-and-prevent-the-formation-of-b",totalDownloads:95,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"304",title:"Sediment Transport in Aquatic Environments",subtitle:null,isOpenForSubmission:!1,hash:"0eb11af1d03ad494253c41e1d3c998e9",slug:"sediment-transport-in-aquatic-environments",bookSignature:"Andrew J. Manning",coverURL:"https://cdn.intechopen.com/books/images_new/304.jpg",editedByType:"Edited by",editors:[{id:"23008",title:"Prof.",name:"Andrew James",surname:"Manning",slug:"andrew-james-manning",fullName:"Andrew James Manning"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3100",title:"Sediment Transport",subtitle:"Processes and Their Modelling Applications",isOpenForSubmission:!1,hash:"a1aae9d236b0fa1150b6bc2a98fd0ce0",slug:"sediment-transport-processes-and-their-modelling-applications",bookSignature:"Andrew J. Manning",coverURL:"https://cdn.intechopen.com/books/images_new/3100.jpg",editedByType:"Edited by",editors:[{id:"23008",title:"Prof.",name:"Andrew James",surname:"Manning",slug:"andrew-james-manning",fullName:"Andrew James Manning"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5219",title:"Greenhouse Gases",subtitle:"Selected Case Studies",isOpenForSubmission:!1,hash:"edf0ad164729f5ce157c34f9978fcc61",slug:"greenhouse-gases-selected-case-studies",bookSignature:"Andrew J. Manning",coverURL:"https://cdn.intechopen.com/books/images_new/5219.jpg",editedByType:"Edited by",editors:[{id:"23008",title:"Prof.",name:"Andrew James",surname:"Manning",slug:"andrew-james-manning",fullName:"Andrew James Manning"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7746",title:"Lagoon Environments Around the World",subtitle:"A Scientific Perspective",isOpenForSubmission:!1,hash:"372053f50e624aa8f1e2269abb0a246d",slug:"lagoon-environments-around-the-world-a-scientific-perspective",bookSignature:"Andrew J. Manning",coverURL:"https://cdn.intechopen.com/books/images_new/7746.jpg",editedByType:"Edited by",editors:[{id:"23008",title:"Prof.",name:"Andrew James",surname:"Manning",slug:"andrew-james-manning",fullName:"Andrew James Manning"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5962",title:"Estuary",subtitle:null,isOpenForSubmission:!1,hash:"43058846a64b270e9167d478e966161a",slug:"estuary",bookSignature:"William Froneman",coverURL:"https://cdn.intechopen.com/books/images_new/5962.jpg",editedByType:"Edited by",editors:[{id:"109336",title:"Prof.",name:"William",surname:"Froneman",slug:"william-froneman",fullName:"William Froneman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"56527",title:"Studying Side Effects of Tyrosine Kinase Inhibitors in a Juvenile Rat Model with Focus on Skeletal Remodeling",doi:"10.5772/intechopen.70006",slug:"studying-side-effects-of-tyrosine-kinase-inhibitors-in-a-juvenile-rat-model-with-focus-on-skeletal-r",body:'
1. Introduction
The introduction of tyrosine kinase inhibitors (TKIs) for targeted treatment of chronic myeloid leukemia (CML) marked a paradigm shift in the field of hemato-oncology [1, 2]. However, soon after CML became most successfully treated cancer—first in adults and thereafter in children—it was learned that chronic exposure to TKIs impaired modeling of the osseous skeleton as an off-target effect [3]. This skeletal side effect resulted in impaired longitudinal growth in not outgrown minors [4, 5]. With regard to a potential lifelong necessity of TKI intake, children with CML differ from a typical patient with CML who is about 60 years old [6]. Thus, the rational of the research of TKIs’ off-target effects is to generate a clear picture of early and late sequelae of long-term drug intake.
On this background, the essential objective of this chapter is the description of a juvenile (still growing) rat model that allows a chronic administration of TKIs via the drinking water in order (i) to mimic osseous changes observed in humans, (ii) to further characterize and investigate the causative pathophysiologically mechanisms resulting in impaired bone growth, (iii) to test approaches in growing animals for ameliorating the off-target effect resulting in growth impairment, and (iv) to check further organs beside bone for long-term TKI toxicity.
In this chapter, sections describe i) the highly effective role that TKIs play in standardized attempts to operationally cure CML in adults as well as in children, ii) elucidate the role of the established juvenile male Wistar rat model to investigate with ease the skeletal changes at all developmental stages, and iii) focus on the administration of TKI via the drinking water over many weeks as an adequate and convenient way resulting in the achievement of therapeutic drug blood levels. TKI-induced changes in long bones, as well as vertebrae, can be investigated with dedicated small imaging devices while blood levels of bone turnover markers, growth hormone, and vitamin D metabolites can be followed at different stages of development. The results of these investigations as well as the derived hypothesis on the pathophysiological cascade, specifically how TKIs impair longitudinal bone growth, are in excellent agreement with clinical observations. In addition, the juvenile animal model is of value to monitor other long-term TKI side effects on the heart and fertility to generate an overall picture on all possible side effects.
2. Role of tyrosine kinase inhibitors in chronic myeloid leukemia treatment
The principal function of tyrosine kinases (TKs) involves the regulation of multicellular aspects of the organism. By transferring a γ-phosphate group from adenosine triphosphate (ATP) to the hydroxyl group of tyrosine residues on signal transduction molecules, cell-to-cell signals, including growth, differentiation, adhesion, motility, and death, are transmitted [7]. Around 90 TK genes have been identified in the human genome [8]. Based on kinase domain structure, 58 are of transmembrane receptor type and can be grouped into 20 subfamilies and 32 are of cytoplasmic non-receptor type which falls into 10 subfamilies [8, 9]. TK receptors play a role in either transmembranous or intracellular signal transduction as they act as relay points controlling intracellular signaling pathways. Non-receptor TKs exhibit no transmembrane protein domain and are located in the cytoplasm. Generally, they are involved in signaling downstream of the receptor TKs.
In humans, TKs have been demonstrated to play significant roles in the development of many malignant diseases like chronic myeloid leukemia (CML) [8]. CML results from a reciprocal chromosomal translocation involving the c-abl proto-oncogene 1 (ABL1) on chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22, thus forming the BCR-ABL1oncogene [10, 11]. This t(9; 22) translocation or Philadelphia chromosome (Ph+) is a characteristic cytogenetic abnormality seen in 95% of patients with CML and in 15–30% of adult patients with acute lymphoblastic leukemia (ALL) [12, 13]. The BCR-ABL1 oncogene codes for two forms of fusion transcripts: p190BCR-ABL1 and p210BCR-ABL1, which are constitutively highly activated and subsequently dysregulate intracellular signaling by enhancing proliferative capability and resistance to apoptosis of hematopoietic stem or progenitor cells, leading to a massive increase in myeloid cell numbers.
About 1–1.5/100,000 residents are diagnosed with CML every year with an age peak between 50 and 60 years [14], representing around 20% of all cases of leukemia in adulthood [15]. Concerning pediatric patients, the frequency of diagnosis is about 0.05–0.40/100,000 residents per year within the age of 0–18 years [16]. Thus, CML represents one of the rarest leukemic disorders in childhood and adolescent age, accounting for only 2–3% of all children suffering from leukemia [16]. In terms of morphological characteristics, childhood CML is not different from adult CML. However, it is a matter of an ongoing debate whether and to what extend molecular differences exist between CML diagnosed at childhood or older age [6]. For example, pediatric CML shows a breakpoint distribution in the BCR gene more similar to adult Ph+ ALL [17].
Still, as the BCR-ABL1 oncogene is the single molecular aberration causing the development of CML, specific TKIs like imatinib (Gleevec®, Novartis) have been developed to inhibit the BCR-ABL1 TK [19]. By achieving hematological and cytogenetic response in over 90% of the patients after a few months of imatinib treatment, imatinib has been very effective in inhibiting progression of CML (Figure 1) [1, 20, 21, 22, 23].
Figure 1.
Survival probabilities by year of diagnosis (1980–2013) of pediatric patients with CML in Germany [18].
However, some patients develop resistance to imatinib resulting in loss of treatment response or even leukemic relapse. Among other underlying mechanisms, BCR-ABL1 kinase domain mutations can cause varying degrees of drug insensitivity [24]. In order to counter these mechanisms, next generation TKIs have been developed like dasatinib (SPRYCEL®, Bristol-Myers-Squibb), nilotinib (Tasigna®, Novartis), bosutinib (BOSULIF®, Pfizer), and ponatinib (ICLUSIG®, Ariad Pharmaceuticals) with different affinities to the ATP-binding pocket of the BCR-ABL1 TK [25].
3. Imatinib as front-line treatment for pediatric CML
As imatinib has proven very effective in adult CML, its accelerated clinical approval was given in the year 2001 for adults with CML and without age restriction in 2003. In several studies, imatinib showed similar antileukemic efficacy in children compared to adults (Figure 1) [26, 27]. Typically, standard dose of imatinib (300 mg/m2) achieved a complete hematologic remission in 95% of the pediatric patients after 3 months, a complete cytogenetic remission in 80% after 12 months, and a major molecular remission (MR3.0 = 0.1 % ratio copy number of gene transcripts BCR-ABL1/control gene) in 60% after 18 months of treatment [16, 28].
Although imatinib acts relatively specifically against the dysregulated BCR-ABL1 TK, it is known that imatinib exerts off-target effects at therapeutic blood levels on other TKs (Table 1). The reason for this is the affinity of imatinib to the ATP-binding pocket of the kinase domain. This domain is a characteristic feature of many members of the kinome, including TKs (review of the human kinome: [29, 30], review structure of the TK: [8, 9]).
Tyrosine kinase
BCR-ABL1
c-abl
c-Kit
PDGF-Rα
PDGF-Rβ
c-FMS
IC50(µM)
0.25
0.19
0.15
0.10
0.39
1.42
Table 1.
Inhibitory effect of imatinib on selected TKs [31].
IC, inhibitory concentration.
Nevertheless, imatinib treatment is generally well tolerated, showing mostly mild side effects. Neutropenia, thrombocytopenia, and anemia occur in up to 45, 20, and 10% of patients, respectively, who are in the chronic phase of CML and receive standard dose imatinib [2]. Nonhematologic adverse effects include nausea, skin rashes, peripheral edemas, muscle cramps, and elevated liver transaminase levels [2].
Studies with imatinib in adult patients also showed disturbed bone metabolism as a specific side effect [3] comprising altered calcium metabolism as well as increased trabecular mineralization and increased bone density in stamp biopsies [32]. In children, imatinib therapy has been associated with severe longitudinal growth retardation [4, 5, 33, 34, 35, 36, 37, 38, 39, 40, 41] (Figure 2), but the detailed mechanism how imatinib interferes with bone metabolism and the final consequences are not fully understood.
Figure 2.
Growth failure in pediatric CML patients during imatinib treatment [4]. SDS: Standard deviation score. One hundred and two patients (54 male/48 female; median age 12 years, range: 1–18 years) at diagnosis of CML receiving imatinib as upfront treatment were enrolled retrospectively in the trial CML-PAED II during the period 02/2006 to 06/2014. Height standard deviation scores (SDS) were derived from WHO-AnthroPlus, version 1.04 software, a global growth-monitoring tool providing normal range values for the age cohorts from birth till 19 years. Eighty-one out of 102 patients fulfilled the criteria for continuous assessment of growth scheduled at 3- months intervals during imatinib exposure. Twenty-one patients were analyzed at intervals ≠ 3 months. Calculation: Δ SDS = SDSTKI therapy–SDSDiagnosis; data are shown as Whiskers box plot (median ± 5th/95th percentile).
Regardless the type of kinase, imatinib binds to all structurally accessible ATP-binding pockets. Accordingly, other membrane-bound and cytosolic TKs, e.g., c-abl, PDGF-R α/β, c-KIT, and c-FMS [31, 42, 43, 44], are inhibited which play a major role in bone remodeling. Underlying dynamic processes of the growing skeleton are subject to strict regulation/communication of bone formation and resorption and can be easily influenced by interfering factors. At present, it is not possible to study simultaneously these complex bone remodeling processes such as the interaction of bone forming osteoblasts and bone resorbing osteoclasts by culturing systems in vitro. Therefore, it is only possible to study bone breakdown, bone structure, changes in the mineral content, and the overall structure of the bone in vivo in appropriate juvenile animal models.
In addition, TKI treatment for CML is not curative in most patients. Although first results from stopping TKI trials in adult patients after achieving sustainable deep molecular remission look promising most patients probably require a lifelong TKI treatment. This poses an increased risk to pediatric CML patients exposed to TKI treatment for decades as the long-term side effects on bone or other organs in a still growing organism presently are totally unknown.
4. Juvenile animal model for chronic TKI exposure
All regulatory authorities (Food and Drug Administration (FDA), Health Canada, European Medical Agency (EMA)) require animal tests to be conducted before humans are exposed to a new molecular entity. In drug developmental process, every potential new therapeutic agent has to pass clinical phase I-III studies in humans to verify safety, dosage, efficacy, side effects, and monitoring adverse reactions. All these studies are done in adult volunteers or adult patients if the disease under study occurs not exclusively at pediatric age [45]. Thus, in order to gain insight into side effects occurring specifically in the still growing organism during the preclinical research phase, in vivo studies in young growing animals are of main importance.
However, almost in all instances, primarily adult animal models are used in preclinical research (for reviews about the ongoing debate about animal models in clinical research see Refs. [46, 47, 48]). Adult animals were also used to study the influence of imatinib on the skeletal system [49, 50]. But as the growth process of the juvenile bone differs significantly from a mature bone, results described so far in adult patients/animals cannot readily be transferred to pediatric cohorts. Furthermore, Juvenile animal models cannot easily be selected as they are not established to match every single “research question” or disease on a routine basis.
Therefore, we describe here our established juvenile animal model to study side effects of a chronic exposure of imatinib primarily on the growing bone and to a lesser extent on other organs.
When establishing a juvenile animal model, several issues should be considered like the rodent species itself (mouse vs. rat), the strain (inbred vs. outbred), the overall speed of development (age when puberty starts), and convenient ways of drug administration in the situation of long-term exposure (intraperitoneal vs. subcutaneous vs. oral gavages vs. micro-osmotic pumps). Overall, the developmental stages must be comparable to human life.
4.1. Mice versus rat
Most of the animals used in biomedical research are mice and rats because of their availability, ease of handling, and fast reproduction rate. Mice are an excellent model for human diseases because genetically they share 98% homology with human genome as well as a similar organization of their DNA and gene expression. However, the genome of a rat is smaller than its human equivalent but larger than that of a mouse.
Compared to mice, rats offer many advantages as, for example, their physiology is easier to monitor and is more like the corresponding human condition. But the most important advantage of the rat is its bigger size, not just because of the added ease to perform surgical procedures, but because of larger substructures (e.g., bone growth line, metaphysis) in organs thus influencing (i) which ratio of the organ is prone to an experimental lesion and (ii) the distance effects drugs exert to a specific anatomical area [51].
As we questioned about side effects of a chronic imatinib exposure on the growing organism, we were interested in the side effects on the long bones, which are much bigger in rats as compared to mice. As an additional benefit, we could also monitor side effects on other growing and developing organs like heart and testis as rats are a preferred model in cardiac and reproduction questions [52].
4.2. Inbred versus outbred strain
In general, the difference between outbred and inbred strains lies in their genetic background. Inbred strains are characterized by almost 99% homogeneity of the genome resulting from a long inbreeding of this strain, whereas outbred strains have a diverse genetic background. Due to this genetic characteristic, animals of inbred strains react nearly identical to a specific intervention, like medical treatment, surgery, etc., wherefore the influence of this intervention on a particular parameter can be identified more precisely. However, outbred strains reflect the natural situation more accurately as every individual is genetically different from the other. Every animal of an outbred strain will react slightly different to a specific intervention, which discloses all possible effects of this intervention on the metabolism and mimics more the situation in the clinic. Therefore, depending on the experimental question and if you need a genetic diversity in your test population, inbred or outbred strains are used. Our study focused on side effects of long-term TKI treatment on bone remodeling and to mimic the human situation, we choose juvenile rats of the outbred strain “Wistar.”
4.3. Male versus female
We exclusively studied Wistar rats of male gender, as males tend to be more sensitive to bone influencing agents than female animals due to more rapid weight development and gender-specific hormones.
Prepubertal young Wistar rats triple their body weight, regardless of sex, from about 60 to 180 g in 14 days from the 3rd to 5th week of life due to the increasing growth hormone (GH) pulse amplitudes. The duration of GH pulses is significantly longer in males versus females, a pattern that continues throughout adulthood. Between 5th and 7th week of life, GH pulse amplitudes are similarly increased in both sexes [53, 54]. The rapid skeletal growth associated with this is particularly strongly influenced by interfering factors. In postpuberty, the growth slows down, especially in female rats, who weigh 200 g in the 8th week of life and 220 g in the 10th week of life. Contrary, male animals reach a body weight of 300 g postpubertally in the 8th week of life and 390 g in the 10th week of life. These differences in growth dynamics should also make postpubertal bone alterations due to TKI exposure more prominent in male animals.
Nevertheless, additional factors especially endocrine changes in hormones, such as testosterone, 17ß-estradiol, and corticosterone, inducing and associated with the onset of puberty and puberty itself may be more important than GH to decide about the sex when setting up an animal model. It is commonly considered that puberty lasts until the 8th week of age [54]. However, onset of puberty in the rat (as measured by the age at vaginal opening and the onset of estrous cyclicity) occurs between 4th and 5th week in females, whereas in males (as measured by preputial separation which is an androgen-dependent event) occurs around 7th week of life depending on the strain used [55]. The onset of puberty in male Wistar rats based on the increase in plasma testosterone levels starts at 46–50 days of age and progressively increases until 76 days of age [56, 57, 58]. However, related to the increased production of estrogen and its positive influence on bone formation, trabecular bone density increases significantly both in women and in female rats with the onset of puberty [59, 60]. Because of this hormonal influence, effects on the bones, which are only mild, would be more difficult to detect in the female organism.
4.4. Drug administration
For chronic drug exposure, we choose administration via the drinking water. Drug application via subcutaneous (s.c.) or intraperitoneal injection (i.p.) or oral gavage is the most accurate type of body weight-related exposure. However, young animals are prone to risks of injury and subsequent infection in the pharynx and/or esophagus [61, 62]. Micro-osmotic pumps could also be considered for s.c. administration but repeated implantation and removal of the pumps combined with the increased risk of infection should be taken into account [63]. For a detailed review of routes for chronic drug administration, see ref. [64]. However, due to the pharmacodynamics of the TKI, single shot by s.c. or i.p. administration would need at least two TKI applications daily over 10 weeks. Considering animal ethics as well as personal resources over several weeks including shifts on weekends, these numerous manipulations are hardly tolerable and affordable. For these reasons, the chosen intake of the drug via the drinking water was the most adequate and convenient form of chronic TKI exposure. Also, the stability of the TKIs in aqueous solution at room temperature facilitated this approach. Hence, the drug intake is dependent on the daily drinking volume considering age and associated body weight. Other possible interfering factors are loss of liquid when changing the water bottles or leaking water bottles and changes in the drinking behavior due to changes in the environment like fluctuation in the room temperature or humidity, or social conflicts between the animals. To counteract this, the care of the experimental animals, the measuring of the drinking volume, and the determination of weight gain were always carried out on a fixed schedule and by identical staff members including weekends.
Age-dependent drinking behavior of mammals varies. According to body weight, higher volumes are ingested by younger animals [65, 66]. Furthermore, rodents show a circadian rhythm of their food and drinking water intake. About 80% of the maximum daily intake of liquids occur at night [64]. This allows the conclusion that by administration via the drinking water, a peak level was achieved during the night, comparable to the single administration in human patients during the daytime.
4.5. Developmental stages
Due to the well-documented developmental stages of the rat, it is possible to carry out a comparison with human developmental stages in order to interpret the generated data in an orientated manner (Table 2).
Considering the rapid maturation of the rats and the objective of examining the development (infancy, puberty, and young adulthood), we selected an exposure period of 10 weeks starting at 4 weeks of age.
Summing key issues in the juvenile animal model described, we chronically exposed healthy 4-week-old male Wistar rats to varying concentrations (low dose vs. high dose) of imatinib via drinking water over a period of 10 weeks while growing. We applied different treatment schedules to mimic possible new treatment strategies (continuous vs. intermittent). During the entire exposure time, the developmental stages from the end of weaning until young adolescence were covered (Figure 3). During ongoing imatinib exposure, a defined number of animals from each cohort were humanely sacrificed at prepubertal stage (age 6 weeks; after 2 weeks of exposure), at pubertal stage (age 8 weeks; after 4 weeks of exposure), and at postpubertal stage (age 14 weeks; after 10 weeks of exposure) [68].
Figure 3.
Experimental design of the juvenile animal model.
5. Side effects of chronic imatinib treatment on growing bone
At defined time points of analysis (Figure 3), blood serum was collected to measure TKI concentration by high-performance liquid chromatography (HPLC), biochemical markers of bone turnover, and hormone levels by ELISA technique. Long bones (tibia and femur) and lumbar vertebrae L1–L4 were isolated to determine bone length, vertebral height, bone mass, and strength by using quantitative computed tomography (pQCT), micro-computed tomography (μCT), and biomechanical testing [68].
