",isbn:"978-1-83881-922-4",printIsbn:"978-1-83881-921-7",pdfIsbn:"978-1-83881-923-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"dcfc52d92f694b0848977a3c11c13d00",bookSignature:"Dr. Fiaz Ahmad and Prof. Muhammad Sultan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10454.jpg",keywords:"Agricultural Engineering, Technologies, Application, Sustainable Agriculture, Information Technology in Agriculture, Food Security, Renewable Energies, Precision Farming, Smart Agriculture, Farm Mechanization, Robotics, Post Harvest Technologies",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 25th 2020",dateEndSecondStepPublish:"December 23rd 2020",dateEndThirdStepPublish:"February 21st 2021",dateEndFourthStepPublish:"May 12th 2021",dateEndFifthStepPublish:"July 11th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Ahmad is a researcher in the field of agricultural mechanization and agricultural equipment engineering, in-charge of Farm Machinery Design Laboratory at Bahauddin Zakariya University, with expertise in modeling and simulation. He applied for two patents at the national level.",coeditorOneBiosketch:"Renowned researcher with a focus on developing energy-efficient heat- and/or water-driven temperature and humidity control systems for agricultural storage, greenhouse, agricultural livestock and poultry applications including HVAC, desiccant air-conditioning, adsorption, Maisotsenko cycle (M-cycle), and adsorption desalination.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"338219",title:"Dr.",name:"Fiaz",middleName:null,surname:"Ahmad",slug:"fiaz-ahmad",fullName:"Fiaz Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/338219/images/system/338219.jpg",biography:"Fiaz Ahmad obtained his Ph.D. (2015) from Nanjing Agriculture University China in the field of Agricultural Bioenvironmental and Energy Engineering and Postdoc (2020) from Jiangsu University China in the field of Plant protection Engineering. He got the Higher Education Commission, Pakistan Scholarship for Ph.D. studies, and Post-Doctoral Fellowship from Jiangsu Government, China. During postdoctoral studies, he worked on the application of unmanned aerial vehicle sprayers for agrochemical applications to control pests and weeds. He passed the B.S. and M.S. degrees in agricultural engineering from the University of Agriculture Faisalabad, Pakistan in 2007. From 2007 to 2008, he was a Lecturer in the Department of Agricultural Engineering, Bahauddin Zakariya University, Multan-Pakistan. Since 2009, he has been an Assistant Professor in the Department of Agricultural Engineering, BZ University Multan, Pakistan. He is the author of 33 journal articles. He also supervised 6 master students and is currently supervising 5 master and 2 Ph.D. students. In addition, Dr. Ahmad completed three university-funded projects. His research interests include the design of agricultural machinery, artificial intelligence, and plant protection environment.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}}],coeditorOne:{id:"199381",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sultan",slug:"muhammad-sultan",fullName:"Muhammad Sultan",profilePictureURL:"https://mts.intechopen.com/storage/users/199381/images/system/199381.jpeg",biography:"Muhammad Sultan completed his Ph.D. (2015) and Postdoc (2017) from Kyushu University (Japan) in the field of Energy and Environmental Engineering. He was an awardee of MEXT and JASSO fellowships (from the Japanese Government) during Ph.D. and Postdoc studies, respectively. In 2019, he did Postdoc as a Canadian Queen Elizabeth Advanced Scholar at Simon Fraser University (Canada) in the field of Mechatronic Systems Engineering. He received his Master\\'s in Environmental Engineering (2010) and Bachelor in Agricultural Engineering (2008) with distinctions, from the University of Agriculture, Faisalabad. He worked for Kyushu University International Institute for Carbon-Neutral Energy Research (WPI-I2CNER) for two years. Currently, he is working as an Assistant Professor at the Department of Agricultural Engineering, Bahauddin Zakariya University (Pakistan). He has supervised 10+ M.Eng./Ph.D. students so far and 10+ M.Eng./Ph.D. students are currently working under his supervision. He has published more than 70+ journal articles, 70+ conference articles, and a few magazine articles, with the addition of 2 book chapters and 2 edited/co-edited books. Dr. Sultan is serving as a Leading Guest Editor of a special issue in the Sustainability (MDPI) journal (IF 2.58). In addition, he is appointed as a Regional Editor for the Evergreen Journal of Kyushu University. His research is focused on developing energy-efficient heat- and/or water-driven temperature and humidity control systems for agricultural storage, greenhouse, livestock, and poultry applications. His research keywords include HVAC, desiccant air-conditioning, evaporative cooling, adsorption cooling, energy recovery ventilator, adsorption heat pump, Maisotsenko cycle (M-cycle), wastewater, energy recovery ventilators; adsorption desalination; and agricultural, poultry and livestock applications.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@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:"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"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"55476",title:"Development of Tumor-Specific Caffeine-Potentiated Chemotherapy Using Span 80 Nano-Vesicles DDS",doi:"10.5772/intechopen.69155",slug:"development-of-tumor-specific-caffeine-potentiated-chemotherapy-using-span-80-nano-vesicles-dds",body:'\n
1. Introduction
\n
At present, osteosarcoma cases with metastasis, especially in lungs, have poor prognosis [1, 2]. In recent years, caffeine-potentiated chemotherapy, which is chemotherapy with caffeine dosage against malignancies, has manifested potently high efficacy [3, 4]. Nevertheless, this method may induce adverse effects that patients suffer, which include most commonly tachycardia, nausea, psychiatric symptoms, as well as lethal arrhythmia with individual diversity [5]. On the other hand, there have been numerous developments in novel drug delivery systems (DDSs) for drug carriers for the treatment of various diseases that enabled target-specific drug delivery resulting in the prevention of side effects [6–8].
\n
Recently, we demonstrated that nonionic vesicles prepared from Span 80 have promising physicochemical properties, such as high membrane fluidity associated with low-phase transition temperature, which make them an attractive possible alternative to the commonly used liposomes. Lipid vesicles have been extensively studied. Since the discovery of mechanism for liposome by Bangham et al. that aqueous phase of phosphatidylcholines includes self-closed phospholipid bilayers, which can capture and obtain water-soluble molecules [9], lipid vesicles have been actively investigated.Following early reports on vesicle formation from completely synthetic amphiphiles [10], vesicles have been prepared from a large number of different surfactants [11, 12]. Many vesicle systems have been characterized to some extent and applied in various research areas, ranging from pharmaceuticals [12–15], food technology [12, 16, 17],and analyticalapplications to origin-of-life [18, 19]and artificial cell studies [20]. Vesicles based on nonionic surfactants (so-called “niosomes”) [12, 21]were first used in the cosmetic industry [10, 21, 22]as alternatives to phospholipid-based vesicles (liposomes). One of the many surfactants used for niosome preparations is Span 80, a cheap, molecularly heterogeneous nonionic surfactant that is also applied as food emulsifier and in oral pharmaceuticals [23, 24]. Span 80 is known as sorbitan mono-oleate generally; nevertheless, commercially available Span 80 may be a heterogeneous mixture of sorbitan mono-, di-, tri, and tetra-esters which could let high fluidity and vascular permeability [25–27].
\n
A successful therapeutic murine model of transplanted colon cancer employs the DDS using Span 80 vesicles which have immobilized polysaccharides [28]. In this chapter, we introduce a novel DDS by using Span 80 nano-vesicles, and manifested that tumor-specific caffeine-potentiated chemotherapy for murine osteosarcoma using a novel DDS with Span 80 nano-vesicles showed significant antitumor effects, as well as limited adverse effects.
\n
\n
2. Span 80 nano-vesicles
\n
2.1. Characteristics of Span 80 as a material for food and pharmaceuticals
\n
As mentioned above, Span 80 is known as sorbitan mono-oleate; nevertheless, commercially available Span 80 might be heterogeneous mixture, rather mainly diesters, in addition to triesters and tetraesters [23, 25]. Furthermore, the polar headgroup of the different esters present in Span 80 is not sorbitol, but more likely one of the different forms of anhydrized sorbitol [29, 30], a cheap, molecularly heterogeneous nonionic surfactant that is also applied as food emulsifier and in oral pharmaceuticals [31]. The substantial molecular heterogeneity of commercial Span 80 is (i) a consequence of the conditions used for the synthesis (reaction of sorbitol with fatty acids (mainly oleic acid) at elevated temperature) [24, 29] and (ii) based on the fact that there are no purification method following the synthesis with excellent cost-performance ratio for yielding inexpensive products and applicable to large-scale purification. Commercially available Span 80 was determined by its molecular composition. The property of it may even be better when compared to the properties of the individual purified components of commercially available Span 80.
\n
\n
2.2. Preparation of Span 80 nano-vesicles in different forms
\n
In our study, we prepared several variations of Span 80 vesicles as follows: Commercially available Span 80 was processed using the two-step emulsification method (Span 80 vesicles type 1), sequentially extruded by a polycarbonate membrane (Span 80 vesicles type 2) or ultrafiltrated (Span 80 vesicles type 3). Fractionation of commercially available Span 80 by chromatography into the different ester groups (see Figure 1) and vesicular preparation using the defined mixture of the four kinds of different ester groups (Span 80 vesicles type 4) or preparation from the diester fraction (Span 80 vesicles type 5) were performed [25].
\n
Figure 1.
Electron microscopic analysis of Span 80 vesicles type 2 (100 nm), prepared in PBS. (A) Cryo-TEM micrographs showing unilamellar- and bilamellar vesicles and bilayer fragments (arrow). Length of the bar: 100 nm. Freeze fracture (B) and negative-staining (C) electron micrographs of Span 80 vesicles type 2 (100 nm), prepared in PBS solution. Length of the bar: 100 nm. The arrow in C points to one of the fragments present. [Reprinted with permission from Ref. [25]. Copyright (2008) American Chemical Society].
\n
\n
2.3. Evaluation of diameter and homology by a dynamic light scattering
\n
Vesicle characterization by dynamic light scattering (DLS) and electron microscopy was performed. The different types of Span 80 vesicles prepared either in distilled water or in phosphate-buffered saline (PBS) solution were analyzed after vesicle preparation by dynamic light scattering. As expected from the different preparation methods used, the average vesicle size and size distribution depend on the vesicle type, independent of whether PBS or distilled water was used as aqueous medium. (a) The vesicle size would depend on the employed method; therefore, the prepared Span 80 vesicles should be kinetically trapped aggregates and might not have thermodynamically equilibrium structures, just like most of phosphatidylcholine vesicles. (b) The most homogeneous vesicles with the lowest polydispersity index were prepared by the extrusion method. When employing PBS as the aqueous medium, the size of Span 80 vesicle type 1 with an apparent size of 250 ± 45 nm, which was obtained by DLS, could be reduced into 105 ± 13 nm by extrusion through polycarbonate membranes with a nominal pore diameter of 100 nm. Extrusion method enabled to make more homogeneous vesicles with less polydispersity index. Span 80 vesicles type 2 manifested the appropriate diameter (c.a. 100 nm) for the drug delivery; therefore, these types of vesicles were employed for further analyses in the development of DDS.
\n
\n
2.4. Evaluation of diameter and physicochemical property by electron microscopy
\n
Span 80 vesicles type 2 (100 nm) prepared in PBS was also statistically analyzed by cryo-transmission electron microscopy (cryo-TEM, Figure 1A), yielding a number-weighted average vesicle size of 63. This value is lower than the z-average value (scattering intensity weighted) determined by DLS. Next, the hydrodynamic diameter was evaluated; on the other hand, in cryo-TEM images, the projected, “true” size of a spherical vesicle was obtained. The discrepancy among these methods could be addressed that the electron dense headgroup area made vesicles more boundary. Conclusively, electron microscopy revealed the diameter and bilayer thickness of the vesicles by Cryo-TEM, as well as the presence of uniformity of the vesicles by freeze fracture scanning electron microscopy (Figure 1). Electron micrographs revealed that Span 80 vesicle suspensions contain not only vesicles but also bilayer fragments. The clear contrast was observed among 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or dioleoylphosphatidylcholine (DOPC) vesicles which might be due to the molecular heterogeneity of Span 80 vesicles.
\n
\n
2.5. Temperature sensitivity of Span 80 vesicles
\n
The temperature sensitivity of Span 80 vesicles might not link directly to the Tm value, because the observed fusion phenomenon did not develop at Tm as the temperature-sensitive vesicles based on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) [32].In DPPC-based vesicles, the thermos-responsive effect is the leakage of the aqueous contents when the temperature reaches Tm [33].
\n
The Span 80 vesicles develop fusion in response to an increase in temperature. Therefore, the molecular mechanisms of thermos-response in each kind of vesicles are different. The presence of bilayer fragments in fused Span 80 vesicles at an elevated temperature is not clear at this moment. However, the nonionic headgroup in Span 80 could be dehydrated and result in vesicle-vesicle aggregation and fusion at the temperature above Tm.
\n
\n
2.6. Vesicle membrane fusion property
\n
The vesicle fusion property may be advantageous for efficient drug delivery, and applications of the several types of Span 80 vesicles described and characterized in this chapter, and previous papers largely depend on the vesicle’s cytotoxicity. Although previous studies of Span 80-based vesicles regarding cytotoxicity either as a drug carrier or as a gene vector were successful, further studies have been required before any conclusions with respect to pharmaceutical applications [25] can be drawn. Among the various types of Span 80 vesicles investigated, Span 80 vesicles type 2 (100 nm) might be the most attractive one (straightforward methodology with the requirement of simple equipment only).
\n
\n
\n
3. Caffeine-potentiated chemotherapy using Span 80 nano-vesicles’ DDS
\n
We developed the murine osteosarcoma therapeutic model of caffeine-potentiated chemotherapy. In this model, as the therapeutic agents, ifosfamide (IFO) was employed as well as caffeine sodium benzoate (CSB) as an enhancer. As the murine osteosarcoma therapeutic model, C3H/HeJ mice underwent transplanted murine osteosarcoma cell line LM8. The detailed procedures were described in the original paper [34].
\n
3.1. Preparation of Span 80 nano-vesicles
\n
Span 80 nano-vesicles, which contained IFO and/or caffeine, were freshly prepared as previously described [28]. Briefly, materials for assembling nano-vesicles containing Span 80 and Tween-80 [35], cholesterol, which worked as the stabilizer of the membrane, polyethylene glycol, used as a stealth modifier against macrophages [28], and the solvents, normal hexane and normal saline, were purchased, respectively. All processes were performed under sterilized conditions.
\n
The two-step emulsification method was employed to process and purify the nano-vesicles. Span 80 and cholesterol were dissolved in hexane by homogenization with a micro-homogenizer in a sterilized brown glass bottle. Sequentially, the first emulsion was prepared by adding IFO and/or CSB, which dissolved in normal saline into the Span 80 material followed by homogenization. As a negative control, phosphate-buffered saline was dripped alternatively. The second-stage emulsion was processed by evaporation using a rotary vacuum evaporator on a water bath at 37°C followed by homogenization with Tween-80.
\n
The second emulsion was centrifuged using ultra-centrifugation equipment. After aspiration of the supernatant, the sediment of the Span 80 vesicles was weighed and then suspended in normal saline at a concentration of 20% w/v. By this method, IFO Span 80 vesicles (IV), CSB Span 80 vesicles (CV), and PBS-alone Span 80 vesicles (PV) were prepared. Immediately before the use in vivo or in vitro, these suspensions became extruded by a custom-made extruder with a drain disk of 100-μm thickness and a Nucleopore membrane® of 100-nm pore size to control the vesicular size. As a result, the diameter of the vesicles was evaluated by the dynamic light-scattering device and revealed 117 nm at average.
\n
\n
3.2. In vitro evaluation of the antitumor effects of the nano-vesicles
\n
The murine osteosarcoma cell line, LM8, was obtained and employed as an osteosarcoma model. LM8 cells in Dulbecco\'s modified Eagle\'s medium were plated and cultured in 24-well culture dishes for a few days until the cells showed semi-confluent state. Next, antitumor agents with or without Span 80 vesicles, including PV, IV, CV, direct administration of IFO or CSB, as well as the combination of IV + CSB, IFO + CV and IV + CV were administered. Cells were incubated with the antitumor agents at 37°C for 1 or 2 h, and then the cells were harvested and evaluated for apoptosis and cell viability, respectively.
\n
In vitro analyses revealed cultured LM8 murine osteosarcoma cells with IV + CV almost complete cell death by the trypan blue assay, on the other hand, PBS, CSB, PV, and CV manifested almost no cell death. IFO resulted in 13%, IV resulted in 28%, and IFO + CV resulted in 75% cell death (Figure 2 and Table 1).
\n
Figure 2.
Representative photomicrographs of the trypan blue-stained LM8 cells after a 2-h incubation with antitumor agents: (A) PV, (B) CV, (C) IFO, (D) IV, (E) IFO + CV, and (F) IV + CV. [Reprinted with permission from Ref. [34]. Copyright (2014) Spandidos Publications].