5.1. TKI serum concentration
Imatinib mean serum levels of 1600 and 5600 ng/mL were achieved by continuous drug exposure via the drinking water to either low or high dose, respectively [68]. These serum concentrations match well with therapeutic imatinib levels of pediatric patients ranging from 2000 to 8000 ng/mL on imatinib administered at doses of 260–570 mg/m2 daily [26], whereas in adult patients, serum levels in the range of ~1000–3400 ng/mL on imatinib doses of 400–600 mg daily were measured [69, 70]. Reflecting the half-life of imatinib in rats reported to be 12.3 h [71], serum levels of animals receiving high dose imatinib intermittently were below the detection limit of the assay (10.0 ng/mL) when serum was collected at the end of a 4-day period without drug exposure.
5.2. Long bone length and bone quality
During growth, a 10-week exposure to imatinib caused a significant reduction of the long bone length dose-dependently (Figure 4) [68]. These findings match with clinical data in children indicating that continuous administration of imatinib—even in high doses—does not result in a complete stop of growth, rather in a decelerated growth rate of the long bones [5, 36, 38, 39, 40, 41, 72]. During growth, pQCT analysis of the bones revealed significantly reduced trabecular bone mineral density (BMD) by imatinib exposure. Analysis of the 3D trabecular structure by μCT emphasizes these findings by demonstration of reduced bone volume density in combination with reduced trabecular number and connectivity [68]. Furthermore, our findings also indicated unchanged cortical BMD and cortical thickness during growth dose- and time-independently, whereas the bone strength of the femora was decreased after long-term exposure to high dose imatinib. This could be explained by decreased cross-sectional area, periosteal, and endosteal circumference of the femora, suggesting a blunted radial appositional bone growth [68]. With regard to pediatric patients, BMD measurements or increased fracture rates under long-term imatinib treatment are not published yet. However, intermittent treatment of the high dose mitigated all bony side effects of the long bones, which might offer a new perspective for pediatric patients.
Figure 4.
Growth impairment of long bones by imatinib is dependent on the cumulative dose [68]. Prep: Prepubertal; Pub: Pubertal; Postpub: Postpubertal. Compared to controls, high dose imatinib (1000 mg/L daily) causes stronger longitudinal growth impairment than low dose exposure (500 mg/L daily). “On/off” exposure (3 days “on”, 4 days “off”) to high dose imatinib mitigates this effect. Of note, the cumulative dose resulting from 1000 mg/L administered “on/off” is approximately identical to 500 mg/L daily administered continuously. The resulting reduction in length reflects the cumulative dose administered.
5.3. Vertebrae height and quality
Concerning lumbar vertebra, 10-week imatinib exposure significantly reduced vertebral height combined with reduced trabecular BMD dose-dependently, whereas total BMD, cortical BMD, cross-sectional area, and cortical thickness were not affected [68, 73]. At the moment, only limited data are available on the effect of imatinib on vertebrae. In adult patients with CML, O´Sullivan et al. observed significantly increased lumbar spine BMD after 24 months of imatinib treatment as assessed by dual energy x-ray absorptiometry (DXA) [74], whereas Vandyke et al. observed unchanged BMD [75]. We predict from our animal model that imatinib also alters vertebral properties, but not to the same extent as in long bones [68].
5.4. Bone turnover markers
The bone resorption marker tartrate-resistant acidic phosphatase (TRAP) revealed significantly decreased serum levels under continuous imatinib exposure indicating reduced osteoclast activity at all developmental stages [68]. This is confirmed by in vitro studies showing that imatinib impairs osteoclastogenesis leading to diminished numbers of TRAP-positive osteoclasts [49, 76]. However, bone resorption marker C-terminal collagen cross-links (CTX-I) revealed by trend elevated serum levels prepubertally, but normal levels during the ongoing exposure time, indicating nearly unchanged osteoclast activity during growth [68]. This is consistent with data from pediatric patients with CML describing by trend elevated CTX-I levels prepubertally while on imatinib [77].
Under imatinib exposure, bone formation marker osteocalcin was decreased but procollagen type I (PINP) levels were by trend elevated, pointing to improved bone formation and mineralization [68]. In vitro assays using human isolated mesenchymal stem cells, primary rat osteoblasts, and mouse osteoblast-like cell line MC3T3-E1 revealed all increased mineralization combined with reduced proliferation under therapeutic imatinib concentration [50].
However, bone turnover markers of pediatric patients with CML exhibited a biphasic response during imatinib therapy with increasing levels within the first 3 months of treatment and a significant decline during long-term treatment (Figure 5) [77, 78].
Figure 5.
Biphasic response (time period 1 [pink background], period 2 [brown background]) of bone remodeling to imatinib treatment in pediatric patients with CML. Data depicted from CML-PAED II study [78]. One hundred and nineteen patients (70 male/49 female, median age 12 years, range 1–18 years) received 260–340 mg imatinib/m2 daily within 1 week after diagnosis of CML (0). Up to 30 patients (range 20–30) out of this cohort could successfully be monitored repeatedly over a median period of 3 years for all parameters planned to be analyzed by collecting blood and urine for 3- months under appropriate circumstances. Assays were performed in a central laboratory as described previously [77]. Age normalized reference values were used as standard deviation scores (SDS).
6. Non bone-related side effects of imatinib treatment
6.1. Growth hormone
Main length growth regulating factors at childhood and adolescence are GH and “insulin-like growth factor 1” (IGF-1), thyroid hormone (T3, T4), glucocorticoids, and sex hormones during puberty [79].
GH is secreted by pituitary somatotrophins in a pulsatile manner and acts on peripheral tissues, either directly or indirectly, through the stimulation of IGF-1 synthesis and secretion [80, 81, 82]. As reported, the increase in body height during childhood is initiated by promoting chondrocyte proliferation and endochondral ossification in the growth plate or induction of osteoblastogenesis, leading to linear bone growth [80].
Owing to growth, children and/or adolescents going through puberty are particularly vulnerable to a possible GH deficiency (GHD) under long-term imatinib treatment [5, 41]. Mimicking those findings in children on imatinib treatment, the juvenile animal model disclosed significantly lowered serum levels of IGF-1 binding protein 3 (IGF-BP3)—a stable and more accurately measurable degradation product of IGF-1—at all concentrations applied and at all ages investigated [37, 83, 84]. Data of clinical studies in pediatric CML patients under TKI therapy revealed IGF-1 and IGFBP-3 levels almost exclusively in the very low or deep pathological range when compared to age-matched controls, independent of treatment duration [83, 84].
6.2. Vitamin D and bone
Within the bone remodeling cycle, vitamin D plays a crucial role by influencing the overall mineralization and bone turnover of the skeleton. The main effects of the active vitamin D metabolite 1.25(OH)2D3 comprises of stimulating the absorption of calcium/phosphorus from the gut to create optimal circumstances for bone mineralization, as well as stimulation of the osteoblast-mediated mineralization and osteoclast differentiation [85]. The consequences of vitamin D deficiency are secondary hyperparathyroidism and bone loss, leading to osteoporosis and fractures, mineralization defects, which may lead to osteomalacia in the long-term, and muscle weakness, causing falls and fractures [86].
Hypophosphatemia, associated with low serum levels of 25-(OH)D3, 1.25(OH)2D3, calcium, and secondary hyperparathyroidism are known side effects in adult patients with CML under imatinib treatment [3]. An explanation for these findings is that imatinib directly stimulates bone formation while restraining resorption, resulting in a net flux of calcium from extracellular fluid into bone, a decreased serum calcium level, and a compensatory rise in the level of parathyroid hormone, which causes phosphaturia and modest hypophosphatemia [50]. Pediatric patients with CML also exhibit moderate secondary hyperparathyroidism in conjunction with pathologically low 25-(OH)D3 and 1.25(OH)2D3 levels but normal serum calcium and phosphate levels under imatinib therapy [77, 78]. Thereby these effects were independent of the duration of imatinib therapy, which underlined once again that regulation and compensatory mechanisms on the growing skeleton are different from those in the adult skeleton.
How imatinib interferes with vitamin D synthesis and metabolism is poorly understood yet. So far only one study investigated in vitro the effect of imatinib on keratinocytes yet and revealed a competitive inhibition of CYP27B1, a vitamin D hydroxylating enzyme, by imatinib [87].
6.3. Fertility
TKs like c-kit and PDGF-R, which are inhibited “off-target” by imatinib, are involved not only in the bone remodeling process but also in the regulation of spermatogenesis [88], raising the question of testicular toxicities by imatinib treatment. Up to now, the influence of TKIs on the male reproductive endocrine system in pediatric patients with CML is still controversially discussed [89].
The first study in neonatal rats revealed that imatinib interferes with postnatal testicular development [90]. Investigations in the juvenile animal model starting at an older age (4 weeks) depicted unchanged testis weight but reduced testosterone levels under long-term imatinib exposure until young adulthood. Inhibin B, a protein that is predominantly produced in the testis controlling follicle stimulating hormone (FSH) [91], did not significantly differ from controls, at all doses, and by all application schemes tested [92]. A clinical study conducted in a small cohort of boys (age: 7.8–18.9 years) with CML receiving TKI treatment revealed testosterone and inhibin B levels within normal age-related reference ranges [83, 84, 92]. Therefore, severe testicular toxicity by imatinib seems to be unlikely.
However, a closer look on spermatogenesis in the juvenile animal model revealed that the spermatogenic cell counts were significantly decreased by high dose imatinib exposure (Figure 6). Additionally, during spermatogenesis cell cycle, the stage of the dominant cell proportion was shifted to more immature stages. Low dose and intermittent imatinib exposure attenuated these findings. Interestingly, spermatogenic cell proliferation was significantly lowered at all imatinib doses applied [93]. Thus, a delayed negative effect of long-term imatinib exposure on spermatogenesis cannot be excluded.
Figure 6.
Number of proliferating testicular epithelium cells (Marker Ki67) in Wistar rats under imatinib exposure [93].
6.4. Cardiac side effects of TKI treatment
In the literature as well as indicated by the manufacturers in the specialist information, cardiotoxic and vascular side effects of imatinib and the next-generation TKIs are of special concern [94, 95, 96, 97, 98, 99]. However, this primarily may play a role in older adult patients with CML (age > 65 years) under TKI treatment.
The juvenile animal model under discussion disclosed an increase in the relative heart weight ratio (= ratio of the heart weight to total body weight at sacrifice) under imatinib exposure. Another study found that imatinib treatment led to mitochondrial-dependent myocyte loss and cardiac dysfunction, occurring more severely in older mice, in part due to an age-dependent increase in oxidative stress [100]. This suggests that cardiac monitoring of older patients receiving imatinib therapy may be especially warranted.
As cardiac side effects were also observed with the use of dasatinib, in the experiment conducted with the juvenile animal model, this 2nd-generation TKI was tested for safety, efficacy, and dose response. Surprisingly, animals died spontaneously in a dose- and exposure time-dependent manner (Figure 7). Data of the surviving animals that were sacrificed according to the experimental set-up schedule (Figure 3) disclosed—dependent on the cumulative dose administered—increased relative heart weights, impaired heart ejection fraction as assessed by echocardiography, and elevated brain natriuretic peptide (BNP) serum levels, an indicator of cardiac dysfunction [101]. Data of this unexpected high toxicity can be explained by the serum elimination half-life time of dasatinib which is rather short and in the range of 2–3 h in rodents [102]. As known from clinical data on treatment of CML by dasatinib, it is not mandatory to achieve steady state drug blood levels as the intracellular concentration of dasatinib is responsible for efficacy, which is sufficiently achieved by once daily drug administration. Initial trials in humans based on drug administration twice daily were characterized by high toxicity requiring treatment interruption or reduction to once daily dosing [103]. Thus, the juvenile rat model also mimics this situation as a continuous intake of small doses of dasatinib via the drinking water evidently is associated with higher toxicity.
Figure 7.
Survival rate of juvenile Wistar rats under chronic dasatinib exposure [101].
Initially, inhibition of the c-abl kinase was assumed to be the reason for cardiac toxicity by TKI [94]. But an extensive in vitro study of 18 TKIs on myocytes showed that their relative ability to inhibit ABL1 or ABL2 did not correlate with myocyte damage, revealing that inhibition of other kinases like MEK1 and MEK2 could be responsible for the cardiotoxicity. However, it was reported that all TKIs induce myocyte damage correlating with their kinase inhibitor selectivity [97]. So, we conclude that it might be prudent to carefully monitor cardiac function in still growing individuals with CML if treated with TKI continuously over long periods.
7. Hypothesized model of osseous damage and clinical relevance
7.1. Model of action of imatinib on bone remodeling
Despite the knowledge accumulated so far, the detailed mechanism how imatinib impairs bone remodeling and growth remains yet speculative. In in vitro studies, it was shown that imatinib impairs osteoblastogenesis as well as osteoclastogenesis revealing its effect on bone remodeling [49, 50, 104, 105]. However, long bone growth is not only based on the balanced action of bone formation and bone resorption but also depends on the endochondral bone formation at the epiphyseal line of the long bones. Here, the column structure of the epiphyseal line, achieved and maintained by chondrocytes, is of main importance. In general, the epiphyseal line or growth plate is divided into different zones: reserve zone (RZ), proliferative zone (PZ), and the hypertrophic zone (HZ) followed by the primary spongiosa (PS)—the initial trabecular bone. The transition zone between HZ and PS is the osteochondral junction (OJ) (Figure 8A).
Figure 8.
Schematic overview of physiologic bone growth (A) and under imatinib exposure (B). On the left side, longitudinal section of the epiphyseal line of a rodent proximal tibial metaphysis is depicted [109]. The epiphyseal plate separates the epiphysis from the metaphysis and is important for endochondral bone formation. The growth plate is divided into reserve zone (RZ), proliferative zone (PZ), and the hypertrophic zone (HZ). The transition of HZ to the primary spongiosa (PS)—the initial trabecular network formed after the vascular invasion and matrix calcification—is the osteochondral junction (OJ). Under physiological conditions, longitudinal growth occurs by endochondral ossification. In this process, new cartilage is formed at one side of the epiphyseal growth plate and is gradually replaced by bone. Chondrocytes of the growth plate are initially in a resting state in the RZ. They differentiate through proliferative and hypertrophic stages (PZ, HZ) as the growth plate moves past. This programmed differentiation pathway ends in cell death in the HZ and the replacement of cartilage by bone by osteoblasts in the OJ resulting in the PS. (For detailed review, see Ref. [110]).
During growth, new cartilage is formed at one side of the epiphyseal growth plate and is gradually replaced by bone. The work by Nurmio et al. disclosed a disorganization of the epiphyseal line by imatinib treatment of neonatal rats (1–15 days old) (Figure 9) [106]. Instead of the typical long, smooth proliferating chondrocyte columns at the epiphyseal line, a thin, disorganized layer of proliferative cells was detected after imatinib treatment resulting in a decreased thickness of PZ and increased the thickness of the HZ. This is in line with an in vitro study revealing an inhibitory effect of imatinib on chondrocyte proliferation [107]. Nurmio et al. also observed that imatinib treatment led to a bone resorption arrest and increased bone formation at the OJ [106].
Figure 9.
Disorganization of the femoral epiphyseal line by long-term imatinib exposure. 2 µm sections of decalcified femora were stained with hematoxylin-eosin (magnification 100 ×). Controls show the typical “column” structure of the epiphyseal line and its physiological narrowing with increasing age. However, under imatinib exposure, the cellular architecture is more disorganized in a dose- and time-dependent manner.
However, combining our data [68] with data from Nurmio et al. [106] and Vandyke et al. [107], it can be hypothesized that imatinib exposure alters metabolism and remodeling of the growing bone in a temporal-spatial stepwise fashion (Figure 8B). In the first instance, migration, proliferation, and activity of chondrocytes will be impaired by imatinib leading to a disturbed organization of the growth plate impairing longitudinal bone growth [106]. Altered growth hormone secretion under imatinib treatment as shown before in the growing organism [39, 41, 83] may aggravate this growth impairment. Thereafter, ongoing drug exposure causes a spatial activity shifting of bone remodeling: initially, the formation will be elevated and shifted to the area of the osteochondral junction, whereas the activity of bone resorption remains unchanged but will be spatially shifted to the distal area of the trabecular bone [106]. Finally, under long-term imatinib treatment, osteoblastogenesis and osteoclastogenesis will be impaired [104, 108], hampering bone remodeling during growth.
As an interesting approach, our juvenile animal model demonstrated that intermittent imatinib exposure will ameliorate growth impairment in rats. The inhibitory effect is not irreversible and we assume that during the days “OFF” imatinib exposure catch-up growth occurred. Therefore, drug administration following a schedule with “days on drug” and “days off drug” might reduce some skeletal side effects in pediatric patients. A single trial in older adults has already proven that intermittent TKI treatment is sufficient to control CML once remission has been achieved [111, 112]. However, the length and frequency of intervals to allow catch-up growth in children on TKI treatment still have to be defined and at least in our rat model, this approach did not recover the biomechanical strength of the long bones.
7.2. Clinical relevance
The established juvenile rat model mimics to a gross extent side effects of long-term TKI exposure on the growing bone in a developmental stage-dependent fashion. Impairment of longitudinal growth, as observed in children under imatinib treatment, could be unequivocally modeled and confirmed.
Our hypothesis of spatiotemporal shifting of skeletal formation and resorption under imatinib is supported by clinical observations of a biphasic reaction of corresponding osseous metabolism serum markers in adult and pediatric patients with CML. In adult patients, an increase in bone formation occurred accompanied by elevated bone formation markers in the serum within the first months of therapy [74]. Pediatric CML patients display a biphasic response of bone formation and bone resorption by increasing levels within the first 3 months of imatinib treatment followed by a significant decline until 12 months of treatment (Figure 5) [77, 78].
Furthermore, we could show that long-term imatinib exposure may result in reduced bone strength possibly posing an elevated fracture risk in pediatric patients. Since 2001, adult CML patients are treated with imatinib but until now, no elevated fracture rates have been described in these patients [113]. As pediatric CML patients are treated with imatinib only since the beginning of this millennium, there is still no long-term experience. Our animal model also revealed that intermittent imatinib treatment mitigated skeletal effects on the growing bone, thus pointing toward a possibility to improve the risk-benefit ratio of long-term TKI exposure in pediatric patients. First clinical data in adults look promising but further studies must be carried out to determine whether the intermittent exposure is also sufficiently effective for the control of CML [111, 112]. Regarding pediatric patients, the results from the juvenile animal model and the clinical experience from adult patients with CML should be combined. This approach can be expected to harbor great potential in translational research.
8. Other animal models
The aim of the animal model described in this chapter was to evaluate side effects on bone remodeling rather than gaining further insight into the biology of CML (e.g., to study elementary mechanisms of CML disease progression) or on a more efficient antileukemic treatment exerted by new drugs (e.g., exploring why resistance develops under TKI therapy) [114, 115]. For these essential questions, the reader is kindly referred to the detailed body of literature on establishing and maintaining acute lymphatic or myeloid leukemic cells in xenograft models, transgenic models, and syngeneic models using a broad range of species [116, 117, 118, 119], whereas mice are used mostly in orthotopic animal models [120, 121, 122, 123].
Our research described, focused on the question how bone metabolism is affected by TKI treatment as an off-targeted side effect and therewith induced structural and mechanical osseous changes in healthy not-outgrown animals [124]. Bone remodeling has been studied in many species and resulted in the current available knowledge [125, 126, 127, 128, 129, 130, 131]. Evidently, the financial burden of animal maintenance and drug doses to be administered when sequelae of chronic exposure are investigated are much lower using small animals like mice and rats. Especially in these species, the time periods concerning defined stages of development are shorter, thus requiring drug exposure only for 2–3 months in order to mimic one to two decades in humans [132].
Most importantly, any intervention on the bone during chronic TKI exposure of the animals was minimized. Bone growth and repair is governed by regulatory mechanisms other than that of the outgrown organism. Therefore, the model described here differs principally from experiments investigating bone healing and growth after surgical procedures performed on the skeleton (for a comprehensive review see Refs. [131, 133, 134]).
Ethical concerns in the last decades resulted in the establishment of studying bone growth and development preclinically in ex vivo cultures mostly making use of embryonic bone of mouse or rat strains [135, 136]. For an overview on conventional versus static versus 3D dynamic bioreactor models as well as a chorioallantoic membrane (CAM)-culture systems, the reader is kindly referred to a comprehensive review by Abubakar et al [137]. The composition of the nursing cell culture medium in these models is a crucial step. However, concerning TKIs whose metabolism in juvenile rodents is still poorly characterized and pleiotropically influences bone remodeling (e.g., impact on synthesis of growth hormone and insulin-like growth factor, liver metabolism, vitamin D metabolism, renal function, etc.) evidently not all components can be added to a cell culture medium mimicking correctly the in vivo situation. Therefore, our investigations had to be restricted to a genetically unchanged—“healthy”—animal model to study the side effects of long-term TKI exposure on bone remodeling during growth and in addition on other developing organs.
9. Conclusion
Long-term toxicity resulting from off-target effects of TKIs can be assessed conveniently by administering TKIs via the drinking water to juvenile male Wistar rats over a prolonged period. During all developmental phases (prepubertal, puberty, postpubertal, and adult), drug blood levels are obtained corresponding to data in humans. The juvenile animal model disclosed reduced long bone length and diminished vertebral height combined with reduced bone mass density and reduced breaking strength dose-dependently after chronic exposure to imatinib. Thus, the juvenile animal model depicted here mimics perfectly clinical observations on osseous changes observed in pediatric patients with CML. Furthermore, intermittent exposure of the high TKI dose mitigated the skeletal side effect and therefore represented a possible treatment option for pediatric patients suffering from longitudinal growth retardation under imatinib therapy. The juvenile animal model might also be of value to predict sequelae of TKI treatment in other human organs following exposure over decades.
Acknowledgments
Disclosures: JTT, BASJ, AU, PG, VG, and LK have nothing to disclose.
MS has received research funding and lecture honoraria from Novartis Pharmaceuticals (Nürnberg, Germany), Bristol-Myers Squibb (Munich, Germany), and Pfizer (Berlin, Germany).
Funding: Continuous financial support was provided by unrestricted research grants from Novartis Pharmaceuticals (Nürnberg, Germany), Sonnenstrahl e. V. (Dresden, Germany), and Stiftung Mitteldeutsche Kinderkrebsforschung (Leipzig, Germany). Additional financial support was given by a research grant from the Deutsche Forschungsgemeinschaft (#SU122/3-1; Bonn, Germany).
\n',keywords:"juvenile, growth, bone, tyrosine kinase inhibitor, side effects, CML",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/56527.pdf",chapterXML:"https://mts.intechopen.com/source/xml/56527.xml",downloadPdfUrl:"/chapter/pdf-download/56527",previewPdfUrl:"/chapter/pdf-preview/56527",totalDownloads:563,totalViews:114,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,dateSubmitted:"November 22nd 2016",dateReviewed:"June 5th 2017",datePrePublished:"December 20th 2017",datePublished:"May 23rd 2018",dateFinished:null,readingETA:"0",abstract:"The tyrosine kinase (TK) inhibitor (TKI) imatinib provides a highly effective treatment for chronic myeloid leukemia (CML) targeting at the causative oncogenic TK BCR-ABL1. However, imatinib exerts off-target effects by inhibiting other TKs that are involved, e.g., in bone metabolism. Clinically, CML patients on imatinib exhibit altered bone metabolism as a side effect, which translates into linear growth failure in pediatric patients. As TKI treatment might be necessary for the whole life, long-term side effects exerted on bone and other developing organs in children are of major concern and not yet studied systematically. Here, we describe a new juvenile rat model to face this challenge. The established model mimics perfectly long-term side effects of TKI exposure on the growing bone in a developmental stage-dependent fashion. Thus, longitudinal growth impairment observed clinically in children could be unequivocally modeled and confirmed. In a “bench-to-bedside” manner, we also demonstrate that this juvenile animal model predicts side effects of newer treatment strategies by second generation TKIs or modified treatment schedules (continuous vs. intermittent treatment) to minimize side effects. We conclude that the results generated by this juvenile animal model can be directly used in the clinic to optimize treatment algorithms in pediatric patients.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/56527",risUrl:"/chapter/ris/56527",book:{slug:"experimental-animal-models-of-human-diseases-an-effective-therapeutic-strategy"},signatures:"Josephine T. Tauer, Bernadette A. S. Jäger, Anna Ulmer, Paula\nGeidel, Vera Girke, Lysann Kroschwald and Meinolf Suttorp",authors:[{id:"202231",title:"Dr.",name:"Josephine",middleName:"Tabea",surname:"Tauer",fullName:"Josephine Tauer",slug:"josephine-tauer",email:"jtauer@shriners.mcgill.ca",position:null,institution:{name:"McGill University",institutionURL:null,country:{name:"Canada"}}},{id:"202232",title:"Prof.",name:"Meinolf",middleName:null,surname:"Suttorp",fullName:"Meinolf Suttorp",slug:"meinolf-suttorp",email:"Meinolf.Suttorp@uniklinikum-dresden.de",position:null,institution:null},{id:"205988",title:"Dr.",name:"Bernadette A.S.",middleName:null,surname:"Jaeger",fullName:"Bernadette A.S. Jaeger",slug:"bernadette-a.s.-jaeger",email:"bernadette.jaeger@med.uni-duesseldorf.de",position:null,institution:null},{id:"205990",title:"Dr.",name:"Paula",middleName:null,surname:"Geidel",fullName:"Paula Geidel",slug:"paula-geidel",email:"paula.geidel@gmail.com",position:null,institution:null},{id:"205991",title:"Dr.",name:"Vera",middleName:null,surname:"Girke",fullName:"Vera Girke",slug:"vera-girke",email:"vera-girke@web.de",position:null,institution:null},{id:"205992",title:"Dr.",name:"Lysann",middleName:null,surname:"Kroschwald",fullName:"Lysann Kroschwald",slug:"lysann-kroschwald",email:"lysann.kroschwald@uniklinikum-dresden.de",position:null,institution:null},{id:"206040",title:"Dr.",name:"Anna",middleName:null,surname:"Ulmer",fullName:"Anna Ulmer",slug:"anna-ulmer",email:"anna.ulmer@uniklinikum-dresden.de",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Role of tyrosine kinase inhibitors in chronic myeloid leukemia treatment",level:"1"},{id:"sec_3",title:"3. Imatinib as front-line treatment for pediatric CML",level:"1"},{id:"sec_4",title:"4. Juvenile animal model for chronic TKI exposure",level:"1"},{id:"sec_4_2",title:"4.1. Mice versus rat",level:"2"},{id:"sec_5_2",title:"4.2. Inbred versus outbred strain",level:"2"},{id:"sec_6_2",title:"4.3. Male versus female",level:"2"},{id:"sec_7_2",title:"4.4. Drug administration",level:"2"},{id:"sec_8_2",title:"4.5. Developmental stages",level:"2"},{id:"sec_10",title:"5. Side effects of chronic imatinib treatment on growing bone",level:"1"},{id:"sec_10_2",title:"5.1. TKI serum concentration",level:"2"},{id:"sec_11_2",title:"5.2. Long bone length and bone quality",level:"2"},{id:"sec_12_2",title:"5.3. Vertebrae height and quality",level:"2"},{id:"sec_13_2",title:"5.4. Bone turnover markers",level:"2"},{id:"sec_15",title:"6. Non bone-related side effects of imatinib treatment",level:"1"},{id:"sec_15_2",title:"6.1. Growth hormone",level:"2"},{id:"sec_16_2",title:"6.2. Vitamin D and bone",level:"2"},{id:"sec_17_2",title:"6.3. Fertility",level:"2"},{id:"sec_18_2",title:"6.4. Cardiac side effects of TKI treatment",level:"2"},{id:"sec_20",title:"7. Hypothesized model of osseous damage and clinical relevance",level:"1"},{id:"sec_20_2",title:"7.1. Model of action of imatinib on bone remodeling",level:"2"},{id:"sec_21_2",title:"7.2. Clinical relevance",level:"2"},{id:"sec_23",title:"8. Other animal models",level:"1"},{id:"sec_24",title:"9. Conclusion",level:"1"},{id:"sec_25",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II study. Blood. 2002;99:3530-3539. Available from: http://www.bloodjournal.org/content/bloodjournal/99/10/3530.full.pdf'},{id:"B2",body:'Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. The New England Journal of Medicine. 2002;346:645-652. DOI: 10.1056/NEJMoa011573'},{id:"B3",body:'Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. The New England journal of Medicine. 2006;354:2006-2013. DOI: 10.1056/NEJMoa051140'},{id:"B4",body:'Tauer JT, Nowasz C, Sedlacek P, et al. Impairment of longitudinal growth by tyrosine kinase inhibitor (TKI) treatment—Data from a large pediatric cohort with chronic myeloid leukemia (CML). Blood. 2014;124(21):522. Available from: http://www.bloodjournal.org/content/124/21/522?sso-checked=true'},{id:"B5",body:'Millot F, Guilhot J, Baruchel A, et al. Growth deceleration in children treated with imatinib for chronic myeloid leukaemia. European Journal of Cancer. 2014;50:3206-3211. DOI: 10.1016/j.ejca.2014.10.007'},{id:"B6",body:'Hijiya N, Schultz KR, Metzler M, et al. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. Blood. 2016;127:392-399. DOI: 10.1182/blood-2015-06-648667'},{id:"B7",body:'Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211-225. Available from: http://www.cell.com/cell/pdf/S0092-8674(00)00114-8.pdf'},{id:"B8",body:'Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19:5548-5557. DOI: 10.1038/sj.onc.1203957'},{id:"B9",body:'Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355-365. DOI: 10.1038/35077225'},{id:"B10",body:'de Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982;300:765-767. DOI: 10.1038/300765a0'},{id:"B11",body:'Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1983;306:277-280. Available from: https://www.ncbi.nlm.nih.gov/pubmed/6580527'},{id:"B12",body:'Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. The New England Journal of Medicine. 1999;341:164-172. DOI: 10.1056/nejm199907153410306'},{id:"B13",body:'Shawver LK, Slamon D, Ullrich A. Smart drugs: Tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 2002;1:117-123. DOI: 10.1016/S1535-6108(02)00039-9'},{id:"B14",body:'Quintas-Cardama A, Cortes JE. Chronic myeloid leukemia: Diagnosis and treatment. Mayo Clinic Proceedings. 2006;81:973-988. DOI: 10.4065/81.7.973'},{id:"B15",body:'An X, Tiwari AK, Sun Y, et al. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review. Leukemia Research. 2010;34:1255-1268. DOI: 10.1016/j.leukres.2010.04.016'},{id:"B16",body:'Suttorp M, Eckardt L, Tauer JT, et al. Management of chronic myeloid leukemia in childhood. Current Hematologic Malignancy Reports. 2012;7:116-124. DOI: 10.1007/s11899-012-0113-6'},{id:"B17",body:'Krumbholz M, Karl M, Tauer JT, et al. Genomic BCR-ABL1 breakpoints in pediatric chronic myeloid leukemia. Genes, Chromosomes & Cancer. 2012;51:1045-1053. DOI: 10.1002/gcc.21989. http://www.kinderkrebsregister.de/dkkr-gb/latest-publications/annual-reports.html?L=1'},{id:"B18",body:'Kaatsch P, Spix C. German Childhood Cancer Registry—Annual Report 2015 (1980-2014). Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany; 2015'},{id:"B19",body:'Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Medicine. 1996;2:561-566. DOI: 10.1038/nm0596-561'},{id:"B20",body:'Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England Journal of Medicine. 2001;344:1031-1037. DOI: 10.1056/nejm200104053441401'},{id:"B21",body:'Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. The New England Journal of Medicine. 2001;344:1038-1042. DOI: 10.1056/nejm200104053441402'},{id:"B22",body:'Soverini S, Martinelli G, Iacobucci I, et al. Imatinib mesylate for the treatment of chronic myeloid leukemia. Expert Review of Anticancer Therapy. 2008;8:853-864. DOI: 10.1586/14737140.8.6.853'},{id:"B23",body:'Deininger MW, Druker BJ. Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacological Reviews. 2003;55:401-423. DOI: 10.1124/pr.55.3.4'},{id:"B24",body:'O’Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007;110:2242-2249. DOI: 10.1182/blood-2007-03-066936'},{id:"B25",body:'Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110:4055-4063. DOI: 10.1182/blood-2007-07-102061'},{id:"B26",body:'Champagne MA, Capdeville R, Krailo M, et al. Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: Results from a children’s oncology group phase 1 study. Blood. 2004;104:2655-2660. DOI: 10.1182/blood-2003-09-3032'},{id:"B27",body:'Millot F, Guilhot J, Nelken B, et al. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia. 2006;20:187-192. DOI: 10.1038/sj.leu.2404051'},{id:"B28",body:'de la Fuente J, Baruchel A, Biondi A, et al. Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years. British Journal of Haematology. 2014;167:33-47. DOI: 10.1111/bjh.12977'},{id:"B29",body:'Manning G, Whyte DB, Martinez R, et al. The protein kinase complement of the human genome. Science (New York, NY). 2002;298:1912-1934. DOI: 10.1126/science.1075762'},{id:"B30",body:'Taylor SS, Kornev AP. Protein kinases: Evolution of dynamic regulatory proteins. Trends in Biochemical Sciences. 2011;36:65-77. DOI: 10.1016/j.tibs.2010.09.006'},{id:"B31",body:'Fabian MA, Biggs 3rd WH, Treiber DK, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotechnology. 2005;23:329-336. DOI: 10.1038/nbt1068'},{id:"B32",body:'Fitter S, Dewar AL, Kostakis P, et al. Long-term imatinib therapy promotes bone formation in CML patients. Blood. 2008;111:2538-2547. DOI: 10.1182/blood-2007-07-104281'},{id:"B33",body:'Mariani S, Giona F, Basciani S, et al. Low bone density and decreased inhibin-B/FSH ratio in a boy treated with imatinib during puberty. Lancet. 2008;372:111-112. DOI: 10.1016/s0140-6736(08)61023-5'},{id:"B34",body:'Schmid H, Jaeger BA, Lohse J, et al. Longitudinal growth retardation in a prepuberal girl with chronic myeloid leukemia on long-term treatment with imatinib. Haematologica. 2009;94:1177-1179. DOI: 10.3324/haematol.2009.008359'},{id:"B35",body:'Kimoto T, Inoue M, Kawa K. Growth deceleration in a girl treated with imatinib. International Journal of Hematology. 2009;89:251-252. DOI: 10.1007/s12185-008-0251-8'},{id:"B36",body:'Bansal D, Shava U, Varma N, et al. Imatinib has adverse effect on growth in children with chronic myeloid leukemia. Pediatric Blood & Cancer. 2012;59:481-484. DOI: 10.1002/pbc.23389'},{id:"B37",body:'Narayanan KR, Bansal D, Walia R, et al. Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis. Pediatric Blood & Cancer. 2013;60:1148-1153. DOI: 10.1002/pbc.24397'},{id:"B38",body:'Giona F, Mariani S, Gnessi L, et al. Bone metabolism, growth rate and pubertal development in children with chronic myeloid leukemia treated with imatinib during puberty. Haematologica. 2013;98:e25–e27. DOI: 10.3324/haematol.2012.067447'},{id:"B39",body:'Hobernicht SL, Schweiger B, Zeitler P, et al. Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy. Pediatric Blood & Cancer. 2011;56:671-673. DOI: 10.1002/pbc.22945'},{id:"B40",body:'Rastogi MV, Stork L, Druker B, et al. Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia. Pediatric Blood & Cancer. 2012;59:840-845. DOI: 10.1002/pbc.24121'},{id:"B41",body:'Shima H, Tokuyama M, Tanizawa A, et al. Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. The Journal of Pediatrics. 2011;159:676-681. DOI: 10.1016/j.jpeds.2011.03.046'},{id:"B42",body:'Davis MI, Hunt JP, Herrgard S, et al. Comprehensive analysis of kinase inhibitor selectivity. Nature Biotechnology. 2011;29:1046-1051. DOI: 10.1038/nbt.1990'},{id:"B43",body:'Dewar AL, Cambareri AC, Zannettino AC, et al. Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood. 2005;105:3127-3132. DOI: 10.1182/blood-2004-10-3967'},{id:"B44",body:'Taylor JR, Brownlow N, Domin J, et al. FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance. Oncogene. 2006;25:147-151. DOI: 10.1038/sj.onc.1209007'},{id:"B45",body:'de Melo-Martín I, Sondhi D, Crystal RG. Novel therapies, high-risk pediatric research, and the prospect of benefit: Learning from the ethical disagreements. Molecular Therapy. 2012;20:1095-1102. DOI: 10.1038/mt.2012.90'},{id:"B46",body:'Mak IWY, Evaniew N, Ghert M. Lost in translation: Animal models and clinical trials in cancer treatment. American Journal of Translational Research. 2014;6:114-118. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902221/pdf/ajtr0006-0114.pdf'},{id:"B47",body:'Denayer T, Stöhr T, Van Roy M. Animal models in translational medicine: Validation and prediction. New Horizons in Translational Medicine. 2014;2:5-11. DOI: 10.1016/j.nhtm.2014.08.001'},{id:"B48",body:'Hepple B, Peckham C. The Ethics of Research Involving Animals. London, UK: Nuffield Council on Bioethics; 2005. ISBN: 1904384102. Available from: http://nuffieldbioethics.org/project/animal-research/'},{id:"B49",body:'Ando W, Hashimoto J, Nampei A, et al. Imatinib mesylate inhibits osteoclastogenesis and joint destruction in rats with collagen-induced arthritis (CIA). Journal of Bone and Mineral Metabolism. 2006;24:274-282. DOI: 10.1007/s00774-006-0684-1'},{id:"B50",body:'Grey A, O’Sullivan S, Reid IR, et al. Imatinib mesylate, increased bone formation, and secondary hyperparathyroidism. The New England Journal of Medicine. 2006;355:2494-2495. DOI: 10.1056/NEJMc062388'},{id:"B51",body:'Cozzi J, Fraichard A, Thiam K. Use of genetically modified rat models for translational medicine. Drug Discovery Today. 2008;13:488-494. DOI: 10.1016/j.drudis.2008.03.021'},{id:"B52",body:'Iannaccone PM, Jacob HJ. Rats! Disease Models & Mechanisms. 2009;2:206-210. DOI: 10.1242/dmm.002733'},{id:"B53",body:'Krinke GJ. The Handbook of Experimental Animals: The Laboratory Rat. In: Bullock G, Bunton TE, editors. New York: Academic Press; 2000'},{id:"B54",body:'Zemunik T, Peruzovic M, Capkun V, et al. Reproductive ability of pubertal male and female rats. Brazilian Journal of Medical and Biological Research = Revista brasileira de pesquisas medicas e biologicas. 2003;36:871-877. Available from: http://www.scielo.br/pdf/bjmbr/v36n7/4675.pdf'},{id:"B55",body:'Sengupta P. A scientific review of age determination for a laboratory rat: How old is it in comparison with human age? Biomedicine International. 2011;2:81-89. Available from: http://www.bmijournal.org/index.php/bmi/article/view/80'},{id:"B56",body:'Zanato VF, Martins MP, Anselmo-Franci JA, et al. Sexual development of male Wistar rats. Brazilian Journal of Medical and Biological Research = Revista brasileira de pesquisas medicas e biologicas. 1994;27:1273-1280. Available from: http://europepmc.org/abstract/med/8000350'},{id:"B57",body:'Freudenberger CB. A comparison of the Wistar albino and the Long-Evans hybrid strain of the Norway rat. American Journal of Anatomy. 1932;50:293-349. DOI: 10.1002/aja.1000500207'},{id:"B58",body:'Robb GW, Amann RP, Killian GJ. Daily sperm production and epididymal sperm reserves of pubertal and adult rats. Journal of Reproduction and Fertility. 1978;54:103-107. Available from: http://www.reproduction-online.org/content/54/1/103.full.pdf'},{id:"B59",body:'Boot AM, de Ridder MA, Pols HA, et al. Bone mineral density in children and adolescents: Relation to puberty, calcium intake, and physical activity. The Journal of Clinical Endocrinology and Metabolism. 1997;82:57-62. DOI: 10.1210/jcem.82.1.3665'},{id:"B60",body:'Sirois I, Cheung AM, Ward WE. Biomechanical bone strength and bone mass in young male and female rats fed a fish oil diet. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2003;68:415-421. Available from: http://www.plefa.com/article/S0952-3278(03)00066-8/fulltext'},{id:"B61",body:'Damsch S, Eichenbaum G, Tonelli A, et al. Gavage-related reflux in rats: Identification, pathogenesis, and toxicological implications (review). Toxicologic Pathology. 2011;39:348-360. DOI: 10.1177/0192623310388431'},{id:"B62",body:'Brown AP, Dinger N, Levine BS. Stress produced by gavage administration in the rat. Contemporary Topics in Laboratory Animal Science. 2000;39:17-21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11178310'},{id:"B63",body:'Tauer JT, Hofbauer LC, Jung R, et al. Micro-osmotic pumps for continuous release of the tyrosine kinase inhibitor bosutinib in juvenile rats and its impact on bone growth. Medical Science Monitor Basic Research. 2013;19:274-278. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24185529'},{id:"B64",body:'Nebendahl K. Routes of administration. In: Bullock G, Bunton TE, editors. The Handbook of Experimental Animals: The Laboratory Rat. New York: Academic Press; 2000. pp. 463-482'},{id:"B65",body:'Tober-Meyer BK, Bieniek HJ, Kupke IR. Studies on the hygiene of drinking water for laboratory animals. 2. Clinical and biochemical studies in rats and rabbits during long-term provision of acidified drinking water. Laboratory Animals. 1981;15:111-117. DOI: 10.1258/002367781780959071'},{id:"B66",body:'Bachmanov AA, Reed DR, Beauchamp GK, et al. Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behavior Genetics. 2002;32:435-443. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1397713/'},{id:"B67",body:'Pass D, Freeth G. The rat. Anzccart News. 1993;6:1-4. Available from: https://www.adelaide.edu.au/ANZCCART/docs/fact-sheets/TheRat_3Arch.pdf'},{id:"B68",body:'Tauer JT, Hofbauer LC, Jung R, et al. Impact of long-term exposure to the tyrosine kinase inhibitor imatinib on the skeleton of growing rats. PLoS One. 2015;10:e0131192. DOI: 10.1371/journal.pone.0131192'},{id:"B69",body:'Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109:3496-3499. DOI: 10.1182/blood-2006-07-036012'},{id:"B70",body:'Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2004;22:935-942. DOI: 10.1200/jco.2004.03.050'},{id:"B71",body:'Bende G, Kollipara S, Movva S, et al. Validation of an HPLC method for determination of imatinib mesylate in rat serum and its application in a pharmacokinetic study. Journal of Chromatographic Science. 2010;48:334-341. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20515524'},{id:"B72",body:'Vandyke K, Zannettino ACW. Effects of tyrosine kinase inhibitors on growth in paediatric patients. In: Akhtari M, Elhemaidi I, editors. Imatinib/Chemical Structure, Pharmacology and Adverse Effects. Vol. 1. Hauppauge, NY: NovaScience Publisher; 2013'},{id:"B73",body:'Tauer JT, Hofbauer LC, Suttorp M. Impact of the tyrosine kinase inhibitors imatinib, dasatinib, and bosutinib in young rats on the vertebral body. Blood. 2013:1472. Available from: http://www.bloodjournal.org/content/122/21/1472'},{id:"B74",body:'O’Sullivan S, Horne A, Wattie D, et al. Decreased bone turnover despite persistent secondary hyperparathyroidism during prolonged treatment with imatinib. The Journal of Clinical Endocrinology and Metabolism. 2009;94:1131-1136. DOI: 10.1210/jc.2008-2324'},{id:"B75",body:'Vandyke K, Fitter S, Drew J, et al. Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: Evidence for site-specific skeletal effects. The Journal of Clinical Endocrinology and Metabolism. 2013;98:67-76. DOI: 10.1210/jc.2012-2426'},{id:"B76",body:'El Hajj Dib I, Gallet M, Mentaverri R, et al. Imatinib mesylate (Gleevec) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity. European Journal of Pharmacology. 2006;551:27-33. DOI: 10.1016/j.ejphar.2006.09.007'},{id:"B77",body:'Jaeger BA, Tauer JT, Ulmer A, et al. Changes in bone metabolic parameters in children with chronic myeloid leukemia on imatinib treatment. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2012;18:CR721–CR728. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23197234'},{id:"B78",body:'Tauer JT, Glauche I, Suttorp M. Changes in bone metabolic parameters under imatinib treatment in children with chronic myeloid leukemia (CML). Blood. 2015;126(23):1574. Available from: http://www.bloodjournal.org/content/126/23/1574'},{id:"B79",body:'van der Eerden BC, Karperien M, Wit JM. Systemic and local regulation of the growth plate. Endocrine Reviews. 2003;24:782-801. DOI: 10.1210/er.2002-0033'},{id:"B80",body:'Tritos NA, Klibanski A. Chapter nine—Effects of growth hormone on bone. In: Felipe FC, editor. Progress in Molecular Biology and Translational Science. Vol. 138. Academic Press, London, UK; 2016. pp. 193-211'},{id:"B81",body:'Kimura F, Tsai CW. Ultradian rhythm of growth hormone secretion and sleep in the adult male rat. The Journal of Physiology. 1984;353:305-315. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1193308/pdf/jphysiol00591-0314.pdf'},{id:"B82",body:'Gamble KL, Berry R, Frank SJ, et al. Circadian clock control of endocrine factors. Nature Reviews Endocrinology. 2014;10:466-475. DOI: 10.1038/nrendo.2014.78'},{id:"B83",body:'Ulmer A, Tabea Tauer J, Glauche I, et al. TK inhibitor treatment disrupts growth hormone axis: Clinical observations in children with CML and experimental data from a juvenile animal model. Klinische Padiatrie. 2013;225:120-126. DOI: 10.1055/s-0033-1343483'},{id:"B84",body:'Ulmer A, Tauer JT, Suttorp M. Impact of treatment with tyrosine kinase inhibitors (TKIs) on blood levels of growth hormone-related parameters, testosterone, and inhibin b in juvenile rats and pediatric patients with chronic myeloid leukemia (CML). Blood. 2012;120(21):3752. Available from: http://www.bloodjournal.org/content/120/21/3752'},{id:"B85",body:'Yoshida T, Stern PH. How vitamin D works on bone. Endocrinology and Metabolism Clinics of North America. 2012;41:557-569. DOI: 10.1016/j.ecl.2012.04.003'},{id:"B86",body:'Lips P, van Schoor NM. The effect of vitamin D on bone and osteoporosis. Best Practice & Research Clinical Endocrinology & Metabolism. 2011;25:585-591. DOI: 10.1016/j.beem.2011.05.002'},{id:"B87",body:'Mehlig LM, Garve C, Tauer JT, et al. Inhibitory effects of imatinib on vitamin D(3) synthesis in human keratinocytes. Molecular Biology Reports. 2015;11:3143-3147. DOI: 10.3892/mmr.2014.3074'},{id:"B88",body:'Zhang M, Zhou H, Zheng C, et al. The roles of testicular c-kit positive cells in de novo morphogenesis of testis. Scientific Reports. 2014;4:5936. DOI: 10.1038/srep05936'},{id:"B89",body:'Samis J, Lee P, Zimmerman D, et al. Recognizing endocrinopathies associated with tyrosine kinase inhibitor therapy in children with chronic myelogenous leukemia. Pediatric Blood & Cancer. 2016;63:1332-1338. DOI: 10.1002/pbc.26028'},{id:"B90",body:'Nurmio M, Toppari J, Zaman F, et al. Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat. International Journal of Andrology. 2007;30:366-376. discussion 376. DOI: 10.1111/j.1365-2605.2007.00755.x'},{id:"B91",body:'Meachem SJ, Nieschlag E, Simoni M. Inhibin B in male reproduction: Pathophysiology and clinical relevance. European Journal of Endocrinology. 2001;145:561-571. Available from: http://www.eje-online.org/content/145/5/561.full.pdf'},{id:"B92",body:'Tauer JT, Ulmer A, Glauche I, et al. Long-term imatinib treatment does not cause testicular toxicity in male adolescents with chronic myeloid leukemia and in a juvenile rat model. Klinische Padiatrie. 2014;226:169-174. DOI: 10.1055/s-0034-1372643'},{id:"B93",body:'Girke V, Tauer JT, Glauche I, et al. Impact of long-term tyrosine kinase inhibitor exposure on spermatogenesis in juvenile rats. Blood. 2016;128(22): 1884. Available from: https://ash.confex.com/ash/2016/webprogram/Paper90120.html'},{id:"B94",body:'Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Medicine. 2006;12:908-916. DOI: 10.1038/nm1446'},{id:"B95",body:'Bhave M, Akhter N, Rosen ST. Cardiovascular toxicity of biologic agents for cancer therapy. Oncology (Williston Park, NY). 2014;28:482-490. Available from: http://www.cancernetwork.com/oncology-journal/cardiovascular-toxicity-biologic-agents-cancer-therapy'},{id:"B96",body:'Haguet H, Douxfils J, Mullier F, et al. Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: A systematic review and meta-analysis. Expert Opinion on Drug Safety. 2017;16:5-12. DOI: 10.1080/14740338.2017.1261824'},{id:"B97",body:'Hasinoff BB, Patel D, Wu X. The myocyte-damaging effects of the BCR-ABL1-targeted tyrosine kinase inhibitors increase with potency and decrease with specificity. Cardiovascular Toxicology. 2016. DOI: 10.1007/s12012-016-9386-7'},{id:"B98",body:'Galinsky I, Buchanan S. Practical management of dasatinib for maximum patient benefit. Clinical Journal of Oncology Nursing. 2009;13:329-335. DOI: 10.1188/09.cjon.329-335'},{id:"B99",body:'Orphanos GS, Ioannidis GN, Ardavanis AG. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncologica (Stockholm, Sweden). 2009;48:964-970. DOI: 10.1080/02841860903229124'},{id:"B100",body:'Maharsy W, Aries A, Mansour O, et al. Ageing is a risk factor in imatinib mesylate cardiotoxicity. European Journal of Heart Failure. 2014;16:367-376. DOI: 10.1002/ejhf.58'},{id:"B101",body:'Geidel P, Tauer JT, Steinbronn N, et al. Cardiac failure in juvenile rats caused by continuous long-term exposure to the tyrosine kinase inhibitor dasatinib can be circumvented by an intermittent application schedule. Blood. 2013;122(21):3984. Available from: http://www.bloodjournal.org/content/122/21/3984'},{id:"B102",body:'Kamath AV, Wang J, Lee FY, et al. Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): A potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Cancer Chemotherapy and Pharmacology. 2008;61:365-376. DOI: 10.1007/s00280-007-0478-8'},{id:"B103",body:'McCormack PL, Keam SJ. Dasatinib: A review of its use in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Drugs. 2011;71:1771-1795. DOI: 10.2165/11207580-000000000-00000'},{id:"B104",body:'Jonsson S, Hjorth-Hansen H, Olsson B, et al. Imatinib inhibits proliferation of human mesenchymal stem cells and promotes early but not late osteoblast differentiation in vitro. Journal of Bone and Mineral Metabolism. 2012;30:119-123. DOI: 10.1007/s00774-011-0323-3'},{id:"B105",body:'Vandyke K, Fitter S, Dewar AL, et al. Dysregulation of bone remodeling by imatinib mesylate. Blood. 2010;115:766-774. DOI: 10.1182/blood-2009-08-237404'},{id:"B106",body:'Nurmio M, Joki H, Kallio J, et al. Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats. Toxicology and Applied Pharmacology. 2011;254:267-279. DOI: 10.1016/j.taap.2011.04.019'},{id:"B107",body:'Vandyke K, Dewar AL, Fitter S, et al. Imatinib mesylate causes growth plate closure in vivo. Leukemia. 2009;23:2155-2159. DOI: 10.1038/leu.2009.150'},{id:"B108",body:'O’Sullivan S, Naot D, Callon K, et al. Imatinib promotes osteoblast differentiation by inhibiting PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent mechanisms. Journal of bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research. 2007;22:1679-1689. DOI: 10.1359/jbmr.070719'},{id:"B109",body:'Wongdee K, Krishnamra N, Charoenphandhu N. Endochondral bone growth, bone calcium accretion, and bone mineral density: How are they related? The Journal of Physiological Sciences. 2012;62:299-307. DOI: 10.1007/s12576-012-0212-0'},{id:"B110",body:'Gilbert SF. Osteogenesis: The development of bones. In: Developmental Biology. 6th ed. Sunderland (MA): Sinauer Associates; 2000. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10056/'},{id:"B111",body:'Russo D, Malagola M, Skert C, et al. Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment. Blood Cancer Journal. 2015;5:e347. DOI: 10.1038/bcj.2015.75'},{id:"B112",body:'Russo D, Martinelli G, Malagola M, et al. Updating long-term outcome of intermittent imatinib (INTERIM) treatment in elderly patients with Ph+-CML. Blood.2014;124(21):1794. Available from: http://www.bloodjournal.org/content/124/21/1794?sso-checked=true'},{id:"B113",body:'Farmer S, Horváth-Puhó E, Vestergaard H, et al. Chronic myeloproliferative neoplasms and risk of osteoporotic fractures; a nationwide population-based cohort study. British Journal of Haematology. 2013;163:603-610. DOI: 10.1111/bjh.12581'},{id:"B114",body:'Fava C, Morotti A, Dogliotti I, et al. Update on emerging treatments for chronic myeloid leukemia. Expert Opinion on Emerging Drugs. 2015;20:183-196. DOI: 10.1517/14728214.2015.1031217'},{id:"B115",body:'Kang Y, Hodges A, Ong E, et al. Identification of drug combinations containing imatinib for treatment of BCR-ABL+ leukemias. PLoS One. 2014;9:e102221. DOI: 10.1371/journal.pone.0102221'},{id:"B116",body:'Sontakke P, Jaques J, Vellenga E, et al. Modeling of chronic myeloid leukemia: An overview of in vivo murine and human xenograft models. Stem Cells International. 2016;2016:1625015. DOI: 10.1155/2016/1625015'},{id:"B117",body:'Harrison NR, Laroche FJ, Gutierrez A, et al. Zebrafish models of human leukemia: Technological advances and mechanistic insights. Advances in Experimental Medicine and Biology. 2016;916:335-369. DOI: 10.1007/978-3-319-30654-4_15'},{id:"B118",body:'Duran-Struuck R, Matar AJ, Huang CA. Myeloid leukemias and virally induced lymphomas in miniature inbred swine: Development of a large animal tumor model. Frontiers in Genetics. 2015;6:332. DOI: 10.3389/fgene.2015.00332'},{id:"B119",body:'Ma W, Ma N, Chen X, et al. An overview of chronic myeloid leukemia and its animal models. Science China Life Sciences. 2015;58:1202-1208. DOI: 10.1007/s11427-015-4965-6'},{id:"B120",body:'Giotopoulos G, van der Weyden L, Osaki H, et al. A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression. The Journal of Experimental Medicine. 2015;212:1551-1569. DOI: 10.1084/jem.20141661'},{id:"B121",body:'Schneckenleithner C, Hoelbl-Kovacic A, Sexl V. Modeling BCR/ABL-driven malignancies in the mouse. Methods in Molecular Biology (Clifton, NJ). 2015;1267:263-282. DOI: 10.1007/978-1-4939-2297-0_12'},{id:"B122",body:'Askmyr M, Agerstam H, Lilljebjorn H, et al. Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells. Blood Cancer Journal. 2014;4:e269. DOI: 10.1038/bcj.2014.89'},{id:"B123",body:'Wicklein D, Schmidt A, Labitzky V, et al. E- and p-selectins are essential for repopulation of chronic myelogenous and chronic eosinophilic leukemias in a scid mouse xenograft model. PLoS One. 2013;8:e70139. DOI: 10.1371/journal.pone.0070139'},{id:"B124",body:'Pogoda P, Priemel M, Schilling AF, et al. Mouse models in skeletal physiology and osteoporosis: Experiences and data on 14,839 cases from the Hamburg Mouse Archives. Journal of Bone and Mineral Metabolism. 2005;23(Suppl):97-102. Available from: http://link.springer.com/article/10.1007/BF03026332'},{id:"B125",body:'Parra-Torres AY, Valdés-Flores M, Orozco L, et al. Molecular aspects of bone remodeling. In: Flores MV, editor. Topics in Osteoporosis. Rijeka: InTech; 2013. Ch. 01'},{id:"B126",body:'Favus MJ. Primer on the metabolic bone diseases and disorders of mineral metabolism. In: Favus MJ, editor. 4th ed. Hagerstown, Maryland, USA: Lippincott Williams & Wilkins; 1999. p. 502. ISBN: 0-7817-2038-9'},{id:"B127",body:'Wang Q, Seeman E. Skeletal Growth and Peak Bone Strength. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 8th ed. John Wiley & Sons, Inc.; 2013. pp. 127-134. ISBN: 978-1-118-45388-9. DOI: 10.1002/9781118453926.ch16'},{id:"B128",body:'Yang T, Grover M, Joeng KS, et al. Human Fetal and Neonatal Bone Development. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 8th ed. John Wiley & Sons, Inc.; 2013. pp. 119-126. ISBN: 978-1-118-45388-9. DOI: 10.1002/9781118453926.ch15'},{id:"B129",body:'Holm IA. Skeletal Complications of Childhood Cancer. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 8th ed. John Wiley & Sons, Inc.; 2013. pp. 734-740. ISBN: 978-1-118-45388-9. DOI: 10.1002/9781118453926.ch89'},{id:"B130",body:'Inui A, Itamoto K, Takuma T, et al. Age-related changes of bone mineral density and microarchitecture in miniature pigs. The Journal of Veterinary Medical Science. 2004;66:599-609. Available from: https://www.jstage.jst.go.jp/article/jvms/66/6/66_6_599/_pdf'},{id:"B131",body:'Allori AC, Sailon AM, Pan JH, et al. Biological basis of bone formation, remodeling, and repair-part III: Biomechanical forces. Tissue Engineering Part B, Reviews. 2008;14:285-293. DOI: 10.1089/ten.teb.2008.0084'},{id:"B132",body:'Kilborn SH, Trudel G, Uhthoff H. Review of growth plate closure compared with age at sexual maturity and lifespan in laboratory animals. Contemporary Topics in Laboratory Animal Science. 2002;41:21-26. Available from: http://www.ingentaconnect.com/content/aalas/jaalas/2002/00000041/00000005/art00005?crawler=true'},{id:"B133",body:'Viateau V, Logeart-Avramoglou D, Guillemin G, et al. Animal models for bone tissue engineering purposes. In: Conn PM, editor. Sourcebook of Models for Biomedical Research. Totowa, NJ: Humana Press; 2008. pp. 725-736'},{id:"B134",body:'Muschler GF, Raut VP, Patterson TE, et al. The design and use of animal models for translational research in bone tissue engineering and regenerative medicine. Tissue Engineering Part B, Reviews. 2010;16:123-145. DOI: 10.1089/ten.TEB.2009.0658'},{id:"B135",body:'Wood MW, Hart LA. Selecting appropriate animal models and strains: Making the best use of research, information and outreach. 6th World Congress on Alternatives and Animal Use in the Life Sciences; August 21-25, 2007; Tokyo, Japan. AATEX; 2008. pp. 303-306'},{id:"B136",body:'Kojima H. The use of 3-D models as alternatives to animal testing. Alternatives to Laboratory Animals. 2015;43:P40-P43. Available from: http://pilas.org.uk/wp-content/uploads/2015/10/Opinion-Kojima-FINAL.pdf'},{id:"B137",body:'Abubakar AA, Noordin MM, Azmi TI, et al. The use of rats and mice as animal models in ex vivo bone growth and development studies. Bone & Joint Research. 2016;5:610-618. DOI: 10.1302/2046-3758.512.bjr-2016-0102.r2'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Josephine T. Tauer",address:"jtauer@shriners.mcgill.ca",affiliation:'
Department of Pediatrics, Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada
'},{corresp:null,contributorFullName:"Bernadette A. S. Jäger",address:null,affiliation:'
Department of Gynecology and Obstetrics, University Hospital, Düsseldorf, Germany
Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital, Dresden, Germany
'}],corrections:null},book:{id:"5932",title:"Experimental Animal Models of Human Diseases",subtitle:"An Effective Therapeutic Strategy",fullTitle:"Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy",slug:"experimental-animal-models-of-human-diseases-an-effective-therapeutic-strategy",publishedDate:"May 23rd 2018",bookSignature:"Ibeh Bartholomew",coverURL:"https://cdn.intechopen.com/books/images_new/5932.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"42384",title:"Dr.",name:"Bartholomew",middleName:null,surname:"Ibeh",slug:"bartholomew-ibeh",fullName:"Bartholomew Ibeh"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"60528",title:"Introductory Chapter: Animal Models for Human Diseases, a Major Contributor to Modern Medicine",slug:"introductory-chapter-animal-models-for-human-diseases-a-major-contributor-to-modern-medicine",totalDownloads:1028,totalCrossrefCites:1,signatures:"Ibeh Bartholomew Okechukwu",authors:[{id:"42384",title:"Dr.",name:"Bartholomew",middleName:null,surname:"Ibeh",fullName:"Bartholomew Ibeh",slug:"bartholomew-ibeh"}]},{id:"57348",title:"Animal Models of Diabetic Retinopathy (Part 1)",slug:"animal-models-of-diabetic-retinopathy-part-1-",totalDownloads:694,totalCrossrefCites:0,signatures:"Larissa H.C. Tang, Ian Y.H. Wong and Amy C.Y. Lo",authors:[{id:"201136",title:"Dr.",name:"Amy",middleName:null,surname:"Lo",fullName:"Amy Lo",slug:"amy-lo"},{id:"205654",title:"Ms.",name:"Larissa H.C.",middleName:null,surname:"Tang",fullName:"Larissa H.C. Tang",slug:"larissa-h.c.-tang"},{id:"205655",title:"Dr.",name:"Ian Y.H.",middleName:null,surname:"Wong",fullName:"Ian Y.H. Wong",slug:"ian-y.h.-wong"}]},{id:"57233",title:"Animal Models of Diabetic Retinopathy (Part 2)",slug:"animal-models-of-diabetic-retinopathy-part-2-",totalDownloads:685,totalCrossrefCites:0,signatures:"Larissa H.C. Tang, Ian Y.H. Wong and Amy C.Y. Lo",authors:[{id:"201136",title:"Dr.",name:"Amy",middleName:null,surname:"Lo",fullName:"Amy Lo",slug:"amy-lo"},{id:"205654",title:"Ms.",name:"Larissa H.C.",middleName:null,surname:"Tang",fullName:"Larissa H.C. Tang",slug:"larissa-h.c.-tang"},{id:"205655",title:"Dr.",name:"Ian Y.H.",middleName:null,surname:"Wong",fullName:"Ian Y.H. Wong",slug:"ian-y.h.