Nonviable cell population in trypan blue analysis.
aP < 0.05 versus PBS, CBS, PV, and CV.
bP < 0.05 versus PBS, CSB, PV, CV, and IFO.
cP < 0.01 versus IFO, P < 0.05 versus IV and IFO + CSB.
dP < 0.01 versus IV + CSB and the other groups
eP < 0.05 versus IFO + CV, P < 0.01 versus the other groups.
\n
\n
3.3. Apoptosis detection by propidium iodide (PI) method
\n
Briefly, cells were suspended in ice-cold Hank\'s balanced saline solution (HBSS), followed by fixation with 70% EtOH at −20°C [36]. Fixed cells were centrifuged, then pellets were re-suspended in extraction buffer of pH 7.8 which contained Na2HPO4, citric acid, and 0.1% Triton X-100 at 37°C. Then, a staining solution of pH 6.8 containing PIPES, NaCl, Mg2Cl, Triton X-100, PI, and 50 RNAse H was added to the cell suspension, and the fluorescence intensity was evaluated and analyzed in triplicate by the FACStation® and CellQuest® software.
\n
PI analyses revealed that almost cell population (97%) underwent apoptotic cell death, which treated with IV + CV. By contrast, PBS, CSB, PV, and CV conducted cell death in very limited population, while IFO and IV let the small population into apoptosis and/or necrosis (8.8–10.2%), as well as IFO + CSB and IV + CSB induced increasing cell death to approximately a quarter to one-third of the population (Figure 3 and Table 2).
\n
Figure 3.
The PI-staining apoptosis assay using flow cytometry. Each panel shows the event count (vertical axis) at each intensity (horizontal axis). The population of apoptotic and/or necrotic cells was measured as M1 and was shown in Table 2. [Reprinted with permission from Ref. [34]. Copyright (2014) Spandidos Publications].
Population of nonviable cells (M1) in flow cytometry.
aP < 0.05 versus PV and CV.
bP < 0.05 versus PV and CV.
cP < 0.001 versus PV and CV.
\n
\n
3.4. Murine osteosarcoma therapeutic model
\n
For the therapeutic model, C3H/HeJ mice were employed because they are H2-matched to LM8 osteosarcoma cell line since this cell line was originated from that strain of mouse [37]. LM8 cells (3.0 × 106 cells per mice) were subcutaneously transplanted into 6-week-old male C3H/HeJ mice. After c.a. 3 weeks, when the tumor volume reached up to 500 mm3, injection of the therapeutic agents was started. The administration protocol is schemed in Figure 4.
\n
Figure 4.
The in vivo therapeutic model. Administration of the antitumor agents was initiated when the tumor volume reached ~500 mm3 (day 0), and continued on days 2 and 4. Then the mice were sacrificed and analyzed on day 7. [Reprinted with permission from Ref. [34]. Copyright (2014) Spandidos Publications].
\n
The agents were administered individually or in combinations as follows: PBS (i.v., sham administration), CV (0.1 mg/g BW), IFO (direct i.v. 0.1 mg/g BW), IV (i.v. 0.1 mg/g BW), IV + CSB, and IV + CV. Five to eight animals in each groups were analyzed in the study. The therapeutic agents were intravenously administered via tail vein on days 0, 2, and 4, followed by the harvest under anesthesia on day 7. Tumor diameter as well as the body weight of each individual was measured every day. At the time of the harvest, volumes and weights of tumors were evaluated; subsequently, the entire organs and the tumors were processed for histopathological analyses.
\n
No significant differences were noted in body weights among each other in the groups. It was marked that the tumor volumes in the IV + CV group were reduced as compared to those of the control groups (PBS and CV), as well as a tendency toward a decrease against the PV- and IFO-direct i.v. groups on days 5–7 (Figure 5) could be shown.
\n
Figure 5.
Trace of tumor volumes after antitumor agent administration. The symbols represent the mean value of each group, and the bars represent standard deviation. [Reprinted with permission from Ref. [34]. Copyright (2014) Spandidos Publications].
\n
\n
3.5. Histopathological analyses
\n
The histopathological analyses of the harvested tumors and entire organs were executed on the formalin-fixed, paraffin-embedded tissue section. The area of viable tumor was evaluated as the viability of the tumor tissue in hematoxylin-eosin (HE)-stained sections. Next, in order to determine the adverse effects, entire organ tissue sections stained with HE, periodic acid-Schiff (PAS), and Elastica-Goldner stains were accessed by skilled pathologists.
\n
IFO, IV, IV + CSB, and IV + CV groups revealed significantly smaller viable tumor areas in comparison to the controls. Moreover, the IV + CV group revealed markedly reduced viable tumor areas against the IFO and IV groups (Figures 6 and 7).
\n
Figure 6.
Representative photomicrographs of the tumors treated with (A) CV, (B) IFO, (C) IV, and (D) IV + CV. [Reprinted with permission from Ref. [34]. Copyright (2014) Spandidos Publications].
\n
Figure 7.
The nonviable tumor area (%) in each animal from each group. The center bars express mean value, as well as the upper and lower bars express standard deviation. [Reprinted with permission from Ref. [34]. Copyright (2014) Spandidos Publications].
\n
\n
3.6. Histopathological analyses for adverse effects in vivo
\n
To determine whether the DDS using Span 80 vesicles could prevent or reduce hazardous adverse effects due to the chemotherapeutic agents, the entire organs were histopathologically examined. Marked prevention of adverse effect was histopathologically observed in the kidney, liver, and testis. Significant tubular injury, which was recognized as a loss of brush border, as well as the glomerular damages such as the expansion of the mesangial matrix was manifested in the IFO-direct i.v. group in contrast to those in the IV and/or IV+CV groups (Figure 8A and B). Furthermore, in the liver, spotty or grouping necrosis as well as reduced glycogen storage in the hepatocytes was observed in the IFO-direct i.v. groups in contrast to those in the IV and IV + CV groups (Figure 8Cand D). Moreover, the IV and IV + CV groups manifested no remarkable changes in spermatogenesis, while the IFO-direct i.v. group revealed marked suppression of spermatogenesis along with the necrosis of the germ cells (Figure 8E and F).
\n
Figure 8.
Representative histopathological characteristics of the renal tissue (A and B), liver (C and D), and testis (E and F), which were harvested from the animals with IV+CV (A, C, and E) and IFO i.v. (B, D, and F) administration.
\n
\n
3.7. Fertility test
\n
In order to elucidate whether the DDS with Span 80 nano-vesicles could be able to prevent the infertility, fertility tests were performed. Three male C3H/HeJ mice in each group that were administered IFO, IV, or IV + CV were cross-mated with 6-week-old female C3H/HeJ mice individually; then the fertility of each male was evaluated.
\n
The test revealed that the male mice after IV + CV administration had normal fertility, and there were no malformations in their progeny.
\n
\n
\n
4. Discussion and conclusion
\n
A promising suggestion from the therapeutic model of the DDS with Span 80 vesicles was conducted that this DDS could enhance the therapeutic effects of IFO and caffeine-potentiated IFO chemotherapy, over and above prevent the hazardous adverse effects induced by chemotherapy. In vitro studies revealed drastic cell death in a very early phase by IV + CV administration in contrast to the “mild” apoptotic cell death inference by the administration of IFO alone, IV alone, or combinations of IFO + CSB, IV + CSB, and IFO + CV. These findings suggested that the immediate delivery of therapeutic agents into the cytosol by IV + CV addition might induce extremely rapid apoptosis. Fusion of Span 80 vesicles and cell membrane could be implicated in this rapid response; nevertheless, the comprehensive mechanisms are still unknown.
\n
Marked development of the DDS employing nano-vesicles has been reported along with the development of many types of phospholipids and/or detergents [6–8, 38]. The Span 80 nano-vesicle might be a promising material among them, based on its favorable physicochemical properties, including membrane fluidity and flexibility. With respect to membrane fluidity, Hayashi et.al. reported that Span 80 vesicles have markedly high fluidity with various cholesterol contents in comparison to conventional phospholipid liposomes, such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes. Not only the high fluidity, also Span 80 vesicles manifest much more flexibility in comparison to DPPC and POPC liposomes [26].
\n
Nonvesicular aggregates are observed often in the common liposome suspensions; on the other hand, Span 80 vesicle suspensions also could contain limited amount of nonvesicular aggregates such as tubulin structures. Recently, Kato et al. manifested that the Span 80 nano-vesicle might be a kind of kinetically trapped aggregates and might not have thermodynamic equilibrium structures, like in most kinds of vesicles prepared from phosphatidylcholines (liposomes) [25].
\n
The adverse effects induced by ifosfamide have been reported in kidney [35, 39–42], liver [43–45], gonadal cells [46–48], and bone marrow more frequently to other organs [49, 50]. In the therapeutic model of Span 80 DDS, the mice in the IFO-direct i.v. group also manifested moderate tubular injury as well as the glomerular damage in kidney, moreover, severe inhibition of spermatogenesis with gonadal cell necrosis. On the other hand, the novel DDS employing Span 80 nano-vesicles manifested marked prevention of the hazardous adverse effects in the kidney, liver, and testis. These favorable results could implicate the tumor selectivity of the Span80 vesicles, which might be at least partially resulting from the refraining from phagocytosis taken on the pegylation of the vesicles and also possibly on the lower permeability at the blood-testis barrier in comparison to the direct injection of low-molecular-weight molecules such as IFO [48, 51].
\n
The results of our study indicated that higher vascular permeability and inclination to fuse with the instable cell membrane of the tumors based on high fluidity and flexibility as well as pegylation could result in the higher tumor selectivity of Span 80 vesicles [52]. Recently, a cell fusion model using Span 80 vesicles has been reported [27]. Furthermore, our results manifested that CV conducted markedly better enhancement of antitumor effects than that of the direct injection of CSB. This might be addressed by the pegylation-associated tumor selectivity as well as the inclination for cell fusion which might enable the immediate caffeine delivery into the cytoplasm. Moreover, the prevention of caffeine toxicity, which causes the withdrawal of numerous patients from caffeine-potentiated chemotherapy, could be prevented based on the selectivity of caffeine delivery by using Span 80 vesicles [5]. Currently, a DDS of doxorubicin containing liposomal nano-vesicles is applied in actual cancer therapy with marked efficacy [6–8, 53–55]. The next-generation liposomes with membrane-bound-targeting molecules have also been under development. An anticarcinoma application of Span 80 vesicles containing doxorubicin with or without membrane-bound-targeting molecule was recently reported [52]. As described above, Span 80 has favorable physicochemical properties; moreover, it also confirmed risk-free information because it has been already used as a stabilizer for injected drugs. Furthermore, the cost of Span 80 vesicles should be drastically cheaper than common liposomes. Therefore, the DDS with Span 80 nano-vesicles might be a promising next-generation DDS.
\n
Recently, a novel treatment method for lymph node metastasis using a lymphatic drug delivery system with nano-/microbubbles has been advocated [56–58]. Those reports suggested that the lymphatic DDS might drastically improve the tissue selectivity and response rates to the metastatic tumors which had been limited in the hematogenous administration of drugs resulting in poor prognosis. Furthermore, those models could prevent the systemic toxic effects of the treatment; nevertheless, they employed highly toxic doxorubicin as the antitumor agent. The caffeine-potentiated chemotherapy employing the DDS with Span 80 vesicles might have excellent affinity to this lymphatic administration and more effective and less harmful treatment onto the tumor with lymph-nodal metastasis.
\n
In conclusion, the DDS with Span 80 vesicles may enhance the antitumor effects of IFO and of caffeine-potentiated IFO chemotherapy against osteosarcoma. Moreover, the usage of this DDS may suppress the adverse effects, which were induced by the chemotherapy. Thus, this DDS model has promising importance for clinical application in the therapy of metastatic osteosarcoma as well as the primary tumors.
\n
Acknowledgments
\n
We would like to thank Dr Keita Hayashi (Nara National College of Technology) and Dr Yosuke Omokawa (Nanocareer Inc. Ltd.) for their kind technical support, permission of documentation of their data, and useful advice. We are also deeply thankful to Professor Peter Walde (ETH, Zürich, Switzerland) for his helpful scientific discussion and advice. This study was supported by JSPS Kakenhi Grant Numbers 23592191, 25460496, and 16K08735.
\n
\n',keywords:"DDS, Span 80 nano-vesicles, caffeine-potentiated chemotherapy, mouse model",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/55476.pdf",chapterXML:"https://mts.intechopen.com/source/xml/55476.xml",downloadPdfUrl:"/chapter/pdf-download/55476",previewPdfUrl:"/chapter/pdf-preview/55476",totalDownloads:1346,totalViews:137,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"November 1st 2016",dateReviewed:"April 12th 2017",datePrePublished:null,datePublished:"June 21st 2017",dateFinished:null,readingETA:"0",abstract:"Osteosarcoma cases with metastasis have poor prognosis in general. Recently, caffeinepotentiated chemotherapy, which is chemotherapy with caffeine dosage against malignancies, has manifested potently high efficacy as well as diverse effects. Recently, we demonstrated that nonionic vesicles prepared from Span 80 have promising physicochemical properties, which let them an attractive option besides the common liposomes. Here, we manifested the tumor-specific caffeine-potentiated chemotherapy against osteosarcoma in murine model employing a novel drug delivery system (DDS) with Span 80 nano-vesicles. C3H/HeJ mice underwent transplantation of LM8 osteosarcoma cell line and then were doped with therapeutic agents. Caffeine was employed as an enhancer in addition to ifosfamide (IFO) as the antitumor agent. in vitro, the united administration of IV + CV revealed significant induction of tumor apoptosis in the early phase. In vivo study manifested that IV + CV-administration markedly decreased the tumor volume as well as the viable tumor area than in the other groups. No marked organ damage was observed in the IV or IV + CV groups as well as fertility injury and/or malformations in their progeny. This novel DDS might have the importance for clinical application in primary tumors as well as the metastatic osteosarcoma.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/55476",risUrl:"/chapter/ris/55476",book:{slug:"the-question-of-caffeine"},signatures:"Tatsuhiko Miyazaki, Hiroshi Nakata and Keiichi Kato",authors:[{id:"200063",title:"Dr.",name:"Tatsuhiko",middleName:null,surname:"Miyazaki",fullName:"Tatsuhiko Miyazaki",slug:"tatsuhiko-miyazaki",email:"tats_m@gifu-u.ac.jp",position:null,institution:{name:"Gifu University",institutionURL:null,country:{name:"Japan"}}},{id:"205762",title:"Prof.",name:"Keiichi",middleName:null,surname:"Kato",fullName:"Keiichi Kato",slug:"keiichi-kato",email:"keiichi1017@mc.pikara.ne.jp",position:null,institution:null},{id:"205763",title:"Dr.",name:"Hiroshi",middleName:null,surname:"Nakata",fullName:"Hiroshi Nakata",slug:"hiroshi-nakata",email:"h-nakata@m.ehime-u.ac.jp",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Span 80 nano-vesicles",level:"1"},{id:"sec_2_2",title:"2.1. Characteristics of Span 80 as a material for food and pharmaceuticals",level:"2"},{id:"sec_3_2",title:"2.2. Preparation of Span 80 nano-vesicles in different forms",level:"2"},{id:"sec_4_2",title:"2.3. Evaluation of diameter and homology by a dynamic light scattering",level:"2"},{id:"sec_5_2",title:"2.4. Evaluation of diameter and physicochemical property by electron microscopy",level:"2"},{id:"sec_6_2",title:"2.5. Temperature sensitivity of Span 80 vesicles",level:"2"},{id:"sec_7_2",title:"2.6. Vesicle membrane fusion property",level:"2"},{id:"sec_9",title:"3. Caffeine-potentiated chemotherapy using Span 80 nano-vesicles’ DDS",level:"1"},{id:"sec_9_2",title:"3.1. Preparation of Span 80 nano-vesicles",level:"2"},{id:"sec_10_2",title:"3.2. In vitro evaluation of the antitumor effects of the nano-vesicles",level:"2"},{id:"sec_11_2",title:"3.3. Apoptosis detection by propidium iodide (PI) method",level:"2"},{id:"sec_12_2",title:"3.4. Murine osteosarcoma therapeutic model",level:"2"},{id:"sec_13_2",title:"3.5. Histopathological analyses",level:"2"},{id:"sec_14_2",title:"3.6. Histopathological analyses for adverse effects in vivo",level:"2"},{id:"sec_15_2",title:"3.7. Fertility test",level:"2"},{id:"sec_17",title:"4. Discussion and conclusion",level:"1"},{id:"sec_18",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Wu PK, Chen WM, Chen CF, Lee OK, Haung CK, Chen TH. Primary osteogenic sarcoma with pulmonary metastasis: Clinical results and prognostic factors in 91 patients. Japanese Journal of Clinical Oncology. 2009;39(8):514–522. DOI: 10.1093/jjco/hyp057'},{id:"B2",body:'Clark JC, Dass CR, Choong PF. A review of clinical and molecular prognostic factors in osteosarcoma. Journal of Cancer Research and Clinical Oncology. 2008;134(3):281–297. DOI: 10.1007/s00432-007-0330-x'},{id:"B3",body:'Kimura H, Tsuchiya H, Shirai T, Nishida H, Hayashi K, Takeuchi A, Ohnari I, Tomita K. Caffeine-potentiated chemotherapy for metastatic osteosarcoma. Journal of Orthopaedic Science. 2009;14(5):556–565. DOI: 10.1007/s00776-009-1372-5'},{id:"B4",body:'Tsuchiya H, Tomita K, Mori Y, Asada N, Morinaga T, Kitano S, Yamamoto N. Caffeine-assisted chemotherapy and minimized tumor excision for nonmetastatic osteosarcoma. Anticancer Research. 1998;18(1B):657–666'},{id:"B5",body:'Hayashi K, Tsuchiya H, Yamamoto N, Shirai T, Yamauchi K, Takeuchi A, Kawahara M, Miyamoto K, Tomita K. Impact of serum caffeine monitoring on adverse effects and chemotherapeutic responses to caffeine-potentiated chemotherapy for osteosarcoma. Journal of Orthopaedic Science. 2009;14(3):253–258. DOI: 10.1007/s00776-009-1336-9'},{id:"B6",body:'Yang C, Fu ZX. Liposomal delivery and polyethylene glycol-liposomal oxaliplatin for the treatment of colorectal cancer (review). Biomedical Reports. 2014;2(3):335–339. DOI: 10.3892/br.2014.249'},{id:"B7",body:'Brochu H, Polidori A, Pucci B, Vermette P. Drug delivery systems using immobilized intact liposomes: A comparative and critical review. Current Drug Delivery. 2004;1(3):299–312'},{id:"B8",body:'Sultana S, Khan MR, Kumar M, Kumar S, Ali M. Nanoparticles-mediated drug delivery approaches for cancer targeting: A review. Journal of Drug Targeting. 2013;21(2):107–125. DOI: 10.3109/1061186X.2012.712130'},{id:"B9",body:'Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. Journal of Molecular Biology. 1965;13(1):238–252'},{id:"B10",body:'Vanlerberghe G. Niosomes and other non-phospholipid vesicular systems. In: Uchegbu IF, editor. Synthetic Surfactant Vesicles. Amsterdam: Harwood Academic Publishers; 2000. pp. 3–7'},{id:"B11",body:'Fendler JH. Membrane Mimetic Chemistry. New York, NY: Wiley and Sons; 1982'},{id:"B12",body:'Lasic DD. Liposomes. Physics to Applications. Amsterdam: Elsevier; 1993'},{id:"B13",body:'Lasic DD. Novel applications of liposomes. Trends in Biotechnology. 1998;16(7):307–321'},{id:"B14",body:'Storm G, ten Kate MT, Working PK, Bakker-Woudenberg IA. Doxorubicin entrapped in sterically stabilized liposomes: Effects on bacterial blood clearance capacity of the mononuclear phagocyte system. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 1998;4(1):111–115'},{id:"B15",body:'Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nature Reviews Drug Discovery. 2005;4(2):145–160. DOI: 10.1038/nrd1632'},{id:"B16",body:'Gibbs BF, Kermasha S, Alli I, Mulligan CN. Encapsulation in the food industry: A review. International Journal of Food Science Nutrition. 1999;50(3):213–224'},{id:"B17",body:'Taylor TM, Davidson PM, Bruce BD, Weiss J. Liposomal nanocapsules in food science and agriculture. Critical Reviews in Food Science and Nutrition. 2005;45(7–8):587–605. DOI: 10.1080/10408390591001135'},{id:"B18",body:'Edwards KA, Baeumner AJ. Liposomes in analyses. Talanta. 2006;68(5):1421–1431'},{id:"B19",body:'Monnard PA, Deamer DW. Membrane self-assembly processes: Steps toward the first cellular life. The Anatomical Record. 2002;268(3):196–207. DOI: 10.1002/ar.10154'},{id:"B20",body:'Luisi PL, Ferri F, Stano P. Approaches to semi-synthetic minimal cells: a review. Naturwissenschaften. 2006;93(1):1–13. DOI: 10.1007/s00114-005-0056-z'},{id:"B21",body:'Uchegbu IF, Vyas SP. Non-ionic surfactant based vesicles (niosomes) in drug delivery. International Journal of Pharmaceutics. 1998;172(1–2):33–70. http://dx.doi.org/10.1016/S0378-5173(98)00169-0'},{id:"B22",body:'Uchegbu IF, Florence AT. Non-ionic surfactant vesicles (niosomes): Physical and pharmaceutical chemistry. Advances in Colloid and Interface Science. 1995;581(1):1–55'},{id:"B23",body:'Wang ZF, M. Analysis of sorbitan ester surfactants. 2. Capillary supercritical-fluid chromatography. High Resolution Chromatography. 1994;17:85–90'},{id:"B24",body:'Cottrell, T. van Peij, J. Sorbitan esters and polysorbates. In: Whitehurst RJ, editor. Emulsifiers in Food Technology. Oxford: Blackwell Publishing Ltd.; 2004. pp. 162–185'},{id:"B25",body:'Kato K, Walde P, Koine N, Ichikawa S, Ishikawa T, Nagahama R, Ishihara T, Tsujii T, Shudou M, Omokawa Y, Kuroiwa T. Temperature-sensitive nonionic vesicles prepared from Span 80 (sorbitan monooleate). Langmuir: The ACS Journal of Surfaces and Colloids. 2008;24(19):10762–10770. DOI: 10.1021/la801581f'},{id:"B26",body:'Hayashi K, Shimanouchi T, Kato K, Miyazaki T, Nakamura A, Umakoshi H. Span 80 vesicles have a more fluid, flexible and “wet” surface than phospholipid liposomes. Colloids and Surfaces B: Biointerfaces. 2011;87(1):28–35. DOI: 10.1016/j.colsurfb.2011.04.029'},{id:"B27",body:'Hayashi K, Tatsui T, Shimanouchi T, Umakoshi H. Membrane interaction between Span 80 vesicle and phospholipid vesicle (liposome): Span 80 vesicle can perturb and hemifuse with liposomal membrane. Colloids and Surfaces B: Biointerfaces. 2013;106:258–264. DOI: 10.1016/j.colsurfb.2012.12.022'},{id:"B28",body:'Omokawa Y, Miyazaki T, Walde P, Akiyama K, Sugahara T, Masuda S, Inada A, Ohnishi Y, Saeki T, Kato K. In vitro and in vivo anti-tumor effects of novel Span 80 vesicles containing immobilized Eucheuma serra agglutinin. International Journal of Pharmaceuticals. 2010;389(1–2):157–167. DOI: 10.1016/j.ijpharm.2010.01.033'},{id:"B29",body:'Brandner JD. The composition of NF-defined emulsifiers: Sorbitan monolaurate, monopalmitate, monostearate, monooleate, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. Drug Development and Industrial Pharmacy. 1998;24(11):1049–1054. DOI: 10.3109/03639049809089948'},{id:"B30",body:'Lu DR, Rhodes D.G. Mixed compositions films of Spans and Tween-80 at the air-water interface. Langmuir: The ACS Journal of Surfaces and Colloids. 2000;16:8107–8112'},{id:"B31",body:'Yoshioka, T. Stermberg, B. Florence, A.T. Preparation and properties of vesicles (niosomes) of sorbitan monoesters (Span 20, 40, 60, and 80) and a sorbitan triester (Span 85). International Journal of Pharmaceuticals. 1994;105:1–6'},{id:"B32",body:'Kono K, Takagishi T. Temperature-sensitive liposomes. Methods in Enzymology. 2004;387:73–82. DOI: 10.1016/S0076-6879(04)87005-8'},{id:"B33",body:'Needham D, Dewhirst MW. The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors. Advanced Drug Delivery Reviews. 2001;53(3):285–305'},{id:"B34",body:'Nakata H, Miyazaki T, Iwasaki T, Nakamura A, Kidani T, Sakayama K, Masumoto J, Miura H. Development of tumor-specific caffeine-potentiated chemotherapy using a novel drug delivery system with Span 80 nano-vesicles. Oncological Reports. 2015;33(4):1593–1598. DOI: 10.3892/or.2015.3761'},{id:"B35",body:'Oberlin O, Fawaz O, Rey A, Niaudet P, Ridola V, Orbach D, Bergeron C, Defachelles AS, Gentet JC, Schmitt C, Rubie H, Munzer M, Plantaz D, Deville A, Minard V, Corradini N, Leverger G, de Vathaire F. Long-term evaluation of ifosfamide-related nephrotoxicity in children. Journal of Clinical Oncology. 2009;27(32):5350–5355. DOI: 10.1200/jco.2008.17.5257'},{id:"B36",body:'Hotz MA, Gong J, Traganos F, Darzynkiewicz Z. Flow cytometric detection of apoptosis: Comparison of the assays of in situ DNA degradation and chromatin changes. Cytometry. 1994;15(3):237–244. DOI: 10.1002/cyto.990150309'},{id:"B37",body:'Asai T, Ueda T, Itoh K, Yoshioka K, Aoki Y, Mori S, Yoshikawa H. Establishment and characterization of a murine osteosarcoma cell line (LM8) with high metastatic potential to the lung. International Journal of Cancer. 1998;76(3):418–422'},{id:"B38",body:'Elbayoumi TA, Torchilin VP. Enhanced cytotoxicity of monoclonal anticancer antibody 2C5-modified doxorubicin-loaded PEGylated liposomes against various tumor cell lines. European Journal of Pharmaceutical Science. 2007;32(3):159–168. DOI: 10.1016/j.ejps.2007.05.113'},{id:"B39",body:'Skinner R, Cotterill SJ, Stevens MC. Risk factors for nephrotoxicity after ifosfamide treatment in children: A UKCCSG Late Effects Group study. United Kingdom Children\'s Cancer Study Group. British Journal of Cancer. 2000;82(10):1636–1645. DOI: 10.1054/bjoc.2000.1214'},{id:"B40",body:'Patterson WP, Khojasteh A. Ifosfamide-induced renal tubular defects. Cancer. 1989;63(4):649–651'},{id:"B41",body:'Skinner R, Pearson AD, Coulthard MG, Skillen AW, Hodson AW, Goldfinch ME, Gibb I, Craft AW. Assessment of chemotherapy-associated nephrotoxicity in children with cancer. Cancer Chemotherapy and Pharmacology. 1991;28(2):81–92'},{id:"B42",body:'McCune JS, Friedman DL, Schuetze S, Blough D, Magbulos M, Hawkins DS. Influence of age upon ifosfamide-induced nephrotoxicity. Pediatric Blood Cancer. 2004;42(5):427–432. DOI: 10.1002/pbc.20011'},{id:"B43",body:'Wagner T. Ifosfamide clinical pharmacokinetics. Clinical Pharmacokinetics. 1994;26(6):439–456. DOI: 10.2165/00003088-199426060-00003'},{id:"B44",body:'Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. Journal of Oncology Pharmacy Practice. 2008;14(3):157–162. DOI: 10.1177/1078155208093930'},{id:"B45",body:'Cheung MC, Jones RL, Judson I. Acute liver toxicity with ifosfamide in the treatment of sarcoma: A case report. Journal of Medical Case Reports. 2011;5:180. DOI: 10.1186/1752-1947-5-180'},{id:"B46",body:'Yonemoto T, Ishii T, Takeuchi Y, Hagiwara Y, Iwata S, Tatezaki S. Recently intensified chemotherapy for high-grade osteosarcoma may affect fertility in long-term male survivors. Anticancer Research. 2009;29(2):763–767'},{id:"B47",body:'Ridola V, Fawaz O, Aubier F, Bergeron C, de Vathaire F, Pichon F, Orbach D, Gentet JC, Schmitt C, Dufour C, Oberlin O. Testicular function of survivors of childhood cancer: A comparative study between ifosfamide- and cyclophosphamide-based regimens. European Journal of Cancer. 2009;45(5):814–818. DOI: 10.1016/j.ejca.2009.01.002'},{id:"B48",body:'Longhi A, Macchiagodena M, Vitali G, Bacci G. Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. Journal of Pediatric Hematology/Oncology. 2003;25(4):292–296'},{id:"B49",body:'Thomson B, Hawkins D, Felgenhauer J, Radich J. RT-PCR evaluation of peripheral blood, bone marrow and peripheral blood stem cells in children and adolescents undergoing VACIME chemotherapy for Ewing\'s sarcoma and alveolar rhabdomyosarcoma. Bone Marrow Transplantation. 1999;24(5):527–533. DOI: 10.1038/sj.bmt.1701939'},{id:"B50",body:'Lotz JP, Andre T, Donsimoni R, Firmin C, Bouleuc C, Bonnak H, Merad Z, Esteso A, Gerota J, Izrael V. High dose chemotherapy with ifosfamide, carboplatin, and etoposide combined with autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and metastatic trophoblastic disease in adults. Cancer. 1995;75(3):874–885'},{id:"B51",body:'Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatric Blood Cancer. 2008;50(2):347–351. DOI: 10.1002/pbc.21323'},{id:"B52",body:'Hayashi K, Tatsui T, Shimanouchi T, Umakoshi H. Enhanced cytotoxicity for colon 26 cells using doxorubicin-loaded sorbitan monooleate (Span 80) vesicles. International Journal of Biological Science. 2013;9(2):142–148. DOI: 10.7150/ijbs.5453'},{id:"B53",body:'Iwamoto T. Clinical application of drug delivery systems in cancer chemotherapy: Review of the efficacy and side effects of approved drugs. Biological & Pharmaceutical Bulletin. 2013;36(5):715–718'},{id:"B54",body:'Eckes J, Schmah O, Siebers JW, Groh U, Zschiedrich S, Rautenberg B, Hasenburg A, Jansen M, Hug MJ, Winkler K, Putz G. Kinetic targeting of pegylated liposomal doxorubicin: A new approach to reduce toxicity during chemotherapy (CARL-trial). BMC Cancer. 2011;11:337. DOI: 10.1186/1471-2407-11-337'},{id:"B55",body:'Maeng JH, Lee DH, Jung KH, Bae YH, Park IS, Jeong S, Jeon YS, Shim CK, Kim W, Kim J, Lee J, Lee YM, Kim JH, Kim WH, Hong SS. Multifunctional doxorubicin loaded superparamagnetic iron oxide nanoparticles for chemotherapy and magnetic resonance imaging in liver cancer. Biomaterials. 2010;31(18):4995–5006. DOI: 10.1016/j.biomaterials.2010.02.068'},{id:"B56",body:'Kato S, Mori S, Kodama T. A novel treatment method for lymph node metastasis using a lymphatic drug delivery system with nano/microbubbles and ultrasound. Journal of Cancer. 2015;6(12):1282–1294. DOI: 10.7150/jca.13028'},{id:"B57",body:'Kato S, Shirai Y, Kanzaki H, Sakamoto M, Mori S, Kodama T. Delivery of molecules to the lymph node via lymphatic vessels using ultrasound and nano/microbubbles. Ultrasound in Medicine & Biology. 2015;41(5):1411–1421. DOI: 10.1016/j.ultrasmedbio.2014.12.014'},{id:"B58",body:'Sato T, Mori S, Arai Y, Kodama T. The combination of intralymphatic chemotherapy with ultrasound and nano-/microbubbles is efficient in the treatment of experimental tumors in mouse lymph nodes. Ultrasound in Medicine & Biology. 2014;40(6):1237–1249. DOI: 10.1016/j.ultrasmedbio.2013.12.012'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Tatsuhiko Miyazaki",address:"tats_m@gifu-u.ac.jp",affiliation:'