-wong"}]},{id:"55947",title:"Animal Models of Central Diabetes Insipidus: Oxytocin and Low-Sodium Diets as Complementary Treatments",slug:"animal-models-of-central-diabetes-insipidus-oxytocin-and-low-sodium-diets-as-complementary-treatment",totalDownloads:590,totalCrossrefCites:0,signatures:"Antonio Bernal, Javier Mahía and Amadeo Puerto",authors:[{id:"202073",title:"Ph.D.",name:"Antonio",middleName:null,surname:"Bernal",fullName:"Antonio Bernal",slug:"antonio-bernal"},{id:"202078",title:"Dr.",name:"Javier",middleName:null,surname:"Mahía",fullName:"Javier Mahía",slug:"javier-mahia"},{id:"202079",title:"Dr.",name:"Amadeo",middleName:null,surname:"Puerto",fullName:"Amadeo Puerto",slug:"amadeo-puerto"}]},{id:"58438",title:"Animal Models of Obesity Characterized by Non-alcoholic Fatty Liver Disease (NAFLD)",slug:"animal-models-of-obesity-characterized-by-non-alcoholic-fatty-liver-disease-nafld-",totalDownloads:1318,totalCrossrefCites:1,signatures:"Melina Ribeiro Fernandes, Priscila Silva Figueiredo, Karoline Silva\nRezende, Karine de Cássia Freitas, Priscila Aiko Hiane and Rita de\nCássia Avellaneda Guimarães",authors:[{id:"193805",title:"Dr.",name:"Rita De Cássia",middleName:null,surname:"Avellaneda Guimarães",fullName:"Rita De Cássia Avellaneda Guimarães",slug:"rita-de-cassia-avellaneda-guimaraes"},{id:"195952",title:"Dr.",name:"Priscila Aiko",middleName:null,surname:"Hiane",fullName:"Priscila Aiko Hiane",slug:"priscila-aiko-hiane"},{id:"219249",title:"MSc.",name:"Melina",middleName:"Ribeiro",surname:"Fernandes",fullName:"Melina Fernandes",slug:"melina-fernandes"},{id:"221510",title:"Mrs.",name:"Karoline",middleName:"Silva",surname:"Rezende",fullName:"Karoline Rezende",slug:"karoline-rezende"},{id:"222406",title:"MSc.",name:"Priscila",middleName:null,surname:"Silva Figueiredo",fullName:"Priscila Silva Figueiredo",slug:"priscila-silva-figueiredo"},{id:"222408",title:"Dr.",name:"Karine De Cássia",middleName:null,surname:"Freitas",fullName:"Karine De Cássia Freitas",slug:"karine-de-cassia-freitas"}]},{id:"59623",title:"Rodent Models of Obesity and Diabetes",slug:"rodent-models-of-obesity-and-diabetes",totalDownloads:683,totalCrossrefCites:0,signatures:"María José Hernández-Granados, Joel Ramírez-Emiliano and Elena\nFranco-Robles",authors:[{id:"219102",title:"Dr.",name:"Elena",middleName:null,surname:"Franco-Robles",fullName:"Elena Franco-Robles",slug:"elena-franco-robles"},{id:"219380",title:"Dr.",name:"Joel",middleName:null,surname:"Ramírez-Emiliano",fullName:"Joel Ramírez-Emiliano",slug:"joel-ramirez-emiliano"},{id:"219382",title:"Dr.",name:"María José",middleName:null,surname:"Hernández-Granados",fullName:"María José Hernández-Granados",slug:"maria-jose-hernandez-granados"}]},{id:"56334",title:"Animal Models of Double Incontinence: “Fecal and Urinary”",slug:"animal-models-of-double-incontinence-fecal-and-urinary-",totalDownloads:568,totalCrossrefCites:0,signatures:"Raheela Mohsin Rizvi and Sanam Imtiaz",authors:[{id:"185970",title:"Dr.",name:"Raheela",middleName:"Mohsin",surname:"Rizvi",fullName:"Raheela Rizvi",slug:"raheela-rizvi"}]},{id:"55853",title:"Relevance of the CDE and DDC Mouse Models to Study Ductular Reaction in Chronic Human Liver Diseases",slug:"relevance-of-the-cde-and-ddc-mouse-models-to-study-ductular-reaction-in-chronic-human-liver-diseases",totalDownloads:845,totalCrossrefCites:3,signatures:"Laure-Alix Clerbaux, Noémi Van Hul, Annette S.H. Gouw, Rita\nManco, Regina Español-Suñer and Isabelle A. Leclercq",authors:[{id:"94627",title:"Prof.",name:"Isabelle",middleName:null,surname:"Leclercq",fullName:"Isabelle Leclercq",slug:"isabelle-leclercq"},{id:"202128",title:"Dr.",name:"Laure-Alix",middleName:null,surname:"Clerbaux",fullName:"Laure-Alix Clerbaux",slug:"laure-alix-clerbaux"},{id:"202129",title:"Dr.",name:"Noemi",middleName:null,surname:"Van Hul",fullName:"Noemi Van Hul",slug:"noemi-van-hul"},{id:"202130",title:"Dr.",name:"Regina",middleName:null,surname:"Espanol-Suner",fullName:"Regina Espanol-Suner",slug:"regina-espanol-suner"},{id:"202131",title:"Ms.",name:"Rita",middleName:null,surname:"Manco",fullName:"Rita Manco",slug:"rita-manco"},{id:"206088",title:"Prof.",name:"Annette S.H.",middleName:null,surname:"Gouw",fullName:"Annette S.H. Gouw",slug:"annette-s.h.-gouw"}]},{id:"60960",title:"Experimental Animal Models of HIV/AIDS for Vaccine Trials",slug:"experimental-animal-models-of-hiv-aids-for-vaccine-trials",totalDownloads:1707,totalCrossrefCites:0,signatures:"Bartholomew Okechukwu Ibeh and Efejiro Ashano",authors:[{id:"42384",title:"Dr.",name:"Bartholomew",middleName:null,surname:"Ibeh",fullName:"Bartholomew Ibeh",slug:"bartholomew-ibeh"}]},{id:"56083",title:"Animal Inhalation Models to Investigate Modulation of Inflammatory Bowel Diseases",slug:"animal-inhalation-models-to-investigate-modulation-of-inflammatory-bowel-diseases",totalDownloads:782,totalCrossrefCites:0,signatures:"Giuseppe Lo Sasso, Walter K. Schlage, Blaine Phillips, Manuel C.\nPeitsch and Julia Hoeng",authors:[{id:"202261",title:"Dr.",name:"Julia",middleName:null,surname:"Hoeng",fullName:"Julia Hoeng",slug:"julia-hoeng"},{id:"202450",title:"Dr.",name:"Giuseppe",middleName:null,surname:"Lo Sasso",fullName:"Giuseppe Lo Sasso",slug:"giuseppe-lo-sasso"},{id:"202451",title:"Dr.",name:"Blaine",middleName:null,surname:"Philips",fullName:"Blaine Philips",slug:"blaine-philips"},{id:"202452",title:"Prof.",name:"Walter",middleName:null,surname:"Schlage",fullName:"Walter Schlage",slug:"walter-schlage"},{id:"205866",title:"Dr.",name:"Manuel C.",middleName:null,surname:"Peitsch",fullName:"Manuel C. Peitsch",slug:"manuel-c.-peitsch"}]},{id:"60088",title:"Use of Animal Models in the Study of Colitis",slug:"use-of-animal-models-in-the-study-of-colitis",totalDownloads:898,totalCrossrefCites:0,signatures:"Karoline S. Rezende, Melina R. Fernandes, Bernardo B. de Faria, Rita\nC. A. Guimarães and Karine C. Freitas",authors:[{id:"193805",title:"Dr.",name:"Rita De Cássia",middleName:null,surname:"Avellaneda Guimarães",fullName:"Rita De Cássia Avellaneda Guimarães",slug:"rita-de-cassia-avellaneda-guimaraes"},{id:"219249",title:"MSc.",name:"Melina",middleName:"Ribeiro",surname:"Fernandes",fullName:"Melina Fernandes",slug:"melina-fernandes"},{id:"221510",title:"Mrs.",name:"Karoline",middleName:"Silva",surname:"Rezende",fullName:"Karoline Rezende",slug:"karoline-rezende"},{id:"222408",title:"Dr.",name:"Karine De Cássia",middleName:null,surname:"Freitas",fullName:"Karine De Cássia Freitas",slug:"karine-de-cassia-freitas"},{id:"236679",title:"Dr.",name:"Bernardo",middleName:null,surname:"Faria",fullName:"Bernardo Faria",slug:"bernardo-faria"}]},{id:"56216",title:"Evaluation of Animal Models Suitable for Hair Research and Regeneration",slug:"evaluation-of-animal-models-suitable-for-hair-research-and-regeneration",totalDownloads:875,totalCrossrefCites:0,signatures:"Meda Sandra Orăsan and Andrei Coneac",authors:[{id:"202125",title:"Dr.",name:"Meda",middleName:"Sandra",surname:"Orasan",fullName:"Meda Orasan",slug:"meda-orasan"},{id:"205669",title:"Dr.",name:"Andrei",middleName:null,surname:"Coneac",fullName:"Andrei Coneac",slug:"andrei-coneac"}]},{id:"58567",title:"Animal Models of Rheumatoid Arthritis",slug:"animal-models-of-rheumatoid-arthritis",totalDownloads:1058,totalCrossrefCites:0,signatures:"María Eugenia Castañeda-Lopez, Idalia Garza-Veloz, José Manuel\nOrtiz-Rodriguez, Rodrigo Castañeda-Miranda, Luis Octavio Solis-\nSanchez, Héctor Rene Vega-Carrillo, María del Rosario Martinez-\nBlanco, Fabiola Trejo-Vazquez, Gerardo Ornelas-Vargas, Iram Pablo\nRodriguez-Sanchez, Héctor Alonso Guerrero-Osuna, Iván Delgado-\nEnciso, Oscar Gustavo Meza-Zavala and Margarita de la Luz\nMartinez-Fierro",authors:[{id:"19773",title:"Dr.",name:"Jose Manuel",middleName:null,surname:"Ortiz-Rodriguez",fullName:"Jose Manuel Ortiz-Rodriguez",slug:"jose-manuel-ortiz-rodriguez"},{id:"176990",title:"MSc.",name:"Iram Pablo",middleName:null,surname:"Rodriguez-Sanchez",fullName:"Iram Pablo Rodriguez-Sanchez",slug:"iram-pablo-rodriguez-sanchez"},{id:"211746",title:"Dr.",name:"Margarita de la Luz",middleName:null,surname:"Martinez-Fierro",fullName:"Margarita de la Luz Martinez-Fierro",slug:"margarita-de-la-luz-martinez-fierro"},{id:"220027",title:"M.Sc.",name:"María E",middleName:null,surname:"Castañeda-López",fullName:"María E Castañeda-López",slug:"maria-e-castaneda-lopez"},{id:"221391",title:"Dr.",name:"Idalia",middleName:null,surname:"Garza-Veloz",fullName:"Idalia Garza-Veloz",slug:"idalia-garza-veloz"},{id:"222002",title:"Dr.",name:"Rodrigo",middleName:null,surname:"Castañeda-Miranda",fullName:"Rodrigo Castañeda-Miranda",slug:"rodrigo-castaneda-miranda"},{id:"222003",title:"Dr.",name:"Luis Octavio",middleName:null,surname:"Solis-Sanchez",fullName:"Luis Octavio Solis-Sanchez",slug:"luis-octavio-solis-sanchez"},{id:"222004",title:"Dr.",name:"Héctor Rene",middleName:null,surname:"Vega-Carrillo",fullName:"Héctor Rene Vega-Carrillo",slug:"hector-rene-vega-carrillo"},{id:"222005",title:"Dr.",name:"Maria Del Rosario",middleName:null,surname:"Martinez-Blanco",fullName:"Maria Del Rosario Martinez-Blanco",slug:"maria-del-rosario-martinez-blanco"},{id:"222164",title:"Dr.",name:"Fabiola",middleName:null,surname:"Trejo-Vazquez",fullName:"Fabiola Trejo-Vazquez",slug:"fabiola-trejo-vazquez"},{id:"222166",title:"Dr.",name:"Iván",middleName:null,surname:"Delgado-Enciso",fullName:"Iván Delgado-Enciso",slug:"ivan-delgado-enciso"},{id:"222167",title:"Dr.",name:"Oscar Gustavo",middleName:null,surname:"Meza-Zavala",fullName:"Oscar Gustavo Meza-Zavala",slug:"oscar-gustavo-meza-zavala"}]},{id:"56420",title:"Animal Models for Chronic Stress-Induced Oxidative Stress in the Spleen: The Role of Exercise and Catecholaminergic System",slug:"animal-models-for-chronic-stress-induced-oxidative-stress-in-the-spleen-the-role-of-exercise-and-cat",totalDownloads:625,totalCrossrefCites:2,signatures:"Ljubica Gavrilović, Vesna Stojiljković, Nataša Popović, Snežana Pejić,\nAna Todorović, Ivan Pavlović and Snežana B. Pajović",authors:[{id:"81583",title:"Dr.",name:"Vesna",middleName:null,surname:"Stojiljković",fullName:"Vesna Stojiljković",slug:"vesna-stojiljkovic"},{id:"123496",title:"Dr.",name:"Ljubica",middleName:null,surname:"Gavrilović",fullName:"Ljubica Gavrilović",slug:"ljubica-gavrilovic"},{id:"173330",title:"Dr.",name:"Snezana",middleName:null,surname:"Pejic",fullName:"Snezana Pejic",slug:"snezana-pejic"},{id:"173513",title:"Dr.",name:"Ana",middleName:null,surname:"Todorovic",fullName:"Ana Todorovic",slug:"ana-todorovic"},{id:"173514",title:"MSc.",name:"Ivan",middleName:null,surname:"Pavlovic",fullName:"Ivan Pavlovic",slug:"ivan-pavlovic"},{id:"173515",title:"MSc.",name:"Natasa",middleName:null,surname:"Popovic",fullName:"Natasa Popovic",slug:"natasa-popovic"},{id:"173516",title:"Dr.",name:"Snezana",middleName:null,surname:"Pajovic",fullName:"Snezana Pajovic",slug:"snezana-pajovic"}]},{id:"56527",title:"Studying Side Effects of Tyrosine Kinase Inhibitors in a Juvenile Rat Model with Focus on Skeletal Remodeling",slug:"studying-side-effects-of-tyrosine-kinase-inhibitors-in-a-juvenile-rat-model-with-focus-on-skeletal-r",totalDownloads:563,totalCrossrefCites:2,signatures:"Josephine T. Tauer, Bernadette A. S. Jäger, Anna Ulmer, Paula\nGeidel, Vera Girke, Lysann Kroschwald and Meinolf Suttorp",authors:[{id:"202231",title:"Dr.",name:"Josephine",middleName:"Tabea",surname:"Tauer",fullName:"Josephine Tauer",slug:"josephine-tauer"},{id:"202232",title:"Prof.",name:"Meinolf",middleName:null,surname:"Suttorp",fullName:"Meinolf Suttorp",slug:"meinolf-suttorp"},{id:"205988",title:"Dr.",name:"Bernadette A.S.",middleName:null,surname:"Jaeger",fullName:"Bernadette A.S. Jaeger",slug:"bernadette-a.s.-jaeger"},{id:"205990",title:"Dr.",name:"Paula",middleName:null,surname:"Geidel",fullName:"Paula Geidel",slug:"paula-geidel"},{id:"205991",title:"Dr.",name:"Vera",middleName:null,surname:"Girke",fullName:"Vera Girke",slug:"vera-girke"},{id:"205992",title:"Dr.",name:"Lysann",middleName:null,surname:"Kroschwald",fullName:"Lysann Kroschwald",slug:"lysann-kroschwald"},{id:"206040",title:"Dr.",name:"Anna",middleName:null,surname:"Ulmer",fullName:"Anna Ulmer",slug:"anna-ulmer"}]},{id:"60219",title:"Animal Models of Fetal Medicine and Obstetrics",slug:"animal-models-of-fetal-medicine-and-obstetrics",totalDownloads:1076,totalCrossrefCites:8,signatures:"Maria Dahl Andersen, Aage Kristian Olsen Alstrup, Christina\nSøndergaard Duvald, Emmeli Fredsgaard Ravnkilde Mikkelsen,\nMikkel Holm Vendelbo, Per Glud Ovesen and Michael Pedersen",authors:[{id:"220651",title:"Prof.",name:"Michael",middleName:null,surname:"Pedersen",fullName:"Michael Pedersen",slug:"michael-pedersen"},{id:"220652",title:"Ms.",name:"Maria Dahl",middleName:null,surname:"Andersen",fullName:"Maria Dahl Andersen",slug:"maria-dahl-andersen"},{id:"225411",title:"Mr.",name:"Aage Kristian",middleName:null,surname:"Olsen Alstrup",fullName:"Aage Kristian Olsen Alstrup",slug:"aage-kristian-olsen-alstrup"},{id:"226454",title:"B.Sc.",name:"Christina",middleName:null,surname:"Søndergaard Duvald",fullName:"Christina Søndergaard Duvald",slug:"christina-sondergaard-duvald"},{id:"226455",title:"MSc.",name:"Emmeli",middleName:null,surname:"Fredsgaard Ravnkilde Mikkelsen",fullName:"Emmeli Fredsgaard Ravnkilde Mikkelsen",slug:"emmeli-fredsgaard-ravnkilde-mikkelsen"},{id:"226457",title:"Dr.",name:"Mikkel",middleName:null,surname:"Holm Vendelbo",fullName:"Mikkel Holm Vendelbo",slug:"mikkel-holm-vendelbo"},{id:"226458",title:"Prof.",name:"Per",middleName:null,surname:"Glud Ovesen",fullName:"Per Glud Ovesen",slug:"per-glud-ovesen"}]},{id:"57264",title:"Animal Model of Parkinson Disease: Neuroinflammation and Apoptosis in the 6-Hydroxydopamine-Induced Model",slug:"animal-model-of-parkinson-disease-neuroinflammation-and-apoptosis-in-the-6-hydroxydopamine-induced-m",totalDownloads:813,totalCrossrefCites:1,signatures:"Daniel Hernandez-Baltazar, Rasajna Nadella, Maria de Jesus\nRovirosa-Hernandez, Laura Mireya Zavala-Flores and Christian de\nJesus Rosas Jarquin",authors:[{id:"210173",title:"Dr.",name:"Daniel",middleName:null,surname:"Hernandez-Baltazar",fullName:"Daniel Hernandez-Baltazar",slug:"daniel-hernandez-baltazar"},{id:"219107",title:"Dr.",name:"Rasajna",middleName:null,surname:"Nadella",fullName:"Rasajna Nadella",slug:"rasajna-nadella"},{id:"219108",title:"Dr.",name:"Maria De Jesus",middleName:null,surname:"Rovirosa-Hernandez",fullName:"Maria De Jesus Rovirosa-Hernandez",slug:"maria-de-jesus-rovirosa-hernandez"},{id:"219110",title:"Dr.",name:"Laura Mireya",middleName:null,surname:"Zavala-Flores",fullName:"Laura Mireya Zavala-Flores",slug:"laura-mireya-zavala-flores"},{id:"220364",title:"BSc.",name:"Christian De Jesus",middleName:null,surname:"Rosas Jarquin",fullName:"Christian De Jesus Rosas Jarquin",slug:"christian-de-jesus-rosas-jarquin"}]}]},relatedBooks:[{type:"book",id:"4546",title:"Trends in Basic and Therapeutic Options in HIV Infection",subtitle:"Towards a Functional Cure",isOpenForSubmission:!1,hash:"16887f63b697317812beb77673449a62",slug:"trends-in-basic-and-therapeutic-options-in-hiv-infection-towards-a-functional-cure",bookSignature:"Ibeh Bartholomew Okechukwu",coverURL:"https://cdn.intechopen.com/books/images_new/4546.jpg",editedByType:"Edited by",editors:[{id:"42384",title:"Dr.",name:"Bartholomew",surname:"Ibeh",slug:"bartholomew-ibeh",fullName:"Bartholomew Ibeh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"48802",title:"Spatiotemporal Dynamics of HIV Distribution Pattern and Application of Indigenous Bioresources and Microbicides in Expanding Preventive Options",slug:"spatiotemporal-dynamics-of-hiv-distribution-pattern-and-application-of-indigenous-bioresources-and-m",signatures:"Habu Josiah Bitrus and Ibeh Bartholomew Okechukwu",authors:[{id:"42384",title:"Dr.",name:"Bartholomew",middleName:null,surname:"Ibeh",fullName:"Bartholomew Ibeh",slug:"bartholomew-ibeh"},{id:"173103",title:"Mr.",name:"Josiah",middleName:null,surname:"Habu",fullName:"Josiah Habu",slug:"josiah-habu"}]},{id:"48604",title:"HIV Infection — A Sociological Approach to the Prevention of the HIV Pandemic",slug:"hiv-infection-a-sociological-approach-to-the-prevention-of-the-hiv-pandemic",signatures:"Carmen Rodríguez Reinado and Teresa Blasco Hernández",authors:[{id:"51796",title:"Dr.",name:"Carmen",middleName:null,surname:"Rodríguez",fullName:"Carmen Rodríguez",slug:"carmen-rodriguez"},{id:"52772",title:"Prof.",name:"Teresa",middleName:null,surname:"Blasco",fullName:"Teresa Blasco",slug:"teresa-blasco"}]},{id:"48990",title:"Vertical Transmission of HIV — Medical Diagnosis, Therapeutic Options and Prevention Strategy",slug:"vertical-transmission-of-hiv-medical-diagnosis-therapeutic-options-and-prevention-strategy",signatures:"Enrique Valdés Rubio and Rodolfo Guiñez Gahona",authors:[{id:"158037",title:"Prof.",name:"Enrique",middleName:null,surname:"Valdes",fullName:"Enrique Valdes",slug:"enrique-valdes"}]},{id:"48850",title:"Inhibition of HIV Replication by Host Cellular Factors",slug:"inhibition-of-hiv-replication-by-host-cellular-factors",signatures:"J.M. Azevedo-Pereira, Pedro Canhão, Marta Calado, Quirina Santos-\nCosta and Pedro Barroca",authors:[{id:"156781",title:"Prof.",name:"José Miguel",middleName:null,surname:"Azevedo-Pereira",fullName:"José Miguel Azevedo-Pereira",slug:"jose-miguel-azevedo-pereira"},{id:"172260",title:"MSc.",name:"Pedro",middleName:null,surname:"Canhão",fullName:"Pedro Canhão",slug:"pedro-canhao"},{id:"173225",title:"MSc.",name:"Pedro",middleName:null,surname:"Barroca",fullName:"Pedro Barroca",slug:"pedro-barroca"},{id:"174017",title:"Prof.",name:"Quirina",middleName:null,surname:"Santos-Costa",fullName:"Quirina Santos-Costa",slug:"quirina-santos-costa"},{id:"175087",title:"MSc.",name:"Marta",middleName:null,surname:"Calado",fullName:"Marta Calado",slug:"marta-calado"}]},{id:"49045",title:"Immunological and Haematological Changes in HIV Infection",slug:"immunological-and-haematological-changes-in-hiv-infection",signatures:"Wan Majdiah Wan Mohamad, Wan Suriana Wan Ab Rahman,\nSuhair Abbas Ahmed Al-Salih and Che Maraina Che Hussin",authors:[{id:"172799",title:"Dr.",name:"Wan Suriana",middleName:null,surname:"Wan Ab Rahman",fullName:"Wan Suriana Wan Ab Rahman",slug:"wan-suriana-wan-ab-rahman"},{id:"172963",title:"Dr.",name:"Wan Majdiah",middleName:null,surname:"Wan Mohamad",fullName:"Wan Majdiah Wan Mohamad",slug:"wan-majdiah-wan-mohamad"}]},{id:"48915",title:"The Impact of Modern Antiretroviral Therapy on Lipid Metabolism of HIV-1 Infected Patients",slug:"the-impact-of-modern-antiretroviral-therapy-on-lipid-metabolism-of-hiv-1-infected-patients",signatures:"Joel da Cunha, Luciana Morganti Ferreira Maselli, Sérgio Paulo\nBydlowski and Celso Spada",authors:[{id:"89691",title:"Dr.",name:"Sérgio",middleName:null,surname:"Bydlowski",fullName:"Sérgio Bydlowski",slug:"sergio-bydlowski"},{id:"172916",title:"Prof.",name:"Celso",middleName:null,surname:"Spada",fullName:"Celso Spada",slug:"celso-spada"},{id:"173202",title:"Dr.",name:"Joel",middleName:null,surname:"Da Cunha",fullName:"Joel Da Cunha",slug:"joel-da-cunha"},{id:"173203",title:"Dr.",name:"Luciana",middleName:null,surname:"Morganti Ferreira Maselli",fullName:"Luciana Morganti Ferreira Maselli",slug:"luciana-morganti-ferreira-maselli"}]},{id:"48627",title:"Oxidative Stress, Redox Regulation and Elite Controllers of HIV Infection: Towards a Functional Cure",slug:"oxidative-stress-redox-regulation-and-elite-controllers-of-hiv-infection-towards-a-functional-cure",signatures:"Ibeh Bartholomew Okechukwu",authors:[{id:"42384",title:"Dr.",name:"Bartholomew",middleName:null,surname:"Ibeh",fullName:"Bartholomew Ibeh",slug:"bartholomew-ibeh"}]},{id:"48605",title:"Novel Prospective Treatment Options",slug:"novel-prospective-treatment-options",signatures:"Jeremiah Stanley and Naoki Yamamoto",authors:[{id:"172996",title:"Dr.",name:"Naoki",middleName:null,surname:"Yamamoto",fullName:"Naoki Yamamoto",slug:"naoki-yamamoto"},{id:"174413",title:"Dr.",name:"Jeremiah",middleName:null,surname:"Stanley",fullName:"Jeremiah Stanley",slug:"jeremiah-stanley"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"63460",title:"The Subcutaneous Implantable Cardioverter-Defibrillator",doi:"10.5772/intechopen.80859",slug:"the-subcutaneous-implantable-cardioverter-defibrillator",body:'
1. Introduction
The subcutaneous implantable cardioverter defibrillator (S-ICD) offers an alternative rescue device for sudden cardiac death in the form of an implantable device that can offer defibrillation therapy without the need for a transvenous lead. Lead failure is the most frequent source of complication requiring surgical revision. Approximately 20% of transvenous leads fail within 10 years and extraction may lead to devastating complications, including death [1, 2, 3, 4, 5]. The S-ICD differs from conventional transvenous ICD systems in other important ways: an S-ICD requires no transvenous leads (the most frequent source of device complications) but S-ICDs do not offer bradycardia pacing, antitachycardia pacing, cardiac resynchronization, plus they have limited programmability. Approved in Europe in 2009, the S-ICD system (SQ-RX 1010, Boston Scientific, Natick, Massachusetts, USA) consists of a pulse generator and a tripolar defibrillation lead, both of which are implanted subcutaneously. In terms of size, weight, and footprint, the S-ICD device is larger and heavier than a conventional transvenous ICD (approximately 130 vs. 60 g, respectively).