Pathology Division, Gifu University Hospital, Gifu, Japan
Ehime University Graduate School of Science and Engineering, Matsuyama, Japan
'}],corrections:null},book:{id:"5706",title:"The Question of Caffeine",subtitle:null,fullTitle:"The Question of Caffeine",slug:"the-question-of-caffeine",publishedDate:"June 21st 2017",bookSignature:"Jolanta Natalia Latosinska and Magdalena Latosinska",coverURL:"https://cdn.intechopen.com/books/images_new/5706.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"77808",title:"Dr.",name:"Jolanta Natalia",middleName:null,surname:"Latosińska",slug:"jolanta-natalia-latosinska",fullName:"Jolanta Natalia Latosińska"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"55854",title:"Introductory Chapter: Caffeine, a Major Component of Nectar of the Gods and Favourite Beverage of Kings, Popes, Artists and Revolutionists, a Drug or a Poison?",slug:"introductory-chapter-caffeine-a-major-component-of-nectar-of-the-gods-and-favourite-beverage-of-king",totalDownloads:1576,totalCrossrefCites:0,signatures:"Magdalena Latosińska and Jolanta Natalia Latosińska",authors:[{id:"77808",title:"Dr.",name:"Jolanta Natalia",middleName:null,surname:"Latosińska",fullName:"Jolanta Natalia Latosińska",slug:"jolanta-natalia-latosinska"}]},{id:"54771",title:"Coffea arabica: A Plant with Rich Content in Caffeine",slug:"coffea-arabica-a-plant-with-rich-content-in-caffeine",totalDownloads:1775,totalCrossrefCites:1,signatures:"Eva Brigitta Patay, Luminiţa Fritea, Andreea Antonescu, Angela\nAntonescu and Luciana Dobjanschi",authors:[{id:"192598",title:"Dr.",name:"Fritea",middleName:null,surname:"Luminita",fullName:"Fritea Luminita",slug:"fritea-luminita"},{id:"196166",title:"Ph.D. Student",name:"Patay",middleName:null,surname:"Eva Brigitta",fullName:"Patay Eva Brigitta",slug:"patay-eva-brigitta"},{id:"196168",title:"Dr.",name:"Antonescu",middleName:null,surname:"Ina Andreea",fullName:"Antonescu Ina Andreea",slug:"antonescu-ina-andreea"},{id:"196170",title:"Dr.",name:"Antonescu",middleName:null,surname:"Angela",fullName:"Antonescu Angela",slug:"antonescu-angela"},{id:"196171",title:"Dr.",name:"Dobjanschi",middleName:null,surname:"Luciana",fullName:"Dobjanschi Luciana",slug:"dobjanschi-luciana"}]},{id:"55623",title:"How Much Caffeine in Coffee Cup? Effects of Processing Operations, Extraction Methods and Variables",slug:"how-much-caffeine-in-coffee-cup-effects-of-processing-operations-extraction-methods-and-variables",totalDownloads:4476,totalCrossrefCites:1,signatures:"Carla Severini, Antonio Derossi, Ilde Ricci, Anna Giuseppina Fiore\nand Rossella Caporizzi",authors:[{id:"200710",title:"Prof.",name:"Carla",middleName:null,surname:"Severini",fullName:"Carla Severini",slug:"carla-severini"}]},{id:"54894",title:"Caffeine Dose-Response Relationship and Behavioral Screening in Zebrafish",slug:"caffeine-dose-response-relationship-and-behavioral-screening-in-zebrafish",totalDownloads:1225,totalCrossrefCites:2,signatures:"Luana C. Santos, Julia Ruiz-Oliveira, Priscila F. Silva and Ana C.\nLuchiari",authors:[{id:"191359",title:"Dr.",name:"Ana Carolina",middleName:null,surname:"Luchiari",fullName:"Ana Carolina Luchiari",slug:"ana-carolina-luchiari"},{id:"204927",title:"MSc.",name:"Luana",middleName:null,surname:"Santos",fullName:"Luana Santos",slug:"luana-santos"},{id:"204928",title:"Ms.",name:"Julia",middleName:null,surname:"Ruiz-Oliveira",fullName:"Julia Ruiz-Oliveira",slug:"julia-ruiz-oliveira"},{id:"204929",title:"Dr.",name:"Priscila",middleName:null,surname:"Silva",fullName:"Priscila Silva",slug:"priscila-silva"}]},{id:"55476",title:"Development of Tumor-Specific Caffeine-Potentiated Chemotherapy Using Span 80 Nano-Vesicles DDS",slug:"development-of-tumor-specific-caffeine-potentiated-chemotherapy-using-span-80-nano-vesicles-dds",totalDownloads:1346,totalCrossrefCites:0,signatures:"Tatsuhiko Miyazaki, Hiroshi Nakata and Keiichi Kato",authors:[{id:"200063",title:"Dr.",name:"Tatsuhiko",middleName:null,surname:"Miyazaki",fullName:"Tatsuhiko Miyazaki",slug:"tatsuhiko-miyazaki"},{id:"205762",title:"Prof.",name:"Keiichi",middleName:null,surname:"Kato",fullName:"Keiichi Kato",slug:"keiichi-kato"},{id:"205763",title:"Dr.",name:"Hiroshi",middleName:null,surname:"Nakata",fullName:"Hiroshi Nakata",slug:"hiroshi-nakata"}]},{id:"54463",title:"Influence of Exogenously Supplemented Caffeine on Cell Division, Germination, and Growth of Economically Important Plants",slug:"influence-of-exogenously-supplemented-caffeine-on-cell-division-germination-and-growth-of-economical",totalDownloads:1162,totalCrossrefCites:0,signatures:"Wojciech Sledz, Agata Motyka, Sabina Zoledowska, Agnieszka\nPaczek, Emilia Los and Jacek Rischka",authors:[{id:"201947",title:"D.Sc.",name:"Wojciech",middleName:null,surname:"Sledz",fullName:"Wojciech Sledz",slug:"wojciech-sledz"},{id:"205129",title:"MSc.",name:"Agata",middleName:null,surname:"Motyka",fullName:"Agata Motyka",slug:"agata-motyka"},{id:"205130",title:"MSc.",name:"Sabina",middleName:null,surname:"Zoledowska",fullName:"Sabina Zoledowska",slug:"sabina-zoledowska"},{id:"205133",title:"MSc.",name:"Agnieszka",middleName:null,surname:"Paczek",fullName:"Agnieszka Paczek",slug:"agnieszka-paczek"},{id:"205134",title:"MSc.",name:"Emilia",middleName:null,surname:"Los",fullName:"Emilia Los",slug:"emilia-los"},{id:"205137",title:"MSc.",name:"Jacek",middleName:null,surname:"Rischka",fullName:"Jacek Rischka",slug:"jacek-rischka"}]},{id:"55183",title:"Chemistry and Biotransformation of Coffee By-Products to Biofuels",slug:"chemistry-and-biotransformation-of-coffee-by-products-to-biofuels",totalDownloads:2023,totalCrossrefCites:0,signatures:"Bianca Yadira Pérez-Sariñana and Sergio Saldaña-Trinidad",authors:[{id:"199814",title:"Dr.",name:"Bianca",middleName:"Yadira",surname:"Pérez-Sariñana",fullName:"Bianca Pérez-Sariñana",slug:"bianca-perez-sarinana"},{id:"201068",title:"Dr.",name:"Sergio",middleName:null,surname:"Saldaña-Trinidad",fullName:"Sergio Saldaña-Trinidad",slug:"sergio-saldana-trinidad"}]}]},relatedBooks:[{type:"book",id:"5730",title:"Unique Aspects of Anti-cancer Drug Development",subtitle:null,isOpenForSubmission:!1,hash:"9cdd2d8e095ad4f83da2b26cb3e239c7",slug:"unique-aspects-of-anti-cancer-drug-development",bookSignature:"Jolanta Natalia Latosinska and Magdalena Latosinska",coverURL:"https://cdn.intechopen.com/books/images_new/5730.jpg",editedByType:"Edited by",editors:[{id:"77808",title:"Dr.",name:"Jolanta Natalia",surname:"Latosińska",slug:"jolanta-natalia-latosinska",fullName:"Jolanta Natalia Latosińska"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"56099",title:"Introductory Chapter: Having a Brain is Not Necessary to Get Cancer… but Indispensable to Fight It",slug:"introductory-chapter-having-a-brain-is-not-necessary-to-get-cancer-but-indispensable-to-fight-it",signatures:"Magdalena Latosińska and Jolanta Natalia Latosińska",authors:[{id:"77808",title:"Dr.",name:"Jolanta Natalia",middleName:null,surname:"Latosińska",fullName:"Jolanta Natalia Latosińska",slug:"jolanta-natalia-latosinska"}]},{id:"55629",title:"Application of Computer Modeling to Drug Discovery: Case Study of PRK1 Kinase Inhibitors as Potential Drugs in Prostate Cancer Treatment",slug:"application-of-computer-modeling-to-drug-discovery-case-study-of-prk1-kinase-inhibitors-as-potential",signatures:"Abdulkarim Najjar, Fidele Ntie-Kang and Wolfgang Sippl",authors:[{id:"197160",title:"Dr.",name:"Fidele",middleName:null,surname:"Ntie-Kang",fullName:"Fidele Ntie-Kang",slug:"fidele-ntie-kang"},{id:"197408",title:"Prof.",name:"Wolfgang",middleName:null,surname:"Sippl",fullName:"Wolfgang Sippl",slug:"wolfgang-sippl"},{id:"204942",title:"Mr.",name:"Abdulkarim",middleName:null,surname:"Najjar",fullName:"Abdulkarim Najjar",slug:"abdulkarim-najjar"}]},{id:"55654",title:"Annexin Proteins: Novel Promising Targets for Anticancer Drug Development",slug:"annexin-proteins-novel-promising-targets-for-anticancer-drug-development",signatures:"Filiz Bakar",authors:[{id:"199358",title:"Associate Prof.",name:"Filiz",middleName:null,surname:"Bakar",fullName:"Filiz Bakar",slug:"filiz-bakar"}]},{id:"55394",title:"Immunotherapy in Pediatric Acute Leukemia: A Novel Magic Bullet or an Illusory Hope?",slug:"immunotherapy-in-pediatric-acute-leukemia-a-novel-magic-bullet-or-an-illusory-hope-",signatures:"Monika Barełkowska and Katarzyna Derwich",authors:[{id:"205540",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Derwich",fullName:"Katarzyna Derwich",slug:"katarzyna-derwich"}]},{id:"55922",title:"Lupan-Skeleton Pentacyclic Triterpenes with Activity against Skin Cancer: Preclinical Trials Evolution",slug:"lupan-skeleton-pentacyclic-triterpenes-with-activity-against-skin-cancer-preclinical-trials-evolutio",signatures:"Codruţa Şoica, Diana Antal, Florina Andrica, Roxana Băbuţa, Alina\nMoacă, Florina Ardelean, Roxana Ghiulai, Stefana Avram, Corina\nDanciu, Dorina Coricovac, Cristina Dehelean and Virgil Păunescu",authors:[{id:"141027",title:"Dr.",name:"Cristina",middleName:null,surname:"Dehelean",fullName:"Cristina Dehelean",slug:"cristina-dehelean"},{id:"173283",title:"Dr.",name:"Dorina",middleName:null,surname:"Coricovac",fullName:"Dorina Coricovac",slug:"dorina-coricovac"},{id:"186372",title:"Prof.",name:"Corina",middleName:null,surname:"Danciu",fullName:"Corina Danciu",slug:"corina-danciu"},{id:"186678",title:"Dr.",name:"Codruta",middleName:null,surname:"Soica",fullName:"Codruta Soica",slug:"codruta-soica"},{id:"186679",title:"Dr.",name:"Diana",middleName:null,surname:"Antal",fullName:"Diana Antal",slug:"diana-antal"},{id:"186680",title:"Dr.",name:"Roxana",middleName:null,surname:"Ghiulai",fullName:"Roxana Ghiulai",slug:"roxana-ghiulai"},{id:"202526",title:"Dr.",name:"Stefana",middleName:null,surname:"Avram",fullName:"Stefana Avram",slug:"stefana-avram"},{id:"205282",title:"Dr.",name:"Florina",middleName:null,surname:"Ardelean",fullName:"Florina Ardelean",slug:"florina-ardelean"},{id:"205679",title:"Dr.",name:"Florina",middleName:null,surname:"Andrica",fullName:"Florina Andrica",slug:"florina-andrica"},{id:"205680",title:"Dr.",name:"Roxana",middleName:null,surname:"Racoviceanu (Babuta)",fullName:"Roxana Racoviceanu (Babuta)",slug:"roxana-racoviceanu-(babuta)"},{id:"205681",title:"Dr.",name:"Alina",middleName:null,surname:"Moaca",fullName:"Alina Moaca",slug:"alina-moaca"}]},{id:"55525",title:"Recent Progress on the Molecular Mechanisms of Anti-invasive and Metastatic Chinese Medicines for Cancer Therapy",slug:"recent-progress-on-the-molecular-mechanisms-of-anti-invasive-and-metastatic-chinese-medicines-for-ca",signatures:"Wei Guo, Ning Wang and Yibin Feng",authors:[{id:"14428",title:"Prof.",name:"Yibin",middleName:null,surname:"Feng",fullName:"Yibin Feng",slug:"yibin-feng"},{id:"175059",title:"Dr.",name:"Ning",middleName:null,surname:"Wang",fullName:"Ning Wang",slug:"ning-wang"},{id:"201389",title:"Mrs.",name:"Wei",middleName:null,surname:"Guo",fullName:"Wei Guo",slug:"wei-guo"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"64114",title:"Simultaneous Smelling an Incense Outdoor and Putting the Hands Together Activate Specific Brain Areas",doi:"10.5772/intechopen.81624",slug:"simultaneous-smelling-an-incense-outdoor-and-putting-the-hands-together-activate-specific-brain-area",body:'
1. Introduction
In the olfactory neural processing in humans, evoked magnetic fields by odorant synchronized with respiration and sniffing odors are found in orbito-frontal cortex (OFC) and inferior temporal lobe [1, 2, 3, 4, 5, 6]. On the other hand, mirror neurons in the brain are known to activate the inner prefrontal lobe and F5 area which have the function of imitation of behavior in daily life [7, 8, 9]. Therefore, mirror neurons are considered to have the function for imitation of habit [10, 11, 12]. Super mirror neurons are concerned with determination of values, recognition of oneself and others, and reward from one’s work. The inner default mode network controls the fundamental activity of daily movements and the resting state of the human brain [13, 14, 15]. Because this default mode network is strongly related to super mirror neurons, discrimination of oneself from others and the determination of social cognition are considered important in human daily life [16, 17]. The purpose of this study is to clarify that simultaneous smelling an incense outdoor and putting the hands together activate the human brain and to show where specific areas are activated.
2. Materials and methods
2.1 Incense sticks
In this MEG experiment, two types of incense sticks (A: SEIUN-Violet Smokeless, and B: MAINICHI-Kou Sandalwood), which are produced by Nippon Kodo Co. Ltd. in Japan, were used as odors.
2.2 Subjects
Eleven Japanese volunteer subjects (six males, five females) between the ages of 22 and 58 years (mean age 41 ± 11 years) without significant smell loss or a neurologic history participated. All subjects were right-handed and were given the informed consent in accordance with guidelines set by the ethical committee on human studies in both Aino University and the Kansai center in AIST in Japan.
2.2.1 Preparation of subjects
All subjects used non-magnetic clothes, and answered no problem for the questionnaire to exclude metal artifacts. Before the MEG experiments, an individual subject was shown the essence of instructions and possible debriefing for the experiments.
All subjects were given informed consent in accordance with the acceptance for measuring MEG and individual anatomical MRI for each individual brain structure to the experiments.
Participants were requested in seated during MEG experiments, and the head of the participant was positioned in the MEG helmet under the gantry of MEG system in the magnetically shielded room.
Ten of these volunteers (except for one male) were separated into two groups, the A-group, which included individuals with a habit of putting their hands together in their daily life (similar to praying), and the B-group, which included individuals who are not in the habit of putting their hands together or who do not pray.
One person was not included in either group, because he had experience putting his hands together and sometimes prayed. In this MEG experiment, he did not use a burning incense stick and instead directly sniffed his hands, which were painted with a liquid odorant containing the same ingredients as the incense stick.
2.3 Experimental design
2.3.1 MEG system
This MEG system is Neuro-magnetometer with 122 channel DC-SQUID sensors, whole-cortex type system (Neuromag-122™, Electa Co. Ltd., made in Finland).
SQUID sensor is planner DC-SQUID type. Inner helmet of the head, at the 62 points which were selected around the whole head two the first derivative DC-SQUID sensors were located individually (so, the number of total sensors are 122 = 62 × 2). This system’s version of the acquisition software is Neuromag-Aquis122-Ver.3. Sampling frequency was used Max 600 Hz, with an analog pass-band filter of 0.01–200 Hz for acquisition filters.
As the location of the head relative to MEG sensors differ across participants, projection onto a common source space would address this issue through well-established techniques for spatial normalization [18], although realignment of the data could also be done in sensor space [19, 20, 21].
2.3.2 MRI system
This MRI system is 0.4T Hitachi open type MRI system (AIRIS-Light MRI system: permanent magnetic type, made in Hitachi Co. Ltd. in Japan).
EOG/ECG/EMG: EOG/ECG/EMG were measured to test for subject’s seating state on the chair in MEG system before the experiments, however these data were not used in MEG experiments because no artifacts and no noise for MEG data.
Head shape system: this MEG system used Head Position Indicator (HPI) for the digital value of the own head shape for individual subjects.
Head movements: head movements of MEG were recorded continuously by using advanced HPI system, and the head movement compensation algorithm was applied [22]. The difference of between head positions before and after the run of MEG was recorrected.
Position of participants: participants were in seated in MEG experiments, and the head of the participant was positioned in the MEG helmet under the gantry of MEG system in the magnetic shielded room.
External stimulation and recording devices: this MEG system has photodiode devices to determine visual stimulus onset with respect to MEG trigger, and MEG has delays of a few msec. MEG data were corrected for these delays.
Coregistration: this MEG system has the following coregistration procedure. Anatomical MRIs were used individually to apply to individual own MEG data only by oneself. The method section is described for the preprocessing of the MEG study as the following, and the order of these preprocessing steps were carried out.
Bad MEG sensors: in this MEG system there are sometimes a few bad MEG sensors. This MEG system has tuning program for all 122 sensor’s tune, and after tuning processing a few bad sensors were found, and a few bad sensors were excluded during acquisition or analysis. The signals of bad sensors were interpolated to the signal estimation by using signal estimation software.
Filtering processing: in this MEG experiments we applied the following filtering. We used the digital band-pass filtering (0.3–40 Hz) the second order forward butterworth filtering with the windows algorithms.
IAC algorithms: ICA program was applied to input data of MEG. The number of components was five for the estimation. Criteria of ICA estimation on the total five components for selecting are determined to 85% to all components of data.
Trials and segments: trials and segments were anyways applied to reject under the criteria when the external bigger noises mix the income to the MEG data and the subject’s unforecasted artifacts of movements.
In this MEG experiment, each subject’s head was placed in a helmet with whole-cortex type SQUID sensors (Neuromag-122™, Electa Co. Ltd.). Three-dimensional orthogonal coordinates were determined in the helmet of the neuromagnetometer. Experiments were performed in the Kansai Center in Ikeda city, National Institute of Advanced Industrial Science and Technology (AIST) in Japan.
An incense outdoor was freely presented to the subject by means of a burning incense stick on a holder that was naturally held in front of the subject while seated in a chair in a magnetically shielded room.
2.3.3 Experiments of the stress state using subject’s saliva
In these experiments, magnetoencephalography (MEG) was performed, and the cortisol value in the subject’s saliva was measured in every state (before and after smelling two different incense outdoors (A and B)).
2.4 MEG experiments for four mode state
MEG response data were measured at the following four mode states, (1): control mode, (2): simple mode of putting the hands together, (3): smelling mode with putting the hands together, (4): only smelling mode. MEG data were added with 100 times averaging with the random sampling method. The subject pushed an optical sensor button with his or her own thumb.
In the control mode, the subject sat quietly and naturally in a chair with his or her eyes open and freely pushed the button of the optical fiber sensor at random times with the right thumb in synchronization with active inspiration (i.e., sniffing with the nose) of his or her own respiration rate, and the average MEG brain waves were obtained from raw data collected about 100 times in the control state [23].
For the next mode, the simple mode for the behavior of putting the hands together was performed as the experimental task, regardless of whether the subject did or did not have the habit of putting his or her hands together or praying in daily life. During this simple mode of putting the hands together, the subject held the optical sensor between the hands and pushed the button with the right thumb at random times while putting the hands together.
By using the above two modes, we tried to measure the subject’s own singular characteristic active area on the control state and to obtain the brain area activated by putting the hand together and we have examined to compare how the brain activity is different for the habit and no habit behavior of putting the hand together in daily life.
In the next mode that included smelling and putting the hands together, we measured the MEG response of both brain activities: smelling the odor in synchronization with active inspiration (i.e., sniffing and smelling the incense odor) and the behavior of putting the hands together [6].
In the last smelling mode, when the subject smelled only the incense odor without putting the hands together, the averaged MEG response was measured by adding the raw MEG data collected about 100 times by pushing the optical sensor button.
Both the control mode and simple mode of putting the hands together were recorded in the absence of the burning incense odor. After one incense odor was tested, the room air including the odor in the magnetically shielded room was exchanged completely with fresh air by using a large fan for about 10 minutes.
2.5 MEG and data analysis
For the purpose of observing brain activity with greater accuracy, we used a whole-head 122-sensor neuromagnetometer (a DC-SQUID device of the first order differential planar type, by Neuromag, Finland). With an attached digital band filter capable of passing only measurements in the bandwidths of 0.3–40 Hz, only valid readings were collected at an actual sampling rate of 400 Hz and converted into digital values. To observe brain functions in several experimental modes, we used a whole-head type DC-SQUID, which allowed us to detect cortical current directly and to monitor brain activities [24]. This detection method is called MEG. The analog readings detected in this manner of the brain magnetic field were digitized at a sampling rate of 400 Hz with an A/D converter, downloaded, and stored in a PC.
2.5.1 122-channel neuromagnetometer of the Planar Type Gradiometer
The 122-channel neuromagnetometer of the Planar Type Gradiometer can calculate the first derivative of the magnetic vector field Bz through individual SQUID sensors installed on the helmet, or it can calculate {(∂Bz/∂x)i, (∂Bz/∂y)i} about SQUID sensor i. Its dimension is fT/cmHz. The x- and y-axes represent the directions of longitude and latitude, respectively. A total of 122 sensor elements on the helmet were paired with the x- and y-axes, and each pair was assigned to measure one part of the head surface. A total of 61 sets (122 data points total) of magnetic field data can be detected, recorded at a particular interval (j), and calculated using the formula {(∂Bz/∂x)i,j, (∂Bz/∂y)i,j, (i = 1, 2, …, t; j = 1, 2, …, t)}.
The advantage of planar gradiometer is the ability to manufacture them using standard thin-film techniques developed for the semiconductor this can reduce manufacturing costs and increase the precision with which the coils can be made since slight imperfections in the size or orientation of the two loops can reduce their ability to perfectly reject the zero-order field.
2.5.2 Signal Space Separation (SSS) system
Signal processing method for noise reduction to this MEG system is Signal Space Separation (SSS)n which reduces environmental noise [25]. This method mathematically decomposes the magnetic field recorded from a spherically distributed array of sensors into a series expansion composed of internal and external terms that represent the proportion of the measured fields arising from inside and outside the sphere, respectively. The measured signal is reconstructed using only the internal terms to discard the environmental noise [19, 20].
2.5.3 Source reconstruction
In general, we use the volume conductor model of the subject’s head (e.g., Sphere model, BEM, FEM) individually and the lead fields algorithms for magnetic fields [26]. Normalization procedure was also used for spatial normalization after source localization by using SPM-12 of MRI software. The coordinates of subject’s brain are linked to individual subject’s brain structures using the source of the lookup table (e.g., FSL atlas).
2.5.4 Dipole fitting
The solutions obtained with dipole fitting approaches depend heavily on the choice that is made by the researcher. Therefore, this choice must be selected in with no intention. The reported solution for dipoles was chosen over a few alternative models. And the minimum current estimation method was used in our dipole fitting to MEG [27]. For example, the choices have to be made about the number of dipoles, time windows (single latency, multiple latencies), exact dipole models (moving, rotating, fixed dipole) for this process are shown as the following [28, 29, 30, 31, 32] and the fitting of the best cost function for the stability of solution [28, 33].
2.5.5 Single current dipole tracing method (single sphere model)
The single current dipole tracing method is a common technique for estimating a single source of magnetic field distribution that emerges on the head surface (on the outer surface of the helmet). Given the hypothesis that the brain magnetic field is not distorted, we surmised that the influence of the distribution current (the so-called “volume current”) is balanced by spatial symmetry and that the first order approximation of reading values is not affected, based on Biot-Savart’s law. If these presumptions are valid, an equivalent current dipole, as displayed in three-dimensional vectors, should emerge in the brains.
A critical step in the use of the single sphere model is the choice of the sphere center. The flow of volume currents would be most influenced by the boundary with the largest change in conductivity, the highly resistive inner skull surface is thought to be the optimal choice for defining the sphere surface. A best-fit sphere superimposed on an individual’s structural MRI scan and obtained from performing a least-squares minimization. We can achieve a relatively good fit of a sphere to the superior and lateral aspects of the inner skull, suggesting that a single sphere model is well justified for modeling sources in the central and lateral portions of the brain.
Still, for more nonspherical portions of intracranial space, such as near the inferior frontal and temporal regions, large deviations from sphericity can introduce errors into solutions [34, 35, 36]. The distortion of volume currents should be taken in consideration. A variant of the spherical head model that is widely used in clinical MEG applications is the model of local or overlapping spheres. Instead of using a single sphere model, spheres of different curvature are fit to the various areas of the skull underlying each MEG sensor. The individual sphere centers are then used in the forward model to better model local distortions in the volume currents based on the assumption that the local curvature influences the volume currents for nearby sensors more than for distant sensors.
The current dipole can be estimated by solving the inverse problem of the magnetic field distribution as projected on the head surface. For estimation, we first drew a magnetic field contour map in reference to the measured values of (∂Bz/∂z)i,j or in reference to the values of {(∂Bz/∂x)i,j and (∂Bz/∂y)i,j} with the inner estimation method. This magnetic field contour map allowed us to estimate a single source by following the least-squares estimation method. Using this method, the signal source can be defined as in the middle position of the extreme and the sink identified on the magnetic field. A single current dipole tracing method relies on the common notion that a higher parameter G value (goodness of fit: GOF) guarantees a higher accuracy in the least-squares estimation, and an estimated single source should therefore be closer to the actual value.
2.5.6 Evaluation method using statistical cost function (GOF)
The statistical cost function measures the goodness of fit (GOF) between the magnetic field predicted by the dipole location and moment and the measured field. Typical statistical cost functions include the percent of variance unexplained (residual variance) or the corresponding chi-square statistic value [37, 38].
Most common approaches for MEG source estimation, and the dominated the field for many decades, is to specify only one or a few equivalent current dipoles (ECDs) to represent the solution. The strength (dipole moment) of ECDs ranges anywhere from 10−9 to 10−7 Am (or 1–100 nAm). The evoked magnetic responses, which have typical source moments ranging from 10 to 30 nAm, may involve the activation of less than 1 cm2 of cortex and are therefore reasonably well modeled as a single ECD.
For highly dipolar field patterns with high SNR, such as the early components of sensory responses, ECD solutions can reach a greater than 90% goodness of fit, with good correspondence to the corresponding sensory projection areas of the brain.
In general, the single current dipole tracing method is extremely useful if only one single cortical current is observed at a given instance as a result of brain activity. The method is not as valuable, however, if the entire brain is perceptively active and cortical current emerges at multiple points on the head surface. In such a case, use of the multi-current dipoles tracing method may provide a solution, as it presumes the appropriate number of dipoles likely to exist and estimates various current sources that may be occurring in the brain. Using this method, the parameter GOF becomes high only if the presumed number of dipoles is appropriate.
The ECD modeling approach was extended to more complex patterns of the brain activity by adding more dipole sources to the model. One solution is to keep adding dipoles until there is little or no improvement in the goodness of fit (GOF) measure or if the percent of variance obtained reaches a criterion. An alternative is to use an objective measure of signal complexity, such as the number of principal components requested to account for a criterion power.
To further stabilize the solutions, constraints can be applied (fixing the location of one source while allowing additional sources to have free parameters) such that very complex source models can sometimes be attained.
However, if it is not, the resulting estimate in the real clinical MEG is not close to the actual value. Because of the constraints in determining the propriety of the presumed number of dipoles and because of the subsequent, laborious calculations, the multi-current dipoles tracing method is usually deemed relatively unrealistic and impractical to the realistic clinical MEG.
2.5.8 Estimation of the current source by observing the magnetic field distribution
Unlike an experimental observing the spontaneous control state, the task of smelling state and putting the hands together state were designed to activate brain.
As the current dipole method was not originally intended to detect such a spontaneous control state, and because dipoles of the magnetic field are expressed in rather complicated patterns by this method, we traced the variations of the magnetic field distribution by their progress over time, as well as at given intervals. Drawing a contour map of the recorded findings, we identified extremes (maxima) and sinks (minima) found in pairs respectively on the magnetic field. We then set a virtual current vector in the middle position between each pair of extremes and sinks and traced the variations of the vector over time. Although this method has not been established for signal estimation and can only give approximations, no other available method seems more practical or acceptable for evaluation of the spontaneous control state, where neither the single dipole method nor the multi-dipole method is useful.
We observed a combination of extremes and sinks on the brain magnetic field contour map, vertically upward from the vertex. Extremes and sinks were aligned in such a way that their magnetic fields were tangential to each other. In between, the cortical current ran in the direction of the tangent vector in accordance with Biot-Savart’s Law [39, 40].
We calculated the magnetic field contour map at a single time, with all three cortical currents in clear view. The test results were analyzed using the method of contrast between extreme and sink. The pattern recognition analysis of the inverse problem method is also available and more precise; however, this method was too time-consuming considering the number of cortical currents we needed to observe [41]. With respect to our test objective, we prioritized efficiency over numerical precision, which is normally preferred in localizing brain functional foci.
In order to reliable ECD fit, we must have fewer models. Another popular approach that has been used in MEG source modeling is the so-called “Spatiotemporal Dipole Fit” introduced Scherg and Von Cramon [38] in which the time-varying amplitude (time course) of each dipole is used as additional information to constrain the solutions.
2.5.9 Data acquisition, processing and analysis
We traced the cortical current using the first-order differential planar type of DC-SQUID. This device enables us to detect the current source of brain activity directly under its sensor, revealing the maximum of the absolute values. This is the greatest advantage of using the differential planar type device, which has a dimension of fT/cmHz. When using neuromagnetometers of the axial type, as explained in Section 2.5.2 above (the single current dipole tracing method), we can estimate the current source as defined as the middle position between the minima and maxima of the cranial nerve magnetic field distribution [42].
Neuromagnetometers of the planar type are useful for determining where the current source of brain activity exists by detecting the maximum of absolute magnetic field values. We therefore used these readings to map the distributions of the cranial nerve magnetic field using MATLAB software, illustrating how the magnetic field varies over time [43]. Data acquisition began at the moment of the signal, although the data we actually used began 500 ms after the starting signal. Thus, we sampled the experimental activities of the brains. In the olfactory neural processing in humans, the responses of event related magnetic fields and evoked magnetic fields were obtained within about 250 ms in healthy subjects. In our MEG experiments, subjects sniff an incense odor actively by using his own nose and when starting to sniff he pushes the optical sensor button as a trigger signal. Therefore, to record the more precise changing of MEG we used the sampling interval with every 50 ms. So, measurements MEG responding data were analyzed by every 50 ms. By observing these cranial nerve magnetic field distributions on the surface of the head, we traced and recorded variations in the current source at each particular moment.
3. Results
3.1 Result of signal source estimation of MEG in the brain obtained with the single current dipole tracing method
3.1.1 Advantage of the real-time response of the brain’s neural activities by analysis of millisecond-time resolution using the single current dipole tracing method of MEG
This single current dipole tracing method has the advantage of directly obtaining real-time responses of the brain’s neural activities. This is different from fMRI and PET methods, which measure metabolism of physiologically active substances. We obtained changing activities of the signal source and estimated the active regions in the brain with analysis using the single current dipole tracing method. In single current dipole tracing method, the first main current dipole is the largest dipole. This current dipole was obtained in the middle position of extreme center and sink center identified on magnetic field. The second and the third current dipoles were smaller and weaker than the first main current dipole. Using this single current dipole tracing method, we can estimate only one current signal source (magnitude, direction, and location) as the most reliable neural activity in the brain.
3.1.2 Mechanism of the real-time estimation method of the active area using the single current dipole tracing method of MEG data
Figure 1 shows the real-time estimation method for obtaining the active area in the subject’s brain. Figure 1(a) shows an example of a MEG response to random activities such as the control state before putting the hands together as assessed with the single current dipole tracing method. We could not obtain the dipole completely, and thus, we could not identify the generally active area in this control state (with no smelling odor and no putting the hands). Figure 1(b) shows contour mapping of MEG response at a control state.
Figure 1.
Real-time active state at a control in our brain.
Figure 1(a) shows over head vision, upper is anterior, lower is posterior of the head. Each curves show 122-channel MEG averaging response waves of duration 0.2 s time. A red vertical line shows starting time point for the inspiration of odorless air.
Figure 1(b) shows the contour mapping of real time MEG response at a control state. We could not almost obtain a constricted dipole completely, then we could not find out the active brain area generally in this control state.
(a) The simple mode of putting the hands together without smelling
3.1.3 The theory of mirror neurons and the default mode network
In this experimental task, the subjects put their hands together or mimicked praying without smelling. We obtained the subject’s type as an individual variation for the priority of brain laterality regarding putting the hands together or praying in daily life. Figure 2 shows an example of the MEG response for the active area obtained with the single current dipole tracing method for this experimental condition. We analyzed estimated active areas continuously using a real-time estimation method. Figure 2(b) shows an MEG response on active area of left side brain as a left priority type after only putting the hands together (with no smelling odor). Figure 2(c) shows a vector of single current dipole estimated in the brain using 3-D coordinates.
Figure 2.
Real-time estimation of the active area in our brain after only putting the hands together.
Figure 2(c) shows a vector of single current dipole estimated in the brain using 3-D coordinates after putting the hands together. X-axis is the horizontal line of right to left ear, and Y-axis is the line from nasion to inion, and Z-axis is the upper to lower line of the vertical of the brain.
Table 1 shows an estimated ECD dipole each subjects for latency tie window (210–1100 ms), priority of the laterality (right or left), activated region, and GOF (statistical goodness of fit, %) for the simple mode of only putting the hands together without smelling.