S-ICDs are indicated for primary and secondary prevention but are seen as particularly useful for primary-prevention patients with a long life expectancy. The selection of an S-ICD system over a transvenous ICD may be based on a variety of factors. Transvenous ICD patients who experience device-related complications, such as lead problems, may be revised to an S-ICD device. In a German multicenter study, 25% of S-ICD patients had a previous transvenous system explanted because of device complications [6].
2. Implant techniques and considerations
The S-ICD system is composed of a tripolar parasternal lead, positioned to the left (about 1–2 cm) and parallel to the sternal midline; this lead plugs into the pulse generator, which is implanted over the fifth to sixth rib and positioned submuscularly between the midaxillarly and anterior axillary lines. The lead has three electrodes, two of which sense only. The defibrillation electrode is positioned between the two sensing electrodes. The sensing vector is created from the sensing electrode to the can, with the device automatically selecting the better electrode for the vector to assure optimal sensing. Device implantation may require minimal (to verify final position) to no fluoroscopy, as much of the technique relies on anatomical landmarks [7]. See Figure 1.
Figure 1.
The S-ICD device is implanted over the fifth to sixth rib and to the side; the parasternal lead senses the subcutaneous ECG and automatically determines which of two sensing vectors to use (top or bottom electrode to can). (Artwork by Todd Cooper, courtesy of Jo Ann LeQuang).
A three-incision technique (plus pocket formation) was originally pioneered for S-ICD implantation, and a newer two-incision approach has been described in the literature [8]. The two-incision approach creates an intermuscular pocket for the pulse generator rather than a subcutaneous pocket by incising the inframammary crease at the anterior border of the latissimus dorsi, allowing the generator to fit between the two muscles. Then a small incision at the xiphoid process (in the same direction as pocket incision) allows an electrode insertion device to tunnel the lead in place [8, 9]. In a study of 36 patients, the two-incision approach was found to be safe and effective and it may produce superior cosmetic results compared to the three-incision approach [9]. See Figure 2.
Figure 2.
Lateral view of a patient with an implanted S-ICD. (Courtesy of Dr. Peter Magnusson with permission of patient.).
The time required for device implantation has been recently reported as an average of 68 ± 20 minutes which includes intraoperative defibrillation threshold (DT) testing [10]. DT testing is of decreasing importance with transvenous ICDs but remains a much-discussed topic for S-ICD systems. Guidelines still recommend DT testing during S-ICD implantation, even though it is often used without intraoperative testing based on generalized findings from transvenous systems [11, 12, 13]. In a study of 98 S-ICD patients, 25% of patients failed to convert their induced arrhythmia with the first intraoperative 65 joule shock, necessitating further therapy delivery and/or external defibrillation. In this study, 24/25 patients could be successfully defibrillated following either reversal of shocking polarity or lead reposition although the desired 10 joules safety margin could not be achieved in 4/24 of these patients [14]. This suggests the importance of perioperative DT testing. However, 100% of patients could be converted from defibrillation with an internal 80 joule shock [14]. In a subsequent study of 110 consecutive S-ICD patients, 50% (n = 55) did not undergo defibrillation testing at implant for any of several reasons (including patient condition, age, and physician preference). In this group, 11% had episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) necessitating therapy delivery and all of them were effectively converted with the first 80 joule shock [15]. Ventricular tachycardia is a rhythm disorder originating in the heart’s lower chambers that has a rate of at least 100 beats per minute; ventricular fibrillation is a much faster, chaotic heart rhythm that causes the heart to quiver rather than pump effectively. Thus, the notion that DT testing at implant is necessary for S-ICD patients has been challenged.
S-ICD implantation may be carried out under local anesthesia [16], conscious sedation, or general anesthesia (64.1% of U.S. implants of S-ICD systems [17]. The rate of complications at implant is low and the most commonly reported complication is infection (1.8%) [18]. By dispensing with the transvenous leads, the S-ICD system avoids periprocedural and complications associated with conventional transvenous defibrillation leads, i.e. pericardial effusion, pneumothorax, accidental arterial puncture, nerve plexus injury, and tricuspid valve damage [19].
3. Safety and efficacy of S-ICDs
S-ICDs appear to have similar rates of infection and other complications as transvenous systems and to be similarly effective in rescuing patients from sudden cardiac death, but there are important distinctions between the two systems.
3.1 Safety
In a retrospective study of 1160 patients who received an implantable defibrillator (either transvenous system or S-ICD) at two centers in the Netherlands, patients were analyzed using propensity matching to yield 140 matched patient pairs. The rates of complications, infection, and inappropriate therapy were statistically similar between groups, but S-ICD patients had significantly fewer lead-related complications than the transvenous group (0.8 vs. 11.5%, p = 0.030) and more non-lead-related complications (9.9 vs. 2.2%, p = 0.047) [20]. The most frequently reported S-ICD complication involved device sensing.(20) Pooled data from the Investigational Device Exemption (IDE) and postmarket registry EFFORTLESS (n = 882) found S-ICD-related complications occurred at a rate of 11.1% at 3 years, but with no lead failures, S-ICD-related endocarditis, or bacteremia [21]. An IDE allows a device that is the subject of a clinical study to be used to collect data about safety and effectiveness that may be later used to submit to the U.S. Food and Drug Administration (FDA). Device-related complications were more frequent with transvenous systems when compared to S-ICD devices in a propensity-matched case–control study of 69 S-ICD and 69 transvenous ICD patients followed for a mean of 31 ± 19 or 32 ± 21 months, respectively. About 29% of transvenous ICD patients experienced a device-related complication compared to 6% of S-ICD patients, reducing the risk of complications for S-ICD patients by 70%; transvenous lead problems were the most frequently reported complication in the former group [22].
In the largest study of S-ICD patients (n = 3717) to date, complications were low at 1.2% overall. The most frequently reported complications were cardiac arrest (0.4%), hematoma (0.3%), death (0.3%), lead dislodgement (0.1%), myocardial infarction (0.1%), and hemothorax (<0.1%) [23]. Device revision during index hospitalization was infrequent (0.1%) [23]. Infections occur at roughly similar rates with S-ICD and transvenous systems but with the important distinction that S-ICD infections may sometimes be resolved with conservative therapy (course of antibiotics with device left in place), whereas most transvenous ICD infections necessitate the extraction of the device and the transvenous leads. In a survey from the U.K. reporting on data from 111 S-ICD patients, 11/111 (10%) of patients experienced infection, of whom 6 could be successfully treated conservatively without device extraction [24]. The EFFORTLESS registry (n = 472) reported a 4% rate of documented or suspected infections and complication-free rates at 30 and 360 days were 97 and 94%, respectively [25].
Once implanted, the S-ICD device delivers a nonprogrammable, high-energy rescue shock (80 joules) to the thorax compared to shocks of 45 joules to the heart administered by conventional transvenous systems. Notably the S-ICD delivers a 65 joule shock during implant testing. Therapy delivery differs markedly between S-ICD and transvenous systems in terms of the amount of energy delivered, location of shocking vectors, and potential for damage to surrounding tissue or the heart. In a porcine study, the mean time to therapy delivery was significantly longer with an S-ICD than a transvenous system (19 vs. 9 seconds, p = 0.001) but the S-ICD shocks were associated with less elevation of cardiac biomarkers. The longer time to therapy may be advantageous in that device patients often experience short runs of nonsustained VT. On the other hand, S-ICD shocks were associated with more skeletal muscle injuries than transvenous device shocks owing to the energy patterns resulting from the device placement but the clinical relevance of this is likely negligible [26].
3.2 Efficacy
Effective shock therapy is often defined as conversion of an episode of VT/VF within five shocks, differing from effective first-shock therapy which occurs when the initial shock converts the arrhythmia. In a study of 79 S-ICD patients at a tertiary center, 7.6% of patients experienced at least one appropriate shock for a ventricular tachyarrhythmia during the follow-up period (mean 12.8 ± 13.7 months) [27]. In a multicenter study from Germany (n = 40), shock efficacy was 96.4% [95% confidence interval (CI), 12.8–100%] and first-shock efficacy was 57.9% (95% CI, 35.6–77.4%) [6]. In an effort to analyze S-ICD efficacy in a large group of diverse patients, data from the Investigation Device Exemption (IDE) clinical study and the EFFORTLESS post-market registry were pooled to provide information about 882 patients followed for 651 ± 345 days. About 59 patients experienced therapy delivery for 111 spontaneous VT/VF episodes with first-shock efficacy in 90.1% of events and shock efficacy (termination with five or fewer shocks) in 98.2% of patients [21]. In the EFFORTLESS registry (n = 472), first-shock efficacy in discrete episodes of VT/VF was 88% and shock efficacy within five shocks was 100% [25].
4. Inappropriate shocks with S-ICDs
Inappropriate shock describes therapy delivery to treat an episode which the device inappropriately detects as a ventricular tachyarrhythmia. Inappropriate shocks have been recognized as a significant clinical challenge with transvenous systems as well as S-ICDs. In a tertiary care center study of 79 S-ICD patients, inappropriate shock occurred in 8.9% (n = 7) of patients, attributable to T-wave oversensing, atrial tachyarrhythmia with rapid atrioventricular conduction, external interference and/or baseline oversensing due to lead movement [27]. T-wave oversensing occurs when the device inappropriately senses ventricular repolarizations (the T-waves on the electrocardiograph) counting them as ventricular events, leading to double counting of the intrinsic ventricular rate. In a multicenter German study (n = 40) with a median follow-up of 229 days, four patients (10%) experienced 21 arrhythmic episodes resulting in 28 therapy deliveries. Four of these episodes were inappropriately identified by the device as ventricular tachyarrhythmias, with the result that two patients received inappropriate shocks. This results in a rate of 10% inappropriately detected ventricular tachycardia and 5% delivery of inappropriate therapy [6]. In a study using pooled data from the IDE and EFFORTLESS post-market registry (n = 882), the three-year rate for inappropriate therapy delivery was 13.1% [21].
It does not appear there are statistically more cases of inappropriate therapy in S-ICD patients compared to transvenous ICD patients. A propensity-matched study (69 patients with a transvenous ICD and 69 with an S-ICD) found the rate of inappropriate shocks was 9% in the transvenous and 3% in the S-ICD groups but this was not statistically significant (p = 0.49) [22]. In a study of 54 S-ICD patients in a real-world prospective registry, the one-year rate for inappropriate therapy delivery was 17%, most of whom had single-zone programming [10].
Inappropriate shocks with S-ICDs may be minimized. Most of them are caused by T-wave oversensing. In a survey from the U.K. (n = 111 implanted patients covered), 24 appropriate shocks were delivered in 12% of the patients (n = 13) and 51 inappropriate shocks were delivered in 15% of the patients (n = 17), of which 80% could be traced to T-wave oversensing [24]. In the EFFORTLESS registry (n = 472), there was a 7% rate of inappropriate therapy delivery in 360 days, mainly due to oversensing [25]. The main causes of inappropriate therapy delivery have been reported to be supraventricular tachycardia (SVT) at a rate above the discrimination zone, T-wave oversensing, other types of oversensing (e.g. interference), SVT discrimination errors, and low-amplitude signals [21]. Inappropriate therapy delivery due to T-wave oversensing can often be remedied by adjusting the sensing vector or adding another discrimination zone (dual-zone programming) [10].
Certain patients may be at elevated risk for inappropriate shock. A single-center study of 18 hypertrophic cardiomyopathy (HCM) patients implanted with an S-ICD system and followed for a mean 31.7 ± 15.4 months concluded that HCM patients may be at elevated risk for T-wave oversensing which could lead to inappropriate therapy delivery. In this study, 39% of these HCM patients had T-wave oversensing and 22% of the study population (n = 4) experienced inappropriate therapy delivery [28]. An evaluation of 581 S-ICD patients found that inappropriate shocks caused by oversensing occurred in 8.3% of S-ICD patients and patients with HCM and/or a history of atrial fibrillation were at elevated risk for inappropriate therapy [29]. There is a paucity of data on the use of S-ICD devices in HCM patients, but a small study of 27 HCM patients screened for possible S-ICD therapy found 85% (n = 23) were deemed appropriate candidates and 15 had the device implanted [30]. At implant testing, all patients were successfully defibrillated with a 65 joules shock and most induced arrhythmias were terminated with a 50 joules shock (12/15). After the median follow-up period of 17.5 months (range 3–35 months), there were no appropriate shocks and one inappropriate shock, attributed to oversensing caused when the QRS amplitude was reduced while the patient bent forward. In this particular high-risk patient group of HCM patients without a pacing indication, the S-ICD was effective at detecting and terminating tachyarrhythmias [30].
5. Mortality
The mortality risk with S-ICD implantation is low, but merits scrutiny. On the one hand, S-ICD implantation is generally associated with fewer risks than transvenous ICD implantation in that no transvenous leads are required. On the other hand, patient selection for S-ICD may favor more high-risk patients (such as those with a prior infection, renal failure, comorbid conditions such as diabetes) but also includes many younger and generally fitter patients. Overall, mortality data from S-ICD studies appears favorable. In a pooled analysis combining IDE data and EFFORTLESS registry information, the one-year and two-year mortality rates were 1.6 and 3.2%, respectively [21]. In a study of real-world use of S-ICDs in 54 primary- and secondary-prevention patients, mortality at the mean follow-up duration of 2.6 ± 1.9 years was 11% but no patient died of sudden cardiac arrest [10]. In a six-month study comparing 91 S-ICD and 182 single-chamber transvenous ICD patients, mortality rates were similar although the S-ICD patients had more severe pre-existing illness at implant [31]. It may be that the similar mortality rates between transvenous and S-ICD populations reflects the patient populations rather than the implantation procedure or device characteristics [23].
6. Troubleshooting S-ICDs
The S-ICD device was designed to be a streamlined system with fewer than 10 programmable features (transvenous ICDs have over 100 programmable features) and to perform in a largely automated fashion in terms of device function. The recent introduction of dual-zone programming to S-ICDs added a degree of programmability and reduced inappropriate shock [32]. Arrhythmia detection in the S-ICD relies on a system of template matching, based on waveform morphology of the subcutaneous ECG obtained at implant [33]. Oversensing and sensing-related problems are the most frequently reported problems but are being addressed in terms of device design and programmability. T-wave oversensing occurs when the device incorrectly identifies a T-wave as a QRS complex and counts it as a native ventricular beat, which leads to double-counting the rate. The use of dual-zone device programming has reduced the incidence of inappropriate therapy as a result of double-counting caused by T-wave oversensing [34]. T-wave inversions and QRS complexes that are overly large or very small may be particularly vulnerable to sensing anomalies. Reprogramming the sensing vector or therapy zones may be helpful in such instances [35, 36]. In a propensity-matched study comparing transvenous ICDs to S-ICDs, there were three inappropriate shocks in the S-ICD group, all of which were due to T-wave oversensing in sinus rhythm and all of which could be eliminated with adjustment of the sensing vector [22]. Furthermore, it has been observed with increasing operator experience and better programming techniques, sensing problems have been reduced [21]. In a study using pooled data from the IDE and EFFORTLESS registry, the rate of inappropriate therapy associated with oversensing was <1% [21]. When inappropriate shock occurs, the stored electrograms will likely help identify the cause. If lead malposition is suspected, a chest X-ray may be appropriate. In case of oversensing, the sensing vector may be optimized, device programming may be revised to add a second detection zone, or pharmacological therapy may be added [32].
SVT discrimination likewise relies on template-matching (which is similar to transvenous systems) but the S-ICD may be able to accomplish this with a higher degree of resolution than transvenous ICDs [33]. The use of dual-zone programming appears advantageous.
7. Primary and secondary prevention
Primary- and secondary-prevention patients represent two distinct patient populations who may be treated with S-ICD therapy, although S-ICDs seem particularly well suited for primary-prevention patients. Secondary-prevention patients have a lower rate of comorbid conditions and significantly higher left-ventricular ejection fractions (LVEF) than primary-prevention patients (48 vs. 36%, p < 0.0001), while primary-prevention patients had a higher incidence of heart failure and were more likely to have had a transvenous ICD implanted before the S-ICD. Primary-prevention patients also have a higher rate of ischemic cardiomyopathy (41 vs. 33%) and nonischemic cardiomyopathy (28 vs. 12%) [18]. S-ICDs have been shown to be effective for both primary- and secondary-prevention patients. In a study of 856 S-ICD patients (mean follow-up 644 days), there were no significant differences between primary- and secondary-prevention populations in the rates of effective arrhythmia conversions, inappropriate therapy, mortality or complications although appropriate therapy delivery was delivered to significantly more secondary-prevention than primary prevention patients (11.9 vs. 5.0%, p = 0.0004) [18].