3.1.3.1 a-1. Right priority brain type
Five of the 11 subjects had the right priority brain type for laterality. Three of these five persons regularly put their hands together in their daily life, and the other two did not.
3.1.3.2 a-2. Left priority brain type
Six of the 11 persons had the left priority brain type for laterality. Two of six subjects regularly put their hands together in their daily life, and the other three did not.
Only one subject of the 11 was not classified in these two groups, and this person (N1) had the left priority brain type estimated in central temporal gyrus (N1: latency 579.0 ms, GOF 32.8%) as shown in the above Table 1.
The priorities of brain laterality are considered important for obtaining the characteristic laterality of the active brain in daily life as described below, regardless of putting the hands together and praying or not.
3.1.3.3 A-group: (A1–A5) habit of putting the hands together or praying
As shown in Table 1, in the A-group which had the habit of putting the hands together in daily life, the main active areas in the brain were generally estimated to be on the right near the superior regions (A1: latency 309.2 ms, GOF 50.2%; A4: latency 405.6 ms, GOF 47.4%) or the left near central (A5: latency 1065.3 ms, GOF 57.6%) or left caudal regions (A2: latency 613 ms, GOF 47.9%) in the temporal gyrus. The right prefrontal area was activated in only one subject (A3: latency 974 ms, GOF 47.9%).
3.1.3.4 B-group: (B1–B5) no habit of putting the hands together or praying
As shown in Table 1, in the B-group, which did not have the habit of putting the hands together or praying, the main active areas in the brain were generally estimated to be the right posterior regions (B1: latency 215.0 ms, GOF 28.1%; B4: latency 419.4 ms) in the frontal gyrus and left central region (B2: latency 236.0 ms, GOF 68.6%) and left caudal regions (B3: latency 303.4 ms, GOF 30.5%; B5: latency 366.3 ms, GOF 27.3%) in the frontal gyrus.
(b) Simultaneous smelling an incense outdoor and putting the hands together mode
All 11 subjects were separated into two groups. The A-group had the habit of putting the hands together or praying according to the Japanese traditional conventional style of putting the hands together for a few minutes every day in their daily life. The B-group did not have this habit.
Table 2 shows an estimated ECD dipole for each subjects for latency time (290–1900 ms), priority of the laterality (right or left), and activated region, and GOF (statistical goodness of fit, %) for simultaneous smelling an incense outdoor and putting the hands together mode.
Table 1.
Results of MEG experiments for the simple modes (a) of only putting the hands together without smelling.
Table 2.
Results of MEG experiments for simultaneous smelling an incense outdoor and putting the hands together mode.
Figure 3 shows that the estimated current dipoles of four subjects were obtained at the F5 language area of the inner region (A5: right priority, latency 981.0 ms, GOF 68.0%; B3: left priority, latency 557.3 ms, GOF 28.3%; B4: left priority, latency 423.9 ms, GOF 58.0%; B5: left priority, latency 328.4 ms, GOF 34.5%) of the frontal gyrus in a simultaneous state of the smelling an incense outdoor and putting the hands together. These responses were presented in two subjects, one is OFC area (A3: right priority, latency 974.1 ms, GOF 33.1%) and another is F5 area (A5: left priority, latency 981.0 ms, GOF 68.0%) in the A-group and four subjects in the B-group after smelling incense odors A and B.
Figure 3.
F5 language area estimated by the simultaneous smelling an incense outdoor and putting the hands together.
Figure 4 shows that the responses of another two subjects (A2: left priority, latency 627.8 ms, GOF 55.1%; A4: right priority, latency 309.3 ms, GOF 33.7%) in the A-group were obtained at the V1 visual area in the calcarine sulcus in the right or left occipital lobe after smelling incense odors A and B with putting the hands together. These V1 responses were not found in the B-group.
Figure 4.
V1 visual area estimated by the simultaneous smelling an incense outdoor and putting the hands together.
Only one in the 11 subjects was classified in neither the A- nor B-group, and this only one subject (N1) was used by coating smell method. He had the left priority brain type. His estimated current dipole was obtained at the OFC orbito-frontal gyrus (Figure 5) (N1: left priority, latency 974.1 ms, GOF 67.6%) when he performed the special activities of directly coating smelling both hands that were coated with the liquid incense odor A and putting his hands together.
Figure 5.
Orbito-frontal area estimated by the coating smell and putting the hands together in only one subject without A and B group.
As shown in the Table 2, another one subject (A1: right priority, latency 443.5 ms, GOF 62.5%) in the A-group with the habit of putting the hands together or praying showed the activity in the inner central temporal area in the right insula, and two subjects (B1: right priority, latency 296.1 ms, GOF 36.7%; B2: left priority, latency 1851.0 ms, GOF 64.6%) in the B-group without this habit also showed activity in the inner area in the right and left insula.
Figure 6 shows the estimated current dipoles of three subjects obtained in insula regions in the right and left temporal gyrus in both the groups after simultaneous smelling incense odors A and B outdoor and putting the hands together. In particular, the responses of almost all subjects in the B-group were found in temporal areas very close to the same regions as during the simple mode of only putting the hands together without smelling.
Figure 6.
Anterior area in the temporal lobe estimated by simultaneous smelling an incense outdoor and putting the hands together in almost all B group.
From the above analyses, in this task of simultaneous smelling an incense outdoor and putting the hands together mode, the brains of four subjects were activated in the F5 language area in the left frontal lobe. Two of four subjects had the right priority brain type and did not have the habit of putting the hands together in their daily life. However, their F5 language area in the left frontal lobe was activated after this task when simultaneous smelling an incense odor outdoor and putting their hands together. On the other hand, in two other persons with a habit of putting their hands together or praying in daily life, the right and left calcarine sulci of the V1 visual area in the occipital lobe were activated after the task of simultaneous smelling the odor outdoor and putting their hands together. From these all results, we consider that the F5 language area in the left frontal lobe and V1 visual area in the right and left occipital lobes were activated by the task of simultaneous smelling an incense outdoor and putting their hands together regardless of whether they had the habit of putting their hands together in their daily life. These phenomena are considered to be guided by the activation of mirror neurons and the default mode neural network’s function.
(c) The mode of smelling only and not putting the hands together
Table 3 shows an estimated ECD dipole for each subjects for latency time (230–1100 ms), priority of the laterality (right or left), activated region and GOF (statistical goodness of fit, %) for the mode (c) of smelling an incense outdoor only and not putting the hands together.
Table 3.
Results of MEG experiments for the mode (c) of smelling an incense outdoor only and not putting the hands together.
3.1.4 One person (N1) not classified in the A- or B-group
3.1.4.1 c-1. Orbito-frontal lobe area
AS shown in the above Table 3, only one subject was not classified in either the A- or B-group, and this person (N1: right priority, latency 414.0 ms, GOF 43.0%) had the right priority brain type. His estimated current dipole was also obtained at the left or right orbito-frontal lobe when he performed only the mode of smelling both hands, which were coated with liquid odor A or B, without putting his hands together. In this experiment, he could smell and clearly perceive the odorants on both hands.
3.1.4.2 A-group: habit of putting the hands together or praying
AS shown in Table 3, one female subject had the right priority brain type. Her estimated current dipole (A4: right priority, latency 473.0 ms, GOF 35.5%) were obtained in the right insula in the temporal gyrus when she performed the mode of smelling only odor A or B without putting her hands together. Also, the estimated current dipoles of a male subject (A3: left priority, latency 563.2 ms, GOF 53.7%) and another female (A5: left priority, latency 520.2 ms, GOF 58.3%) who had the left priority brain type were obtained at the left amygdala in the olfactory nervous pathway system when they performed the mode of smelling odor B without putting their hands together. Another male subject (A1: right priority, latency 1060.3 ms, GOF 28.9%) was obtained at the posterior frontal gyrus and another female subject (A2: left priority, latency 598.3 ms, GOF 21.9 5) was obtained at trigonum olfactorium in the olfactory pathway system in A-group.
They could smell and clearly perceive odor A or B, and therefore, we could obtain their nervous pathway system and active area through olfactory nerve projection regions.
3.1.4.3 B-group: no habit of putting the hands together or praying
As shown in Table 3, two female subjects (B2: left priority, latency 509.7 ms, GOF 38.2; B4: right priority, latency 252.2 ms, GOF 35.2%) and one male subject (B3: left priority, latency 237.1 ms, GOF 57.0%) had the response at insula regions. Their estimated current dipoles were obtained in insula regions at the temporal gyrus when they performed the mode of smelling only odor B without putting their hands together.
On the other hand, other two male subjects had the left priority brain type. Their estimated current dipoles (B1: left priority, latency 502.5 ms, GOF 55.0%; B5: left priority, latency 303.4 ms, GOF 45.3%) were obtained at the left amygdala in the olfactory pathway system when they performed the mode of smelling only odor B without putting their hands together.
Although these subjects did not have the habit of putting the hands together or praying in their daily life, they could smell and clearly perceive odors A and B. Therefore, we could obtain the responses of their olfactory nervous pathway system and active areas through olfactory nerve projection regions.
3.2 Results of statistical analysis of the cortisol level in the saliva of each of the 11 subjects
Cortisol value before smelling the odor and MEG experiments
Cortisol value after smelling incense A
Cortisol value after smelling incense B
The cortisol value (μg/dL) is an index of the state of stress.
Table 4 shows the result of statistical analysis of each value, and the mean and standard deviation of the cortisol value were calculated for all 11 subjects, and for ten subjects, five subjects in the A-group and another five subjects in the B-group. Next, statistical t-tests were performed to compare the cortisol values of each condition in all 10 subjects and each five subjects classified in the A- or B-group, respectively.
No significant difference was found among the mean cortisol value of the conditions 1: before smelling the odor, 2: after smelling incense odor A, and 3: after smelling incense odor B for all 10 subjects (see Figure 7).
The average cortisol value tended to decrease in the order of 1: before smelling the odor, 2: after smelling incense odor A, and 3: after smelling incense odor B in all 10 subjects and the five subjects in the A-group (see Figure 8).
A significant difference (p < 0.078) was found between the mean cortisol value of the condition after smelling incense odor A (2) and after smelling incense odor B (3) for the five subjects in the B-group (see Figure 9).
The average cortisol value tended to decrease in the order of (1) after smelling incense odor A (2), before smelling the odor, and (3) after smelling incense odor B for the five subjects in the B-group.
A different tendency in the average cortisol value was observed between the A-group and B-group. In particular, an effect of stress was observed for smelling incense odor A.
All subjects perceived and smelled incense odor B, which had no effect regarding stress.
For individual subjects, the cortisol value tended to decrease in the order of 1: before smelling the incense odor, 2: after smelling incense odor A, 3: after smelling incense odor B in five subjects in the A-group.
For individual subjects, the cortisol value tended to decrease in the order of 1: after smelling incense odor A, 2: before smelling the odor, 3: after smelling incense odor B in three subjects in the B-group.
For individual subjects, especially in the one subject who was different from the other subjects in the B-group whose cortisol value tended to decrease, the cortisol value tended to decrease in the order of 1: before smelling the odor, 2: after smelling incense odor A, 3: after smelling incense odor B, similar to the A-group.
Cortisol value (μg/dL)
A-group (habit group)
B-group (no-habit group)
Subject
A1
A2
A3
A4
A5
B1
B2
B3
B4
B5
N1
Average
Standard deviation
Before experiment
0.34
0.12
0.1
0.15
0.13
0.08
0.16
0.15
0.34
0.07
0.09
0.16
0.177
After incense A
0.32
0.07
0.08
0.1
0.1
0.12
0.16
0.25
0.15
0.23
0.06
0.15
0.184
After incense B
0.26
0.07
0.07
0.07
0.07
0.07
0.16
0.12
0.09
0.16
0.03
0.11
0.163
Average
0.31
0.09
0.08
0.11
0.1
0.09
0.16
0.17
0.19
0.15
0.06
Standard deviation
0.057
0.035
0.021
0.057
0.042
0.007
0
0.021
0.177
0.064
0.042
Table 4.
Results of cortisol value (μg/dL) in the saliva for each 11 subjects.
Figure 7.
Statistical analysis of cortisol value for all 10 subjects.
Figure 8.
Statistical analysis of cortisol value for habit group A.
Figure 9.
Statistical analysis of cortisol value for no habit group B.
3.3 Relation between the impression of the subject about the incense outdoor and stress measured by the cortisol value
3.3.1 A-group: habit of putting their hands together or praying
Almost all subjects in the A-group, except for one female, felt that incense odor B was more familiar than incense odor A in daily life. However, both incense odors were pleasant for all subjects in the A-group according to psychological inquiries. In these cases, the cortisol value for almost all subjects except this female decreased in the order of 1: before smelling the odor, 2: after smelling incense odor A, and 3: after smelling incense odor B. In other words, almost all subjects except this female reported a decrease in stress in the order 1: odor B, 2: odor A. 3: no odor.
Only one female subject was different from the other subjects in the A-group. She liked incense odor A more than incense odor B. Therefore, she felt not more stress from incense odor A than incense odor B. Her cortisol value decreased in the order 1: no odor, 2: odor A, odor B.
3.3.2 B-group: no habit of putting the hands together or praying
Almost all subjects in the B-group reported feeling more stress for incense odor A than incense odor B, because incense odor B was considered more familiar in their daily life. In contrast, almost all B-group subjects felt stress for unfamiliar odor A more than the state of no odor before smelling. Their cortisol value decreased in the order 1: incense odor A, 2: no odor, 3: incense odor B.
From these analyses about the relationship between the impression of the odor and the measured cortisol value, the nature of the state of stress was different in the A-group and B-group.
3.4 Summary of results
3.4.1 The specific and distinct mirror neuron activities without the error activity on the hand motor system by putting the hands together
Our MEG experiments of the above results using the methods of (1) Control mode in section 2.4 as the obtained Figure 1(a) and (b) showed the distinct and objective activities of our brain on the control state of non-motor system’s activity clinically. However, in the MEG experiments of only putting the hands together without smelling using methods of (2) Simple mode of putting the hands together in section 2.4 as shown at (a) in Figure 2(a)–(c) we obtained the MEG local estimated signal response areas for the distinct mirror neuron activity. In our MEG experimental results for only putting the hands together without smelling an incense outdoor, 11 subject’s detailed responses were obtained as Table 1 in which A-group subjects were obtained in superior and anterior temporal gyrus or central and caudal temporal and frontal gyrus, on the other hand B-group subjects were obtained also the same temporal and frontal areas. These results show that the estimated local activated regions of B-group having the no habit of putting the hands together or praying are almost all resemble to the activated areas in brain of A-group having the habit of putting the hands together in daily lives. These results of the coincidence active areas in A-group and B-group in the behavioral action for putting the hands together show the distinct activities of mirror neurons activities as the imitation in the brain without the simple artifacts of moving error activities in moving neuronal system.
3.4.2 The simultaneous new specific stronger effects of both the distinct mirror neuron’s activity putting the hands together and the activities of smelling an incense outdoor at the same time
Our MEG experiments of the above results using the methods of (3) Smelling mode with putting the hands together in section 2.4 as the obtained (b) in Figure 3(a–c) showed the distinct and objective activities of our brain on the state of simultaneous responses of putting the hands together and at the same time smelling an incense outdoor. In this simultaneous status mode of our MEG experiments, this specific active area in Figure 3 were shown in distinct F5 language areas of the inner regions of the left frontal lobe or orbito-frontal gyrus (OFC) clinically. These responses were presented in two subjects in A-group and four subjects in B-group. These specific results show the simultaneous new distinct stronger effects of both the mirror neuronal activities as the imitation without the artifacts of the simple moving error activities and olfactory activated effects. The specific responses of another two subjects in A-group showed the simultaneous other new specific stronger effects of both the mirror neuron’s activities putting the hands together and the activities of smelling an incense outdoor at the same time in V1 visual areas in the calcarine sulcus in occipital lobe clinically as the another distinct active areas as shown in Figure 4(a) and (b). Only one person of 11 subjects in neither A- nor B-group who used by the direct coating strong smell over the hands showed the specific simultaneous activities in the orbito-frontal lobe as shown in Figure 5(a) and (b). And the simultaneous specific activities in the brain both the putting the hands together and smelling an incense outdoor at the same time of other five subjects were obtained in anterior and posterior areas in the temporal lobes as shown in Figure 6(a)–(c). These detailed MEG response data are shown in Table 2 for simultaneous smelling an incense outdoor and putting the hands together and these results show the specific new strong effects of simultaneous responses in the relation of both the mirror neuron activities and olfactory effects at the same time.
3.4.3 The mode of smelling an incense outdoor only without putting the hands together (olfactory response with non-mirror neuron activity)
The detailed responses of our MEG experiments of the above results in the mode of smelling an incense outdoor only without putting the hands together (non-mirror neuron activity) were shown in Table 3 with almost all subject’s data. From these clinical and objective MEG measurements and analysis we obtained the distinct olfactory activities clearly such as the frontal and temporal regions in the olfactory nervous projection areas and olfactory nervous pathways nevertheless A- and B-group.
4. Discussions
4.1 The inverse problem: source estimation models
We used dipole models for the source estimation of the recorded MEG signals. The simpler spherical model for the head is adequate for MEG source modeling in most cases. In addition, MEG benefits from very precise knowledge of the real sensor geometry, including registration of sensors to the head.
However, source modeling in MEG remains a challenging mathematical problem, especially for more complex configurations of neuronal sources associated with higher cognitive function.
As a realistic clinical tool to for the spatio-temporal localization of the evoked brain activity by simultaneous smelling an incense outdoor and putting the hands together.
A variety of methods have been applied to the MEG source estimation problem to overcome the limitations. Using the individual’s MRI scan of every subjects, template can provide good approximations for realistic head modeling. For example, finite element models (FEMs) could be applied to drastic changes in tissue conductivity and can be modeled more accurately in future [44].
4.2 Mirror neurons and the default mode network
The concept of mirror neurons was described by Marco Iacoboni. These neurons are located in the F5 inner area of the prefrontal lobe [7]. In general, the motion of putting the hands together and mimicking behavior are considered to activate the mirror neuron mechanism [8, 45, 46] and the default mode network in the human brain [9, 47, 48, 49]. These neural effects are considered to increase activity in the central areas of the temporal lobe and the caudal area of the frontal lobe according to the imitation principal [50, 51, 52, 53, 54].
The theory of these mirror neurons revealed the principal of imitation of behavior. Although these F5 areas in the left side of the human brain are in the same areas as Broca’s language regions, F5 areas of both sides of the brain function to mimic motion and behavior. From anatomical research, F5 areas are connected to pre-motor areas and supplemental areas in movement regions in the brain.
Mirror neurons are thus considered to function for imitation of the habit of putting the hands together or praying, which is also performed with both hands by almost all elderly Japanese people in their daily life.
Super mirror neurons are concerned with determination of values, recognition of oneself and others, and reward from one’s work. The inner default mode network controls the fundamental activity of daily movements and the resting state of the human brain. Because this default mode network is strongly related to super mirror neurons, discrimination of oneself from others and the determination of social cognition are considered important in human daily life.
4.3 The meaning of simultaneous smelling an incense outdoor and putting the hands together
Odorants stimulate activity in the olfactory nervous center, orbito-frontal areas, and others in the human brain [1, 2, 3, 4]. Neurophysiological experiments in monkeys have shown that the olfactory nervous center and olfactory pathway project to the orbitofrontal cortex [55, 56, 57]. In humans, olfactory event-related potentials and magnetic fields evoked by odorant pulses synchronized with respiration are also found in the orbitofrontal area [5, 6, 58, 59].
In this experiment, only one subject was not in the A- or B-group and smelled his hands that were coated with liquid odor. By performing this behavior, he clearly experienced strong A and B odors. We estimated that the areas activated by his sniffing of both the A and B odors were the prefrontal area and the right or left orbito-frontal area.
In habits of daily life, the brain of A-group people after smelling incense odors and putting their hands together or praying was activated at the inner lobe of the frontal area, F5 language area, anterior area in the temporal lobe, orbito-frontal area, and others.
The brain of B-group individuals who did not have the habit of smelling incense odor or putting their hands together or praying in their daily life was also activated at the inner lobe of the frontal area, anterior area in the temporal lobe, and F5 language area in the left frontal lobe, similar to the A-group.
These results suggest that mirror neurons or the super mirror neuron system and the default mode network system in the brain of B-group subjects were activated by both smelling the incense odor and their imitation of putting their hands together, although they did not have the habit of smelling incense odors or putting their hands together or praying in their daily life.
From the above analyses, in the task involving simultaneous smelling an incense outdoor and putting the hands together, four person’s brains were activated in the F5 language area in the left frontal lobe. Two of four subjects had the right priority brain type and no habit of putting their hands together in their daily life. However, their F5 language area in the left frontal lobe was activated after this task.
On the other hand, in two persons with a habit of putting their hands together or praying in their daily life, the right and left calcarine sulci of the V1 visual area in the occipital lobe were activated after the task of simultaneous smelling an incense outdoor and putting the hands together [60, 61, 62, 63].
5. Conclusions
This research revealed that simultaneous smelling an incense outdoor and putting hands together increased the activity of specific brain areas, for example inner areas of the prefrontal cortex and F5 regions of the human brain. In our experiments, evoked neuronal activity was recorded by the MEG and the cortisol value in the subject’s saliva was measured in every experimental stage. From a few previous researches, it is known that F5 area is activated during observation of certain actions, during action execution etc. and these results show F5 have multimodal and different type of neurons. Moreover, the F5p is also known as a hand-related area that encoded goal-directed actions, not only mimic or autonomic actions. Our results demonstrated that the sources of MEG which are postsynaptic signals synchronized activation of intracellular currents across dendrites of cortical pyramidal neurons link strongly with anatomic position of mirror neurons. Mirror neurons in our experiment case are considered to have the function for imitation of the habit of putting the hands together or praying, which almost all elderly Japanese peoples often practice in their daily life. Super mirror neurons are concerned with determination of values, recognition of oneself and others, and reward from one’s work. The inner default mode network controls the fundamental activity of daily movements and the resting state of the human brain. Because this default mode network is strongly related to super mirror neurons, discrimination of oneself from others and the determination of social cognition are considered important in human daily life. From these mirror neuron theories and the above summary of our results (1). We can conclude the distinct activities as follows. From these concerns and the above summary results (2) and (3), it can be considered that the specific regions in the brain such as the F5 language area in the left frontal lobe and the V1 visual area in the right and left occipital lobes were distinctly activated by the simultaneous new stronger effects increased with the task of smelling an odor and putting their hands together regardless of the habit in daily lives. These results show that the sources of MEG strongly link with the anatomic positions of mirror neurons and their types. Especially, these phenomena are considered to be guided by the simultaneous new stronger effects increased by both the olfactory activities of smelling an incense outdoor accompanied with the activation of mirror neurons and the default mode neural network [64, 65, 66] for the imitation behavior of putting hands together. From the above results, we consider that the F5 language area in the left frontal lobe and V1 visual area in the right and left occipital lobes and other specific brain areas were activated distinctly by the task of simultaneous smelling an incense outdoor and putting their hands together regardless of whether they had the habit of putting their hands together in their daily life. From our experiments, the cortisol value in saliva for the stress and the specific mirror neuron theories. we conclude that the simultaneous new specific effects both the smelling an incense outdoor and the imitating the behavior of putting the hands together can be considered to increase the activities of these areas in the human brain due to mutual interactions, reciprocal connections, or alternative actions.
Acknowledgments
We thank Mr. Ippei Torige, Mr. Kimiyoshi Yoshino, and Mr. Masaru Yamamoto in Nippon Kodo Co. Ltd. for expert help during the experiments in subject’s attendance and in the preparations of incense odorants.
This study was supported by the Grants for the Alzheimer’s Disease in Osaka Research Association and the Awards of Osaka-Gas for the Research of Alzheimer’s Disease in Japan.
\n',keywords:"incense outdoor, putting the hands together, habit/no habit, MEG, F5 language area, mirror neuron, default mode network",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/64114.pdf",chapterXML:"https://mts.intechopen.com/source/xml/64114.xml",downloadPdfUrl:"/chapter/pdf-download/64114",previewPdfUrl:"/chapter/pdf-preview/64114",totalDownloads:340,totalViews:112,totalCrossrefCites:0,dateSubmitted:"June 22nd 2018",dateReviewed:"September 21st 2018",datePrePublished:"November 5th 2018",datePublished:"April 3rd 2019",dateFinished:null,readingETA:"0",abstract:"Mirror neurons are involved in imitation of habitual behaviors. To increase understanding of the theory of mirror neurons and the default mode network, brain activation was explored in 11 healthy adult volunteers who did or did not have a habit of putting their hands together as if praying. Magnetoencephalography (MEG) data were recorded while the participants simultaneously smelled an odor in two kinds of incenses outdoor and/or while they moved to putting their hands together. A magnetoencephalographic contour map of the recorded findings was drawn and an estimated current dipole (ECD) was set. Regardless of a habit of putting their hands together or not, the inner lobe of the frontal area, anterior area in the temporal lobe, and F5 language area in the left frontal lobe and so on were specifically activated. We used cortisol value as an index of the stress state measured in every state (before and after smelling two different incenses outdoor). These experiments suggest that simultaneous smelling an incense outdoor and the behavior of putting their hands together increased the activity of these specific areas in the human brain due to mutual interactions and enhanced interactions.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/64114",risUrl:"/chapter/ris/64114",signatures:"Mitsuo Tonoike and Takuto Hayashi",book:{id:"7541",title:"Neuroimaging",subtitle:"Structure, Function and Mind",fullTitle:"Neuroimaging - Structure, Function and Mind",slug:"neuroimaging-structure-function-and-mind",publishedDate:"April 3rd 2019",bookSignature:"Sanja Josef Golubic",coverURL:"https://cdn.intechopen.com/books/images_new/7541.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"225125",title:"Ph.D.",name:"Sanja",middleName:null,surname:"Josef Golubic",slug:"sanja-josef-golubic",fullName:"Sanja Josef Golubic"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"264444",title:"Dr.",name:"Mitsuo",middleName:null,surname:"Tonoike",fullName:"Mitsuo Tonoike",slug:"mitsuo-tonoike",email:"gah00161@nifty.ne.jp",position:null,institution:null},{id:"264445",title:"Dr.",name:"Takuyo",middleName:null,surname:"Hayashi",fullName:"Takuyo Hayashi",slug:"takuyo-hayashi",email:"t-hayashi@me-u.aino.ac.jp",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Materials and methods",level:"1"},{id:"sec_2_2",title:"2.1 Incense sticks",level:"2"},{id:"sec_3_2",title:"2.2 Subjects",level:"2"},{id:"sec_3_3",title:"2.2.1 Preparation of subjects",level:"3"},{id:"sec_5_2",title:"2.3 Experimental design",level:"2"},{id:"sec_5_3",title:"2.3.1 MEG system",level:"3"},{id:"sec_6_3",title:"2.3.2 MRI system",level:"3"},{id:"sec_7_3",title:"2.3.3 Experiments of the stress state using subject’s saliva",level:"3"},{id:"sec_9_2",title:"2.4 MEG experiments for four mode state",level:"2"},{id:"sec_10_2",title:"2.5 MEG and data analysis",level:"2"},{id:"sec_10_3",title:"2.5.1 122-channel neuromagnetometer of the Planar Type Gradiometer",level:"3"},{id:"sec_11_3",title:"2.5.2 Signal Space Separation (SSS) system",level:"3"},{id:"sec_12_3",title:"2.5.3 Source reconstruction",level:"3"},{id:"sec_13_3",title:"2.5.4 Dipole fitting",level:"3"},{id:"sec_14_3",title:"2.5.5 Single current dipole tracing method (single sphere model)",level:"3"},{id:"sec_15_3",title:"2.5.6 Evaluation method using statistical cost function (GOF)",level:"3"},{id:"sec_16_3",title:"2.5.7 Multi-current dipoles tracing method (multi source models)",level:"3"},{id:"sec_17_3",title:"2.5.8 Estimation of the current source by observing the magnetic field distribution",level:"3"},{id:"sec_18_3",title:"2.5.9 Data acquisition, processing and analysis",level:"3"},{id:"sec_21",title:"3. Results",level:"1"},{id:"sec_21_2",title:"3.1 Result of signal source estimation of MEG in the brain obtained with the single current dipole tracing method",level:"2"},{id:"sec_21_3",title:"3.1.1 Advantage of the real-time response of the brain’s neural activities by analysis of millisecond-time resolution using the single current dipole tracing method of MEG",level:"3"},{id:"sec_22_3",title:"3.1.2 Mechanism of the real-time estimation method of the active area using the single current dipole tracing method of MEG data",level:"3"},{id:"sec_23_3",title:"Table 1.",level:"3"},{id:"sec_23_4",title:"3.1.3.1 a-1. Right priority brain type",level:"4"},{id:"sec_24_4",title:"3.1.3.2 a-2. Left priority brain type",level:"4"},{id:"sec_25_4",title:"3.1.3.3 A-group: (A1–A5) habit of putting the hands together or praying",level:"4"},{id:"sec_26_4",title:"Table 1.",level:"4"},{id:"sec_28_3",title:"3.1.4 One person (N1) not classified in the A- or B-group",level:"3"},{id:"sec_28_4",title:"3.1.4.1 c-1. Orbito-frontal lobe area",level:"4"},{id:"sec_29_4",title:"3.1.4.2 A-group: habit of putting the hands together or praying",level:"4"},{id:"sec_30_4",title:"3.1.4.3 B-group: no habit of putting the hands together or praying",level:"4"},{id:"sec_33_2",title:"3.2 Results of statistical analysis of the cortisol level in the saliva of each of the 11 subjects",level:"2"},{id:"sec_34_2",title:"3.3 Relation between the impression of the subject about the incense outdoor and stress measured by the cortisol value",level:"2"},{id:"sec_34_3",title:"3.3.1 A-group: habit of putting their hands together or praying",level:"3"},{id:"sec_35_3",title:"3.3.2 B-group: no habit of putting the hands together or praying",level:"3"},{id:"sec_37_2",title:"3.4 Summary of results",level:"2"},{id:"sec_37_3",title:"3.4.1 The specific and distinct mirror neuron activities without the error activity on the hand motor system by putting the hands together",level:"3"},{id:"sec_38_3",title:"3.4.2 The simultaneous new specific stronger effects of both the distinct mirror neuron’s activity putting the hands together and the activities of smelling an incense outdoor at the same time",level:"3"},{id:"sec_39_3",title:"3.4.3 The mode of smelling an incense outdoor only without putting the hands together (olfactory response with non-mirror neuron activity)",level:"3"},{id:"sec_42",title:"4. Discussions",level:"1"},{id:"sec_42_2",title:"4.1 The inverse problem: source estimation models",level:"2"},{id:"sec_43_2",title:"4.2 Mirror neurons and the default mode network",level:"2"},{id:"sec_44_2",title:"4.3 The meaning of simultaneous smelling an incense outdoor and putting the hands together",level:"2"},{id:"sec_46",title:"5. Conclusions",level:"1"},{id:"sec_47",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Takagi SF. Human Olfaction. Tokyo, Japan: University of Tokyo Press; 1989'},{id:"B2",body:'Takagi SF. Olfactory frontal cortex and multiple olfactory processing in primates. In: Peters A, Ones EG, editors. Cerebral Cortex. Vol. 9. New York: Plenum; 1991. pp. 133-152'},{id:"B3",body:'Sobel N, Pranhakaran V, Desmond JE, Glovere GH, Goode RL, Sullivan EV, et al. Sniffing and smelling: Separate subsystems in the human olfactory cortex. Nature. 1998;392:282-286'},{id:"B4",body:'Zatorre RJ, Jones-Gotman M, Evans AC, Meyer E. Functional localization and lateralization of human olfactory cortex. Nature. 