The freedom from any appropriate therapy delivery was 88.4% among primary-prevention patients with an LVEF ≤35 and 96.2% among primary-prevention patients with an LVEF >35%. The freedom from any appropriate therapy delivery among secondary-prevention patients was 92.1% [18]. Spontaneous conversion to sinus rhythm was more frequent among primary-prevention patients (about 48% of all ventricular tachyarrhythmias) compared to secondary-prevention patients (31%) [18]. However, the rates of inappropriate therapy delivery and complications were similar for both primary- and secondary-prevention patients [18].
8. The optimal candidates for S-ICD
S-ICD systems are indicated for patients who require rescue defibrillation but do not need bradycardia pacing support and would not benefit from antitachycardia pacing or cardiac resynchronization therapy. This includes primary- and secondary-prevention patients. By avoiding transvenous leads, the S-ICD is particularly appropriate for patients with occluded veins or limited venous access (who are not suitable candidates for transvenous systems) and the S-ICD may be beneficial for younger, fitter, and active patients. The generator position of the S-ICD patient may make it easier and safer for strong, fit patients to resume active lifestyles without jeopardizing lead position.
Despite the fact that S-ICD devices are larger than transvenous systems, their lateral placement may result in more pleasing esthetic results than a conventional transvenous ICD. Young device patients likely will have a lifetime of device therapy, resulting over time in much hardware in their vasculature; the S-ICD thus presents an advantage in that regard. It appears that S-ICDs are implanted in a younger patient population; a survey of multiple U.K. hospitals (n = 111 patients) found the median patient age was 33 (range 10–87 years) [24]. The mean age of patients in the EFFORTLESS registry was 49 ± 18 years (range 9–88 years) [25]. Younger patients with cardiomyopathy or channelopathy often have a high rate of complications with conventional transvenous ICDs [37] and it has been thought they may be better served with an S-ICD device [9].
In a multicenter case–control study, it was found that 59.4% of S-ICD patients were primary-prevention and the main underlying cardiac conditions were dilated cardiomyopathy (36.2%), ischemic cardiomyopathy (15.9%), and HCM (14.5%) [38]. In particular, these patients have been considered challenging to treat with a conventional transvenous ICD in that they may have an erratic electrical substrate in the heart and increased left-ventricular mass, which could contribute to an elevated DT. First-shock efficacy rates of up to 88% are promising in light of these challenges [25]. In a study of 50 hypertrophic cardiomyopathy patients implanted with S-ICDs, 96% of patients could be induced to an arrhythmia at implant and of the 73 episodes of VF induced, 98% were successfully converted with 65 joules from the S-ICD during DT testing. One patient in this study (2%) required rescue external defibrillation [39]. The patient who failed internal defibrillation had a body mass index of 36 and was successfully converted by an 80 joules shock with reversed polarity from the S-ICD [39].
9. Current guidelines
9.1 Indications
The most recent guidelines to address S-ICD were published by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society in 2017 [40]. The An S-ICD is indicated (Class of Recommendation 1, level of evidence B) for patients who meet indication criteria for a transvenous ICD but who have inadequate vascular access or are at high risk of infection and for whom there is no anticipated need for bradycardia or antitachycardia pacing. Further, implantation of an S-ICD is deemed reasonable for patients with an ICD indication for whom there is no anticipated need for bradycardia or antitachycardia pacing (Class of Recommendation IIa, level of evidence B). An S-ICD is contraindicated in a patient who is indicated for bradycardia pacing, antitachycardia pacing for termination of ventricular tachyarrhythmias, and/or cardiac resynchronization therapy (Class of Recommendation III, level of evidence B) [40].
The European Society of Cardiology guidelines from 2015 report that S-ICDs are effective in preventing sudden cardiac death and the device is recommended as an alternative to transvenous ICDs in patients who are indicated for defibrillation but not pacing support, cardiac resynchronization therapy, or antitachycardia pacing (Class IIa, Level C). Moreover, the S-ICD was considered to be a useful alternative for patients in whom venous access was difficult or for patients who had a transvenous system explanted because of an infection or for young patients expected to need long-term ICD therapy [41].
9.2 Pre-implant testing
Those considered for S-ICD therapy should be screened with a modified version of the three-channel surface electrocardiogram (ECG) set up to represent the sensing vectors of the S-ICD. With the patient both standing and supine, the ratio of R-wave to T-wave should be established and signal quality evaluated. If any of the three vectors does not result in satisfactory sensing, the S-ICD should not be implanted. Once the actual device is implanted in the patient, the system automatically selects the optimal sensing vector [11].
9.3 Programming
The S-ICD may be programmed to detect arrhythmias using a single- or dual-zone configuration. In the dual-zone configuration, a lower cutoff rate defines what might be called a “conditional shock zone” to which a discrimination algorithm is applied so that therapy is withheld if the rhythm might be deemed supraventricular in origin or non-arrhythmic oversensing. This discrimination zone relies on a form of template matching. Above that rate, a cutoff establishes the “shock zone” which delivers a shock based on the rate criterion alone. When the capacitors charge in anticipation of shock delivery, a confirmation algorithm assures the persistence of the arrhythmia prior to sending the shock. Shocks are delivered at the nonprogrammable 80 joules of energy [11].
10. Future directions
The evolution of the S-ICD adds an important new device into the armamentarium for rescuing patients from sudden cardiac death. To further improve S-ICD technology, size reduction, increased battery longevity, and improved T-wave rejection will be needed. In the near future, improvement in sensing function might eliminate the need for a separate screening ECG prior to implant, which could optimize clinical workflow.
Improved battery technology is particularly important as the S-ICD is often used in patients with a relatively long life expectancy. Leadless pacemaker systems that might work together with an S-ICD are in development which would allow for bradycardia pacing support, antitachycardia pacing and a subcutaneous defibrillator without transvenous leads [32]. The development of a leadless epicardial pacemaker might allow for left-atrial and left-ventricular pacing function to be integrated to the S-ICD. Taken altogether, these improvements could make the S-ICD the preferred device in the vast majority of cases for rescue from sudden cardiac death.
11. Conclusion
The subcutaneous implantable cardioverter defibrillator (S-ICD) offers an alternative to transvenous ICDs but the two systems should not be considered interchangeable. The S-ICD is appropriate for patients who require only rescue defibrillation (primary or secondary prevention) but does not offer bradycardia pacing, antitachycardia pacing, overdrive pacing, or cardiac resynchronization therapy. S-ICD devices may be appropriate in patients who have occluded vasculature or device infection with a transvenous system. Effectiveness, rate of infections, and survival rates are similar for both devices although, in general, S-ICDs may be implanted in patients with more serious underlying conditions such as end-stage renal disease or advanced diabetes. Infections with S-ICDs are more likely to be effectively treated with a conservative course of antibiotic therapy and no device extraction. Inappropriate shocks occur at similar rates with both systems but are more likely caused by oversensing in the S-ICD. A main advantage of S-ICDs over transvenous systems is the elimination of the transvenous defibrillation lead which may be considered the Achilles heel of the transvenous system, having a 10-year complication rate of 25%. It is likely that considerable advances in ICD therapy will occur in the next decade as the S-ICD systems are further refined.
Conflict of interest
The authors have no conflicts of interest to declare.
\n',keywords:"lead complications, subcutaneous ICD, sudden cardiac death, S-ICD, transvenous ICD, T-wave oversensing",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/63460.pdf",chapterXML:"https://mts.intechopen.com/source/xml/63460.xml",downloadPdfUrl:"/chapter/pdf-download/63460",previewPdfUrl:"/chapter/pdf-preview/63460",totalDownloads:546,totalViews:178,totalCrossrefCites:1,dateSubmitted:"June 19th 2018",dateReviewed:"August 10th 2018",datePrePublished:"November 5th 2018",datePublished:null,dateFinished:null,readingETA:"0",abstract:"The subcutaneous ICD (S-ICD) represents an important advancement in defibrillation therapy that obviates the need for a transvenous lead, the most frequent complication with transvenous devices. The S-ICD has been shown similarly safe and effective as transvenous ICD therapy, but the two devices are not interchangeable. The S-ICD is only suitable for patients who do not require bradycardia or antitachycardia pacing functionality. In patients with underlying diseases associated with polymorphic ventricular tachycardia and a long life expectancy, an S-ICD may be the preferred choice. Moreover, it is advantageous in the situation of increased risk of endocarditis, i.e., previous device system infection and immunosuppression, including hemodialysis. In patients with abnormal vascular access and/or right-sided heart structural abnormalities, it may be the only option. The S-ICD is bulkier, the battery longevity is shorter, and the device cost is higher, even though remote follow-up is possible. A two- or three-incision implant procedure has been described with a lateral placement of the device and a single subcutaneous lead. The rate of inappropriate therapy for both S-ICD and transvenous systems is similar, but S-ICD inappropriate shocks are more frequently attributable to oversensing, which can often be resolved with sensing adjustments.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/63460",risUrl:"/chapter/ris/63460",signatures:"Peter Magnusson, Joseph V. Pergolizzi and Jo Ann LeQuang",book:{id:"7049",title:"Cardiac Pacing and Monitoring",subtitle:"New Methods, Modern Devices",fullTitle:"Cardiac Pacing and Monitoring - New Methods, Modern Devices",slug:"cardiac-pacing-and-monitoring-new-methods-modern-devices",publishedDate:"April 24th 2019",bookSignature:"Mart Min",coverURL:"https://cdn.intechopen.com/books/images_new/7049.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"62780",title:"Prof.",name:"Mart",middleName:null,surname:"Min",slug:"mart-min",fullName:"Mart Min"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Implant techniques and considerations",level:"1"},{id:"sec_3",title:"3. Safety and efficacy of S-ICDs",level:"1"},{id:"sec_3_2",title:"3.1 Safety",level:"2"},{id:"sec_4_2",title:"3.2 Efficacy",level:"2"},{id:"sec_6",title:"4. Inappropriate shocks with S-ICDs",level:"1"},{id:"sec_7",title:"5. Mortality",level:"1"},{id:"sec_8",title:"6. Troubleshooting S-ICDs",level:"1"},{id:"sec_9",title:"7. Primary and secondary prevention",level:"1"},{id:"sec_10",title:"8. The optimal candidates for S-ICD",level:"1"},{id:"sec_11",title:"9. Current guidelines",level:"1"},{id:"sec_11_2",title:"9.1 Indications",level:"2"},{id:"sec_12_2",title:"9.2 Pre-implant testing",level:"2"},{id:"sec_13_2",title:"9.3 Programming",level:"2"},{id:"sec_15",title:"10. Future directions",level:"1"},{id:"sec_16",title:"11. Conclusion",level:"1"},{id:"sec_20",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Kleemann T, Becker T, Doenges K, Vater M, Senges J, Schneider S, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of >10 years. Circulation. 2007;115:2474-2480. DOI: 10.1161/CIRCULATIONAHA.106.663807'},{id:"B2",body:'Maisel WH, Kramer DB. Implantable cardioverter-defibrillator lead performance. Circulation. 2008;117:2721-2723. DOI: 10.1161/CIRCULATIONAHA.108.776807'},{id:"B3",body:'Alter P, Waldhans S, Plachta E, Moosdorf R, Grimm W. Complications of implantable cardioverter defibrillator therapy in 440 consecutive patients. Pacing and Clinical Electrophysiology: PACE. 2005;28:926-932. DOI: 10.1111/j.1540-8159.2005.00195.x'},{id:"B4",body:'Borleffs CJ, van Erven L, van Bommel RJ, van der Velde ET, van der Wall EE, Bax JJ, et al. Risk of failure of transvenous implantable cardioverter-defibrillator leads. Circulation. Arrhythmia and Electrophysiology. 2009;2:411-416. DOI: 10.1161/CIRCEP.108.834093'},{id:"B5",body:'Kalahasty G, Ellenbogen KA. Management of the patient with implantable cardioverter-defibrillator lead failure. Circulation. 2011;123:1352-1354. DOI: 10.1161/CIRCULATIONAHA.110.986828'},{id:"B6",body:'Aydin A, Hartel FW, Schluter M, Butter C, Kobe J, Seifert M, et al. Shock efficacy of subcutaneous implantable cardioverter-defibrillator for prevention of sudden cardiac death. Circulation. Arrhythmia and Electrophysiology. 2012;5:913-919. DOI: 10.1161/CIRCEP.112.973339'},{id:"B7",body:'Bardy GH, Smith WM, Hood MA, Crozier IG, Melton IC, Jordaens L, et al. An entirely subcutaneous implantable cardioverter-defibrillator. The New England Journal of Medicine. 2010;363:36-44. DOI: 10.1056/NEJMoa0909545'},{id:"B8",body:'Winter J, Siekiera M, Shin DI, Meyer C, Kropil P, Clahsen H, et al. Intermuscular technique for implantation of the subcutaneous implantable cardioverter defibrillator: Long-term performance and complications. Europace. 2017;19:2036-2041. DOI: 10.1093/europace/euw297'},{id:"B9",body:'Migliore F, Allocca G, Calzolari V, Crosato M, Facchin D, Daleffe E, et al. Intermuscular two-incision technique for subcutaneous implantable Cardioverter defibrillator implantation: Results from a multicenter registry. Pacing and Clinical Electrophysiology: PACE. 2017;40:278-285. DOI: 10.1111/pace.12987'},{id:"B10",body:'Mesquita J, Cavaco D, Ferreira A, Lopes N, Santos PG, Carvalho MS, et al. Effectiveness of subcutaneous implantable cardioverter-defibrillators and determinants of inappropriate shock delivery. International Journal of Cardiology. 2017;232:176-180. DOI: 10.1016/jicard.2017.01.034'},{id:"B11",body:'Wilkoff BL, Fauchier L, Stiles MK, Morillo CA, Al-Khatib SM, Almendral J, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Europace. 2016;18:159-183. DOI: 10.1093/europace/euv411'},{id:"B12",body:'Bansch D, Bonnemeier H, Brandt J, Bode F, Svendsen JH, Taborsky M, et al. Intra-operative defibrillation testing and clinical shock efficacy in patients with implantable cardioverter-defibrillators: The NORDIC ICD randomized clinical trial. European Heart Journal. 2015;36:2500-2507. DOI: 10.1093/eurheartj/ehv292'},{id:"B13",body:'Healey JS, Hohnloser SH, Glikson M, Neuzner J, Mabo P, Vinolas X, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: A single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet. 2015;385(14):785, 61903-791, 61906. DOI: 10.1016/S01410-6736'},{id:"B14",body:'Frommeyer G, Zumhagen S, Dechering DG, Larbig R, Bettin M, Loher A, et al. Intraoperative defibrillation testing of subcutaneous implantable Cardioverter-defibrillator systems–A Simple issue. Journal of the American Heart Association. 2016;5:e003181. DOI: 10.1161/JAHA.115.003181'},{id:"B15",body:'Miller MA, Palaniswamy C, Dukkipati SR, Balulad S, Smietana J, Vigdor A, et al. Subcutaneous implantable cardioverter-defibrillator implantation without defibrillation testing. Journal of the American College of Cardiology. 2017;69:3118-3119. DOI: 10.1016/j.jacc.2017.04.037'},{id:"B16",body:'Dabiri Abkenari L, Theuns D, Valk S, Van Belle Y, de Groot N, Haitsma D, et al. Clinical experience with a novel subcutaenous implantable defibrillator system in a single center. Clinical Research in Cardiology: Official Journal of the German Cardiac Society. 2011;100:737-744. DOI: 10.1007/00392-011-0303-6'},{id:"B17",body:'Gold MR, Aasbo JD, El-Chami MF, Niebauer M, Herre J, Prutkin JM, et al. Subcutaneous implantable cardioverter-defibrillator post-approval study: Clinical characteristics and perioperative results. Heart Rhythm: The Official Journal of the Heart Rhythm Society. 2017;14:1456-1463. DOI: 10.1016/j.hrthm.2017.05.016'},{id:"B18",body:'Boersma LV, Barr CS, Burke MC, Leon AR, Theuns DA, Herre JM, et al. Performance of the subcutaneous implantable cardioverter-defibrillator in patients with a primary prevention indication with and without a reduced ejection fraction versus patients with a secondary prevention indication. Heart Rhythm: The Official Journal of the Heart Rhythm Society. 2017;14:367-375. DOI: 10.1016/j.hrthmj.2016.11.025'},{id:"B19",body:'Olde Nordkamp LRA, Conte G, Rosenmoller B, Warnaars JLF, Tan HL, Caputo ML, et al. Brugada syndrome and the subcutaneous implantable cardioverter-defibrillator. Journal of the American College of Cardiology. 2016;68:665-666. DOI: 10.1016/j.jacc.2016.05.058'},{id:"B20",body:'Brouwer TF, Yilmaz D, Lindeboom R, Buiten MS, Olde Nordkamp LR, Schalij MJ, et al. Long-term clinical outcomes of subcutaneous versus transvenous implantable defibrillator therapy. Journal of the American College of Cardiology. 2016;68:2047-2055. DOI: 10.1016/j.jacc.2016.08.044'},{id:"B21",body:'Burke MC, Gold MR, Knight BP, Barr CS, Theuns DA, Boersma LV, et al. Safety and efficacy of the totally subcutaneous implantable defibrillator: 2-year results from a pooled analysis of the IDE study and EFFORTLESS registry. Journal of the American College of Cardiology. 2015;65:1605-1615. DOI: 10.1016/j.jacc.2015.02.047'},{id:"B22",body:'Honarbakhsh S, Providencia R, Srinivasan N, Ahsan S, Lowe M, Rowland E, et al. A propensity matched case-control study comparing efficacy, safety and costs of the subcutaneous vs. transvenous implantable cardioverter defibrillator. International Journal of Cardiology. 2017;228:280-285. DOI: 10.1016/j.ijcard.2016.11.017'},{id:"B23",body:'Friedman DJ, Parzynski CS, Varosy PD, Prutkin JM, Patton KK, Mithani A, et al. Trends and in-hospital outcomes associated with adoption of the subcutaneous implantable cardioverter defibrillator in the United States. JAMA Cardiology. 2016;1:900-911. DOI: 10.1001/jamacardio.2016.2782'},{id:"B24",body:'Jarman JW, Todd DM. United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: Important lessons to learn. Europace. 2013;15:1158-1165. DOI: 10.1093/europace/eut016'},{id:"B25",body:'Lambiase PD, Barr C, Theuns DA, Knops R, Neuzil P, Johansen JB, et al. Worldwide experience with a totally subcutaneous implantable defibrillator: Early results from the EFFORTLESS S-ICD registry. European Heart Journal. 2014;35:1657-1665. DOI: 10.1093/eurheartj/ehu112'},{id:"B26",body:'Garcia R, Inal S, Favreau F, Jayle C, Hauet T, Bruneval P, et al. Subcutaneous cardioverter defibrillator has longer time to therapy but is less cardiotoxic than transvenous cardioverter defibrillator. Study carried out in a preclinical porcine model. Europace. 2018;20:873-879. DOI: 10.1093/europaceeux074'},{id:"B27",body:'Khazen C, Magnusson P, Flandorfer J, Schukro C. The subcutaneous implantable cardioverter-defibrillator: A tertiary center experience. Cardiology Journal. 2 May 2018. DOI: 10.5603/CJ.a2018.0050. [Epub ahead of print]'},{id:"B28",body:'Frommeyer G, Dechering DG, Zumhagen S, Loher A, Kobe J, Eckardt L, et al. Long-term follow-up of subcutaneous ICD systems in patients with hypertrophic cardiomyopathy: A single-center experience. Clinical Research in Cardiology: Official Journal of the German Cardiac Society. 2016;105:89-93. DOI: 10.1007/s00392-015-0901-9'},{id:"B29",body:'Olde Nordkamp LR, Brouwer TF, Barr C, Theuns DA, Boersma LV, Johansen JB, et al. Inappropriate shocks in the subcutaneous ICD: Incidence, predictors and management. International Journal of Cardiology. 2015;195:126-133. DOI: 10.1016/j.ijcard.2015.015.135'},{id:"B30",body:'Weinstock J, Bader YH, Maron MS, Rowin EJ, Link MS. Subcutaneous implantable cardioverter defibrillator in patients with hypertrophic cardiomyopathy: An initial experience. Journal of the American Heart Association. 2016;5:piie002488. DOI: 10.1161/JAHA.115.002488'},{id:"B31",body:'Mithani AA, Kath H, Hunter K, Andriulli J, Ortman M, Field J, et al. Characteristics and early clinical outcomes of patients undergoing totally subcutaneous vs. transvenous single chamber implantable cardioverter defibrillator placement. Europace. 2018;20:308-314. DOI: 10.1093/europace/eux026'},{id:"B32",body:'McLeod CJ, Boersma L, Okamura H, Friedman PA. The subcutaneous implantable cardioverter defibrillator: State-of-the-art review. European Heart Journal. 2017;38:247-257. DOI: 10.1093/eurheartj/ehv507'},{id:"B33",body:'De Maria E, Olaru A, Cappelli S. The entirely subcutaneous defibrillator (s-icd): State of the art and selection of the ideal candidate. Current Cardiology Reviews. 2015;11:180-186. DOI: 10.2174/157403X10666140827094126'},{id:"B34",body:'Weiss R, Knight BP, Gold MR, Leon AR, Herre JM, Hood M, et al. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation. 2013;128:944-953. DOI: 10.1161/CIRCULATIONAHA.113.003042'},{id:"B35",body:'Gold MR, Theuns DA, Knight BP, Sturdivant JL, Sanghera R, Ellenbogen KA, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: The START study. Journal of Cardiovascular Electrophysiology. 2012;23:359-366. DOI: 10.1111/j.1540-8167.2011.02199'},{id:"B36",body:'Kooiman KM, Knops RE, Olde Nordkamp L, Wilde AA, de Groot JR. Inappropriate subcutaneous implantable cardioverter-defibrillator shocks due to T-wave oversensing can be prevented: Implications for management. Heart Rhythm: The Official Journal of the Heart Rhythm Society. 2014;11:426-434. DOI: 10.1016/j.hrthm.2013.12.007'},{id:"B37",body:'Migliore F, Silvano M, Zorzi A, Bertaglia E, Siciliano M, Leoni L, et al. Implantable cardioverter defibrillator therapy in young patients with cardiomyopathies and channelopathies: A single Italian Centre experience. Journal of Cardiovascular Medicine (Hagerstown, Md). 2016;17:485-493. DOI: 10.2459/JCM.0000000000000395'},{id:"B38",body:'Kobe J, Reinke F, Meyer C, Shin DI, Martens E, Kaab S, et al. Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-defibrillators: A multicenter case-control study. Heart Rhythm: The official Journal of the Heart Rhythm Society. 2013;10:29-36. DOI: 10.1016/j.hrthm.2012.09.126'},{id:"B39",body:'Maurizi N, Tanini I, Olivotto I, Amendola E, Limongelli G, Losi MA, et al. Effectiveness of subcutaneous implantable cardioverter-defibrillator testing in patients with hypertrophic cardiomyopathy. International Journal of Cardiology. 2017;231:115-119. DOI: 10.1016/j.ijcard.2016.12.187'},{id:"B40",body:'Al-Khatib SM, Stevenson WG, Ackerman MJ, Gillis AM, Bryant WJ, et al. AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society. Heart Rhythm: The Official Journal of the Heart Rhythm Society. 30 Oct 2017. pii: S1547-5271(17);31249-31253. DOI: 10.1016/j.hrthm.2017.10.035. [Epub ahead of print] No abstract available. PMID: 29097320'},{id:"B41",body:'Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). European Heart Journal. 2015;36:2793-2867. DOI: 10.1093/eurheartj/ehv316'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Peter Magnusson",address:null,affiliation:'
Cardiology Research Unit, Department of Medicine, Karolinska Institute, Sweden
Centre for Research and Development, Uppsala University/Region Gävleborg, Sweden
'},{corresp:null,contributorFullName:"Joseph V. Pergolizzi",address:null,affiliation:'
Native Cardio, Inc., USA
'},{corresp:"yes",contributorFullName:"Jo Ann LeQuang",address:"joann@leqmedical.com",affiliation:'
NEMA Research Inc., USA
'}],corrections:null},book:{id:"7049",title:"Cardiac Pacing and Monitoring",subtitle:"New Methods, Modern Devices",fullTitle:"Cardiac Pacing and Monitoring - New Methods, Modern Devices",slug:"cardiac-pacing-and-monitoring-new-methods-modern-devices",publishedDate:"April 24th 2019",bookSignature:"Mart Min",coverURL:"https://cdn.intechopen.com/books/images_new/7049.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"62780",title:"Prof.",name:"Mart",middleName:null,surname:"Min",slug:"mart-min",fullName:"Mart Min"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"196891",title:"Ms.",name:"Thamires",middleName:null,surname:"Ráfaga Campus E Figueredo",email:"thamiresrafaga@gmail.com",fullName:"Thamires Ráfaga Campus E Figueredo",slug:"thamires-rafaga-campus-e-figueredo",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{title:"Use of Mass Spectrometry for the Determination of Formaldehyde in Samples Potentially Toxic to Humans: A Brief Review",slug:"use-of-mass-spectrometry-for-the-determination-of-formaldehyde-in-samples-potentially-toxic-to-human",abstract:"The chemical characteristics of formaldehyde make it widely used and important in the global economy. It has applications in the health area and in various industrial sectors. However, formaldehyde is considered toxic substance and is classifed as a persistent organic pollutant. Direct and prolonged contact with formaldehyde can cause serious damage to the body and may even lead to death. It is classifed by several agencies as a human carcinogen and may exhibit mutagenic/teratogenic efects and/or damage the endocrine system. Various matrices have been found to contain formaldehyde at concentrations higher than those permited by global health regulatory agencies. To this end, mass spectrometry can provide a very useful tool, enabling the identifcation and quantifcation of formaldehyde. Although various analytical techniques can be used for the determination and quantifcation of volatile organic compounds, chromatography is one of the most widely used methods due to its precision. Coupled to a detection system such as mass spectrometry, it can be employed for the determination of compounds potentially toxic to humans, including formaldehyde. The purpose of this chapter is to summarize some recent and important studies concerning the quantifcation of formaldehyde using mass spectrometry as a powerful analytical tool.",signatures:"Aline de Souza, Isabela Cristina Matos Cunha, Júnior Olair Chagas,\nElisandra Bárbara Pontes Carlos, Luana Lacerda Santos, Thamires\nRáfaga Campos e Figueredo, Lucília Alves Linhares Machado,\nVanessa Moreira Osório, Karla Moreira Vieira and Fabiana\nAparecida Lobo",authors:[{id:"64529",title:"Dr.",name:"Fabiana",surname:"Lobo",fullName:"Fabiana Lobo",slug:"fabiana-lobo",email:"fabs_lobo@yahoo.com.br"},{id:"196885",title:"Ms.",name:"Aline",surname:"Souza",fullName:"Aline Souza",slug:"aline-souza",email:"alinesouza2021@gmail.com"},{id:"196886",title:"MSc.",name:"Isabela",surname:"Cristina Matos Cunha",fullName:"Isabela Cristina Matos Cunha",slug:"isabela-cristina-matos-cunha",email:"isabelacmcunha@gmail.com"},{id:"196887",title:"MSc.",name:"Júnior",surname:"Olair Chagas",fullName:"Júnior Olair Chagas",slug:"junior-olair-chagas",email:"jocfunhouse@gmail.com"},{id:"196888",title:"Dr.",name:"Karla",surname:"Moreira Vieira",fullName:"Karla Moreira Vieira",slug:"karla-moreira-vieira",email:"vieirakarla@decea.ufop.br"},{id:"196889",title:"Ms.",name:"Elisandra",surname:"Bárbara Pontes Carlos",fullName:"Elisandra Bárbara Pontes Carlos",slug:"elisandra-barbara-pontes-carlos",email:"elisandrapontes5@gmail.com"},{id:"196890",title:"Ms.",name:"Luana",surname:"Lacerda Santos",fullName:"Luana Lacerda Santos",slug:"luana-lacerda-santos",email:"luanalacerda66@mail.com"},{id:"196891",title:"Ms.",name:"Thamires",surname:"Ráfaga Campus E Figueredo",fullName:"Thamires Ráfaga Campus E Figueredo",slug:"thamires-rafaga-campus-e-figueredo",email:"thamiresrafaga@gmail.com"},{id:"196892",title:"Dr.",name:"Vanessa",surname:"Moreira Osório",fullName:"Vanessa Moreira Osório",slug:"vanessa-moreira-osorio",email:"moreirava@yahoo.com.br"},{id:"203171",title:"Dr.",name:"Lucília Alves Linhares",surname:"Machado",fullName:"Lucília Alves Linhares Machado",slug:"lucilia-alves-linhares-machado",email:"lucilia@decea.ufop.br"}],book:{title:"Mass Spectrometry",slug:"mass-spectrometry",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"14179",title:"Dr.",name:"Renata",surname:"Raina-Fulton",slug:"renata-raina-fulton",fullName:"Renata Raina-Fulton",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Regina",institutionURL:null,country:{name:"Canada"}}},{id:"188770",title:"Prof.",name:"Zhixun",surname:"Luo",slug:"zhixun-luo",fullName:"Zhixun Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197035",title:"Dr.",name:"Ana Claudia",surname:"Amaral",slug:"ana-claudia-amaral",fullName:"Ana Claudia Amaral",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Rio de Janeiro",institutionURL:null,country:{name:"Brazil"}}},{id:"197039",title:"Dr.",name:"Aline",surname:"De Souza Ramos",slug:"aline-de-souza-ramos",fullName:"Aline De Souza Ramos",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197040",title:"Dr.",name:"Jefferson",surname:"Rocha De Andrade Silva",slug:"jefferson-rocha-de-andrade-silva",fullName:"Jefferson Rocha De Andrade Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197041",title:"Dr.",name:"José Luiz",surname:"Pinto Ferreira",slug:"jose-luiz-pinto-ferreira",fullName:"José Luiz Pinto Ferreira",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197045",title:"MSc.",name:"Marcelo Henrique",surname:"Cunha Chaves",slug:"marcelo-henrique-cunha-chaves",fullName:"Marcelo Henrique Cunha Chaves",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197046",title:"BSc.",name:"Vinicius",surname:"Vaz Cabral Nery",slug:"vinicius-vaz-cabral-nery",fullName:"Vinicius Vaz Cabral Nery",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197048",title:"Mr.",name:"Jefferson",surname:"Diocesano Da Cruz",slug:"jefferson-diocesano-da-cruz",fullName:"Jefferson Diocesano Da Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197049",title:"BSc.",name:"Iasmim",surname:"Castro De Lima",slug:"iasmim-castro-de-lima",fullName:"Iasmim Castro De Lima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"WIS-cost",title:"What Does It Cost?",intro:"
Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.
",metaTitle:"What Does It Cost?",metaDescription:"Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"
We are currently in the process of collecting sponsorship. If you have any ideas or would like to help sponsor this ambitious program, we’d love to hear from you. Contact us at info@intechopen.com.
\\n\\n
All of our IntechOpen sponsors are in good company! The research in past IntechOpen books and chapters have been funded by:
\\n\\n
\\n\\t
European Commission
\\n\\t
Bill and Melinda Gates Foundation
\\n\\t
Wellcome Trust
\\n\\t
National Institute of Health (NIH)
\\n\\t
National Science Foundation (NSF)
\\n\\t
National Institute of Standards and Technology (NIST)
We are currently in the process of collecting sponsorship. If you have any ideas or would like to help sponsor this ambitious program, we’d love to hear from you. Contact us at info@intechopen.com.
\n\n
All of our IntechOpen sponsors are in good company! The research in past IntechOpen books and chapters have been funded by:
\n\n
\n\t
European Commission
\n\t
Bill and Melinda Gates Foundation
\n\t
Wellcome Trust
\n\t
National Institute of Health (NIH)
\n\t
National Science Foundation (NSF)
\n\t
National Institute of Standards and Technology (NIST)
\n\t
Research Councils United Kingdom (RCUK)
\n\t
Foundation for Science and Technology (FCT)
\n\t
Chinese Academy of Sciences
\n\t
Natural Science Foundation of China (NSFC)
\n\t
German Research Foundation (DFG)
\n\t
Max Planck Institute
\n\t
Austrian Science Fund (FWF)
\n\t
Australian Research Council (ARC)
\n
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5775},{group:"region",caption:"Middle and South America",value:2,count:5239},{group:"region",caption:"Africa",value:3,count:1721},{group:"region",caption:"Asia",value:4,count:10411},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15810}],offset:12,limit:12,total:118378},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{sort:"dateendthirdsteppublish",topicid:"11"},books:[],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:18},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:5},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:8},{group:"topic",caption:"Computer and Information Science",value:9,count:6},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:20},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:5},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:25},{group:"topic",caption:"Neuroscience",value:18,count:2},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:3},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:0,limit:12,total:null},popularBooks:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5249},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editedByType:"Edited by",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editedByType:"Edited by",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editedByType:"Edited by",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9669",title:"Recent Advances in Rice Research",subtitle:null,isOpenForSubmission:!1,hash:"12b06cc73e89af1e104399321cc16a75",slug:"recent-advances-in-rice-research",bookSignature:"Mahmood-ur- Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9669.jpg",editedByType:"Edited by",editors:[{id:"185476",title:"Dr.",name:"Mahmood-Ur-",middleName:null,surname:"Rahman Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-Ur- Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1236",title:"Quantum Theory",slug:"quantum-theory",parent:{title:"Quantum Physics",slug:"quantum-physics"},numberOfBooks:1,numberOfAuthorsAndEditors:20,numberOfWosCitations:41,numberOfCrossrefCitations:16,numberOfDimensionsCitations:24,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"quantum-theory",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"3527",title:"Ferromagnetic Resonance",subtitle:"Theory and Applications",isOpenForSubmission:!1,hash:"5018d38d6945912cc51b5733fff95ea7",slug:"ferromagnetic-resonance-theory-and-applications",bookSignature:"Orhan Yalcin",coverURL:"https://cdn.intechopen.com/books/images_new/3527.jpg",editedByType:"Edited by",editors:[{id:"101308",title:"Prof.",name:"Dr. Orhan",middleName:null,surname:"Yalçın",slug:"dr.-orhan-yalcin",fullName:"Dr. Orhan Yalçın"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,mostCitedChapters:[{id:"45530",doi:"10.5772/56058",title:"Microwave Absorption in Nanostructured Spinel Ferrites",slug:"microwave-absorption-in-nanostructured-spinel-ferrites",totalDownloads:3396,totalCrossrefCites:5,totalDimensionsCites:6,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Gabriela Vázquez-Victorio, Ulises Acevedo-Salas\nand Raúl Valenzuela",authors:[{id:"167617",title:"Prof.",name:"Raul",middleName:null,surname:"Valenzuela",slug:"raul-valenzuela",fullName:"Raul Valenzuela"},{id:"167618",title:"MSc.",name:"Gabriela",middleName:null,surname:"Vazquez",slug:"gabriela-vazquez",fullName:"Gabriela Vazquez"},{id:"167619",title:"Dr.",name:"Ulises",middleName:null,surname:"Acevedo Salas",slug:"ulises-acevedo-salas",fullName:"Ulises Acevedo Salas"}]},{id:"45524",doi:"10.5772/55962",title:"Detection of Magnetic Transitions by Means of Ferromagnetic Resonance and Microwave Absorption Techniques",slug:"detection-of-magnetic-transitions-by-means-of-ferromagnetic-resonance-and-microwave-absorption-techn",totalDownloads:2475,totalCrossrefCites:3,totalDimensionsCites:5,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"H. Montiel and G. Alvarez",authors:[{id:"165241",title:"Dr.",name:"Guillermo",middleName:null,surname:"Alvarez",slug:"guillermo-alvarez",fullName:"Guillermo Alvarez"},{id:"165798",title:"Dr.",name:"Herlinda",middleName:null,surname:"Montiel",slug:"herlinda-montiel",fullName:"Herlinda Montiel"}]},{id:"45527",doi:"10.5772/56134",title:"Ferromagnetic Resonance",slug:"ferromagnetic-resonance",totalDownloads:10562,totalCrossrefCites:4,totalDimensionsCites:5,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Orhan Yalçın",authors:[{id:"101308",title:"Prof.",name:"Dr. Orhan",middleName:null,surname:"Yalçın",slug:"dr.-orhan-yalcin",fullName:"Dr. Orhan Yalçın"}]}],mostDownloadedChaptersLast30Days:[{id:"45527",title:"Ferromagnetic Resonance",slug:"ferromagnetic-resonance",totalDownloads:10565,totalCrossrefCites:4,totalDimensionsCites:5,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Orhan Yalçın",authors:[{id:"101308",title:"Prof.",name:"Dr. Orhan",middleName:null,surname:"Yalçın",slug:"dr.-orhan-yalcin",fullName:"Dr. Orhan Yalçın"}]},{id:"45526",title:"FMR Measurements of Magnetic Nanostructures",slug:"fmr-measurements-of-magnetic-nanostructures",totalDownloads:5682,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Manish Sharma, Sachin Pathak and Monika Sharma",authors:[{id:"166931",title:"Dr.",name:"Manish",middleName:null,surname:"Sharma",slug:"manish-sharma",fullName:"Manish Sharma"},{id:"166932",title:"Dr.",name:"Sachin",middleName:null,surname:"Pathak",slug:"sachin-pathak",fullName:"Sachin Pathak"},{id:"166933",title:"Dr.",name:"Monika",middleName:null,surname:"Sharma",slug:"monika-sharma",fullName:"Monika Sharma"}]},{id:"45531",title:"Instrumentation for Ferromagnetic Resonance Spectrometer",slug:"instrumentation-for-ferromagnetic-resonance-spectrometer",totalDownloads:5792,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Chi-Kuen Lo",authors:[{id:"165561",title:"Prof.",name:"Chi-Kuen",middleName:null,surname:"Lo",slug:"chi-kuen-lo",fullName:"Chi-Kuen Lo"}]},{id:"45524",title:"Detection of Magnetic Transitions by Means of Ferromagnetic Resonance and Microwave Absorption Techniques",slug:"detection-of-magnetic-transitions-by-means-of-ferromagnetic-resonance-and-microwave-absorption-techn",totalDownloads:2480,totalCrossrefCites:3,totalDimensionsCites:5,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"H. Montiel and G. Alvarez",authors:[{id:"165241",title:"Dr.",name:"Guillermo",middleName:null,surname:"Alvarez",slug:"guillermo-alvarez",fullName:"Guillermo Alvarez"},{id:"165798",title:"Dr.",name:"Herlinda",middleName:null,surname:"Montiel",slug:"herlinda-montiel",fullName:"Herlinda Montiel"}]},{id:"45530",title:"Microwave Absorption in Nanostructured Spinel Ferrites",slug:"microwave-absorption-in-nanostructured-spinel-ferrites",totalDownloads:3397,totalCrossrefCites:5,totalDimensionsCites:6,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Gabriela Vázquez-Victorio, Ulises Acevedo-Salas\nand Raúl Valenzuela",authors:[{id:"167617",title:"Prof.",name:"Raul",middleName:null,surname:"Valenzuela",slug:"raul-valenzuela",fullName:"Raul Valenzuela"},{id:"167618",title:"MSc.",name:"Gabriela",middleName:null,surname:"Vazquez",slug:"gabriela-vazquez",fullName:"Gabriela Vazquez"},{id:"167619",title:"Dr.",name:"Ulises",middleName:null,surname:"Acevedo Salas",slug:"ulises-acevedo-salas",fullName:"Ulises Acevedo Salas"}]},{id:"45529",title:"FMR Studies of [SnO2/Cu-Zn Ferrite] Multilayers",slug:"fmr-studies-of-sno2-cu-zn-ferrite-multilayers",totalDownloads:1966,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"R. Singh and S. Saipriya",authors:[{id:"165795",title:"Prof.",name:"Rajender",middleName:null,surname:"Singh",slug:"rajender-singh",fullName:"Rajender Singh"}]},{id:"45528",title:"Optical Properties of Antiferromagnetic/Ion-Crystalic Photonic Crystals",slug:"optical-properties-of-antiferromagnetic-ion-crystalic-photonic-crystals",totalDownloads:1818,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Shu-Fang Fu and Xuan-Zhang Wang",authors:[{id:"165669",title:"Dr.",name:"Shufang",middleName:null,surname:"Fu",slug:"shufang-fu",fullName:"Shufang Fu"}]},{id:"45525",title:"Dynamic and Rotatable Exchange Anisotropy in Fe/KNiF3/FeF2 Trilayers",slug:"dynamic-and-rotatable-exchange-anisotropy-in-fe-knif3-fef2-trilayers",totalDownloads:2047,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Stefania Widuch, Robert L. Stamps,\nDanuta Skrzypek and Zbigniew Celinski",authors:[{id:"165706",title:"Ph.D.",name:"Stefania",middleName:null,surname:"Widuch",slug:"stefania-widuch",fullName:"Stefania Widuch"},{id:"167095",title:"Prof.",name:"Robert L.",middleName:null,surname:"Stamps",slug:"robert-l.-stamps",fullName:"Robert L. Stamps"},{id:"167096",title:"Prof.",name:"Danuta",middleName:null,surname:"Skrzypek",slug:"danuta-skrzypek",fullName:"Danuta Skrzypek"},{id:"167097",title:"Prof.",name:"Zbigniew",middleName:null,surname:"Celinski",slug:"zbigniew-celinski",fullName:"Zbigniew Celinski"}]},{id:"45532",title:"Unusual Temperature Dependence of Zero-Field Ferromagnetic Resonance in Millimeter Wave Region on Al-Substituted ε-Fe2O3",slug:"unusual-temperature-dependence-of-zero-field-ferromagnetic-resonance-in-millimeter-wave-region-on-al",totalDownloads:2886,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"ferromagnetic-resonance-theory-and-applications",title:"Ferromagnetic Resonance",fullTitle:"Ferromagnetic Resonance - Theory and Applications"},signatures:"Marie Yoshikiyo, Asuka Namai and Shin-ichi Ohkoshi",authors:[{id:"23211",title:"Prof.",name:"Shin-Ichi",middleName:null,surname:"Ohkoshi",slug:"shin-ichi-ohkoshi",fullName:"Shin-Ichi Ohkoshi"},{id:"167506",title:"BSc.",name:"Marie",middleName:null,surname:"Yoshikiyo",slug:"marie-yoshikiyo",fullName:"Marie Yoshikiyo"},{id:"167507",title:"MSc.",name:"Asuka",middleName:null,surname:"Namai",slug:"asuka-namai",fullName:"Asuka Namai"}]}],onlineFirstChaptersFilter:{topicSlug:"quantum-theory",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/196891/thamires-rafaga-campus-e-figueredo",hash:"",query:{},params:{id:"196891",slug:"thamires-rafaga-campus-e-figueredo"},fullPath:"/profiles/196891/thamires-rafaga-campus-e-figueredo",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()