1992;360:339-340'},{id:"B5",body:'Tonoike M, Yamaguchi M, Kaetsu I, Kida H, Seo R, Koizuka I. Ipsilateral dominance of human olfactory activated centers estimated from event-related magnetic fields measured by 122-channel whole-head neuromagnetometer using odorant stimuli synchronized with respirations. In: Murphy C, editor. Olfaction and Taste XII. Vol. 855. New York: New York Academy of Sciences; 1998. pp. 579-590'},{id:"B6",body:'Tonoike M, Yamaguchi M, Hamada T, Kaetsu I, Koizuka I, Seo R. Odorant perception and active olfaction: A study of olfactory magnetic fields evoked by odorant pulse stimuli synchronized with respiratory cycle. Proceedings of 20th Annual International Conference IEEE/EMBS\'98. 1998;20(4):2213-2216'},{id:"B7",body:'Iacoboni M, Woods RP, Brass M, et al. Cortical mechanisms of human imitation. Science. 1999;286:2526-2528'},{id:"B8",body:'Rizzolatti G, Fadiga L, Fogassi L, Gallese V. From mirror neurons to imitation: Facts and speculations. In: Meltzoff AN, Prinz W, editors. The Imitative Mind. Development, Evolution, and Brain Bases. Cambridge: Cambridge University Press; 2002. pp. 247-266'},{id:"B9",body:'Arbib M. The Mirror System Hypothesis. Linking Language to Theory of Mind. 2005. Retrieved 2006-02-17'},{id:"B10",body:'Ramachandran VS, Vilayanur S. Mirror neurons and imitation learning as the driving force behind “the great leap forward” in human evolution. 2005. http://www.edge.org/3rd_culture/ramachandran/ramachandran_p1.html [Accessed: June 15th, 2005]'},{id:"B11",body:'Rizzolatti G, Fogassi L, Gallese V. Neurophysiological mechanisms underlying the understanding and imitation of action. Nature Reviews Neuroscience. 2001;2:661-670'},{id:"B12",body:'Rizzolatti G, Craighero L. The mirror neuron system. Annual Reviews of Neuroscience. 2004;27:169-192'},{id:"B13",body:'Raiche ME, MacLeod AM, Snyder AZ, et al. A default mode of brain function. Proceedigs of the National Academy of Sciences USA. 2001;98:676-682'},{id:"B14",body:'Cherkassky VL, Kana RK, Keller TA, Just MA. Functional connectivity in a baseline resting-state network in autism. Neuroreport. 2006;17(16):1687-1690'},{id:"B15",body:'Gusnard DA, Raiche ME. Searching for a baseline: Functional imaging and the resting human brain. Nature Reviews Neuroscience. 2001;2:685-694'},{id:"B16",body:'Xu X, Yuan H, Lei X. Activation and connectivity within the default mode network contribute independently to future-oriented thought. Scientific Reports. 2016;6:21001. DOI: 10.1038/srep21001'},{id:"B17",body:'Maresh EL, Allen JP, Coan JA. Increased default mode network activity in socially anxious individuals during reward processing. Biology of Mood & Anxiety Disorders. 2014;4:7. DOI: 10.1186/2045-5380-4-7'},{id:"B18",body:'John A, Friston KJ. Unified segmentation. NeuroImage. 2005;26:839-851'},{id:"B19",body:'Taulu S, Kajola M, Simola J. The signal space separation method. In: 14th Conference of the International Society for Brain Electromagnetic Topography; Santa Fe, NM'},{id:"B20",body:'Taulu S, Simola J, Kajola M. Applications of the signal space separation method. IEEE Transactions on Signal Processing. 2005;53:3359-3372'},{id:"B21",body:'Taulu S, Simola J. Spatiotemporal signal space separation method for rejecting nearby interference in MEG measurements. Physics in Medicine and Biology. 2006;51(7):1759-1768'},{id:"B22",body:'Uutela K, Taulu S, Hamalainen M. Detecting and correcting for head movements. NeuroImage. 2001;14:1424-1431'},{id:"B23",body:'Tonoike M, Yamaguchi M, Kaetsu I, Kida H, Seo R, Koizuka I. Ipsilateral dominance of human olfactory activated centers estimated from event-related magnetic fields measured by 122-channel whole-head neuromagnetometer using stimuli synchronized with respirations. In: Murphy C, editor. Olfaction and Taste Xll. Vol. 855. New York: New York Academy of Sciences; 1998. pp. 579-590'},{id:"B24",body:'Williamson S, Kaufman L. Biomagnetism. Journal of Magnetism and Magnetic Materials. 1981;22:129'},{id:"B25",body:'Uusitalo MA, Ilmoniemi RJ. Signal-space projection method. Medical & Biological Engineering. 1997;32:35-42'},{id:"B26",body:'Uutela K, Hamalainen M, Salmelin R. Global optimization in the localization of neuromagnetic sources. IEEE Transactions on Biomedical Engineering. 1998;45(6):716-723'},{id:"B27",body:'Uutela K, Hamalainen M, Salmelin R. Visualization of magnetoencepalographyic data using minimum current estimates. NeuroImage. 1999;10(2):173-180'},{id:"B28",body:'Kiebel SJ, Daunizeau J, Friston KJ. A hierarchy of time-scales and the brain. PLOS Computational Biology. 2008;4(11):1-12, 4e1000209'},{id:"B29",body:'Kiebel SJ, Garrido MI, Moran R, Chen CC, Friston KJ. Dynamic causal modeling for EEG and MEG. Human Brain Mapping. 2009;30:1866-1876'},{id:"B30",body:'Sanja JG, Susac A, Grilj V, et al. Size matters: MEG empirical and simulation study on source localization of the earliest visual activity in the occipital cortex. Medical & Biological Engineering & Computing. 2011;49(5):545-554'},{id:"B31",body:'Sanja JG, Aine Cheryl J, Stephen Julia M, Adair John C, Knoefel Janice E, Selma S. Modulatory role of the prefrontal generator within the auditory M50 network. NeuroImage. 2014;92:120-131'},{id:"B32",body:'Sanja JG, Aine Cheryl J, Stephen Julia M, Adair John C, Knoefel Janice E, Selma S. MEG biomarker of Alzheimer’s disease: Absence of a prefrontal generator during auditory sensory gating. Human Brain Mapping. 2017;38:5180-5194'},{id:"B33",body:'Darvas F, Pantazis D, Kucukaltun-Yildirim E, Leahy RM. Mapping human brain function with MEG and EEG: Methods and validation. Neuromag. 2004;23(suppl.1):S289-S229'},{id:"B34",body:'Hamalainen M, Sarvas J. Feasibility of the homogenous head model in the interpretation of neuromagnetic fields. Physics in Medicine and Biology. 1987;32:91-97'},{id:"B35",body:'Hamalainen M, Hari R, Ilmoniemi RJ, Knuutila JET, Lounasmaa OV. Magnetoencephalography-theory, instrumentation, and application to noninvasive studies of the working human brain. Reviews of Modern Physics. 1993;65:413-497'},{id:"B36",body:'Hamalainen M, Ilmoniemi RJ. Interpreting magnetic fields of the brain: Minimun norm estimates. Medical and Biological Engineering and Computing. 1994;32(1):35-42'},{id:"B37",body:'Cuffin BN. A comparison of moving dipole inverse solution using EEG’s and MEG’s. IEEE Transactions on Biomedical Engineering. 1985;32(11):905-910'},{id:"B38",body:'Scherg M, Von Cramon D. Evoked dipole source potentials of the human auditory cortex. Electroencephalography and Clinical Neurophysiology. 1986;65(5):344-360'},{id:"B39",body:'Ilmoniemi RJ. Neuromagnetism: Theory, techniques, and measurement [PhD thesis]. Helsinki Univ. of Technology; 1985'},{id:"B40",body:'Sarvas J. Basic mathematical and electromagnetic concepts of the biomagnetic inverse problem. Physics in Medicine and Biology. 1987;32(1):11-22'},{id:"B41",body:'Ioannides A, Liu LC, Kwapien J, Drozdz S, Streit M. Coupling of regional activations in human brain during an object and face affect recognition task. Human Brain Mapping. 2000;11:77-92'},{id:"B42",body:'Tonoike M, Nishimura K, Tobinaga Y. Detection of thinking in human by magnetoencephalography, world congress of medical physics and biological engineering. In: IFMBE Proceedings. Vol. 14. 2006. pp. 2617-2621'},{id:"B43",body:'Nishimura K, Tobinaga Y, Tonoike M. Detection of neural activity associated with thinking in frontal lobe by magnetoencephalography. Progress of Theoretical Physics. 2002;173(Suppl):332-341'},{id:"B44",body:'Haueisen J, Ramon C, Eiselt M, Brauer H, Nowak N. Influence of tissue resistivities on neuromagnetic fields and electric potentials studied with a finite element model of the head. IEEE Transactions on Biomedical Engineering. 1997;44(8):727-735'},{id:"B45",body:'Dapretto M. Understanding emotions in others: Mirror neuron dysfunction in children with autism spectrum disorders. Nature Neuroscience. 2006;9(1):28-30'},{id:"B46",body:'Bastiaansen JACJ, Thioux M, Keysers C. Evidence for mirror systems in emotions. Philosophical Transactions of the Royal Society Biological Science. 2009;364:2391-2404'},{id:"B47",body:'Oberman LM, Hubbard EM, McCleery JP, Altschuler EL, Ramachandran VS, Pineda JA. EEG evidence for mirror neuron dysfunction in autism spectral disorders. Brain Research. Cognitive Brain Research. 2005;24(2):190-198'},{id:"B48",body:'Oberman LM, Pineda JA, Ramachandran VS. The human mirror neuron system: A link between action observation and social skills. SCAN. 2007;2:62-66'},{id:"B49",body:'Kiebel SJ, Friston KJ. Free energy and dendritic self-organization. Frontiers in System Neuroscience. 2011;5:1-13. DOI: 10.3389/fsnys.2011.00080'},{id:"B50",body:'Fadiga L, Fogassi L, Pavesi G, Rizzolatti G. Motor facilitation during action observating: A magnetic stimulation study. Journal of Neurophysiology. 1995;73:2608-2611'},{id:"B51",body:'Gallese V, Goldman A. Mirror neurons and the simulation theory of mindreading. Trends in Cognitive Sciences. 1998;2:493-501'},{id:"B52",body:'McClure SM, Li J, Tomlin D, et al. Neural correlates of behavioral preference for culturally familiar drinks. Neuron. 2004;44:379-387'},{id:"B53",body:'Mukamel R, Ekstrom AD, Kaplan J, Iacoboni M, Fried I. Singleneuron responses in humans during execution and observation of actions. Current Biology. 2010;20(8):750-756'},{id:"B54",body:'Hari R, Forss N, Avikainen S, et al. Activation of human primary motor cortex during action observation: A Neuromagnetic study. Proceedings of the National Academy of Sciences of United States of America. 1998;95(25):15061-15065'},{id:"B55",body:'Yarita H, Iino M, Tanabe T, Kogure S, Takagi SF. A transthalamic olfactory pathway to orbitofrontal cortex in the monkey. Journal of Neurophysiology. 1980;45:69-85'},{id:"B56",body:'Tanabe T, Yarita H, Iino M, Ooshima Y, Takagi SF. An olfactory projection area in orbitofrontal cortex of the monkey. Journal of Neurophysiology. 1975;38:1269-1283'},{id:"B57",body:'Seubert J, Gregory KK, Chamberland J, Dessirier JM, Lundstrom JN. Odor valence linearly modulates attractiveness, but not age assessment, of invariant facial features in a memory-based rating task. PLoS One. 2014;9:e98347. DOI: 10.1371/journal.pone.0098347'},{id:"B58",body:'Tonoike M, Yoshida T, Sakuma H, Wang L-Q. fMRI measurement of integrative effects of visual and chemical senses stimuli in humans. Journal of Integrative Neuroscience. 2013;12(3):369-384'},{id:"B59",body:'Tonoike M. Odor perception: The mechanism of how odor is perceived, human olfactory displays and interfaces: Odor sensing and presentation. In: IGI Global Disseminator and Knowledge. 2013. pp. 44-59'},{id:"B60",body:'Zhou W, Jiang Y, He S, Chen D. Olfaction modulates visual perception in binocular rivalry. Current Biology. 2010;20:1356-1358'},{id:"B61",body:'Calvert GA, Campbell R, Braer MJ. Evidence from functional magnetic resonance imaging of crossmodal binding in the human heteromodal cortex. Current Biology: CB. 2000;10:649-657'},{id:"B62",body:'Calvert GA. Crossmodal processing in the human brain: Insights from functional neuroimaging studies. Cerebral Cortex. 2011;11:1110-1123'},{id:"B63",body:'Davis MH. Measuring indivisual differences in emphathy: Evidence for a multidimensional approach. Journal of Personality & Social Psychology. 1983;44:113-126'},{id:"B64",body:'Simpson JR, Snyder AZ, Gusnard DA, Raichle ME. Emotional-induced changes in human medial prefrontal cortex: 1. During cognitive task performance. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:683-687'},{id:"B65",body:'Buccino G, Binkofski F, Fink GR, Fadiga L, Fogassi L, Gallese V. Action observation activates premotor and parietal areas in a somatotopic manner: An fMRI study. European Journal of Neuroscience. 2001;13:400-404'},{id:"B66",body:'Cherkassky VL, Kana RK, Keller TA, Just MA. Functional connectivity in a baseline resting-state network in autism. Neuroreport. 2006;17(16):1787-1690'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mitsuo Tonoike",address:"gah00161@nifty.ne.jp",affiliation:'
Department of Medical Engineering, Faculty of Health and Science, Aino University, Ibaraki, Osaka, Japan
Department of Medical Engineering, Faculty of Health and Science, Aino University, Ibaraki, Osaka, Japan
'}],corrections:null},book:{id:"7541",title:"Neuroimaging",subtitle:"Structure, Function and Mind",fullTitle:"Neuroimaging - Structure, Function and Mind",slug:"neuroimaging-structure-function-and-mind",publishedDate:"April 3rd 2019",bookSignature:"Sanja Josef Golubic",coverURL:"https://cdn.intechopen.com/books/images_new/7541.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"225125",title:"Ph.D.",name:"Sanja",middleName:null,surname:"Josef Golubic",slug:"sanja-josef-golubic",fullName:"Sanja Josef Golubic"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"114132",title:"Dr.",name:"Tayeb",middleName:null,surname:"Merabti",email:"tayeb.merabti@chu-rouen.fr",fullName:"Tayeb Merabti",slug:"tayeb-merabti",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:{name:"University of Rouen",institutionURL:null,country:{name:"France"}}},booksEdited:[],chaptersAuthored:[{title:"Aligning Biomedical Terminologies in French: Towards Semantic Interoperability in Medical Applications",slug:"methods-to-map-biomedical-terminologies-in-french-contribution-to-semantic-interoperability-between-",abstract:null,signatures:"Tayeb Merabti, Lina F. Soualmia, Julien Grosjean, Michel Joubert and Stefan J. Darmoni",authors:[{id:"114132",title:"Dr.",name:"Tayeb",surname:"Merabti",fullName:"Tayeb Merabti",slug:"tayeb-merabti",email:"tayeb.merabti@chu-rouen.fr"}],book:{title:"Medical Informatics",slug:"medical-informatics",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"22796",title:"Dr.",name:"Vicente",surname:"Ferreira de Lucena Jr",slug:"vicente-ferreira-de-lucena-jr",fullName:"Vicente Ferreira de Lucena Jr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Amazonas",institutionURL:null,country:{name:"Brazil"}}},{id:"100392",title:"MSc.",name:"Anna",surname:"Ribeiro",slug:"anna-ribeiro",fullName:"Anna Ribeiro",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Rio Grande do Norte",institutionURL:null,country:{name:"Brazil"}}},{id:"110076",title:"MSc.",name:"Vandermi",surname:"Silva",slug:"vandermi-silva",fullName:"Vandermi Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Amazonas",institutionURL:null,country:{name:"Brazil"}}},{id:"111689",title:"Dr.",name:"Asmaa",surname:"Rashid",slug:"asmaa-rashid",fullName:"Asmaa Rashid",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},{id:"111694",title:"Dr.",name:"Norizan",surname:"Binti Mohd Yasin",slug:"norizan-binti-mohd-yasin",fullName:"Norizan Binti Mohd Yasin",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},{id:"113481",title:"Dr.",name:"Małgorzata",surname:"Plechawska-Wojcik",slug:"malgorzata-plechawska-wojcik",fullName:"Małgorzata Plechawska-Wojcik",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lublin University of Technology",institutionURL:null,country:{name:"Poland"}}},{id:"115774",title:"Prof.",name:"Hsueh-Chun",surname:"Lin",slug:"hsueh-chun-lin",fullName:"Hsueh-Chun Lin",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"China Medical University",institutionURL:null,country:{name:"Taiwan"}}},{id:"117156",title:"Prof.",name:"Luís",surname:"Velez Lapão",slug:"luis-velez-lapao",fullName:"Luís Velez Lapão",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Nova de Lisboa",institutionURL:null,country:{name:"Portugal"}}},{id:"140206",title:"MSc.",name:"Ricardo",surname:"Erikson Veras De Sena Rosa",slug:"ricardo-erikson-veras-de-sena-rosa",fullName:"Ricardo Erikson Veras De Sena Rosa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"open-access-funding",title:"Open Access Funding",intro:"
IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\\n\\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\\n\\n
\\n\\t
Does your institution already have a budget for covering Open Access publication costs?
\\n\\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\\n
\\n\\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\\n\\n
Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at oapf@intechopen.com
\\n\\n
Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\n\n
Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at oapf@intechopen.com
\n\n
Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
\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:5699},{group:"region",caption:"Middle and South America",value:2,count:5172},{group:"region",caption:"Africa",value:3,count:1689},{group:"region",caption:"Asia",value:4,count:10244},{group:"region",caption:"Australia and Oceania",value:5,count:888},{group:"region",caption:"Europe",value:6,count:15650}],offset:12,limit:12,total:117315},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"dateEndThirdStepPublish"},books:[{type:"book",id:"10578",title:"Pharmacogenetics",subtitle:null,isOpenForSubmission:!0,hash:"ca2bc2ff6e15a7b735d662d9664086b1",slug:null,bookSignature:"Dr. Islam Khalil",coverURL:"https://cdn.intechopen.com/books/images_new/10578.jpg",editedByType:null,editors:[{id:"226598",title:"Dr.",name:"Islam",surname:"Khalil",slug:"islam-khalil",fullName:"Islam Khalil"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10630",title:"New Robots, Techniques and Applications in Industrial Robotics",subtitle:null,isOpenForSubmission:!0,hash:"4a56dacb7c0504f0601f63000d64c1bc",slug:null,bookSignature:"Prof. Antoni Grau and Dr. Rodrigo Munguia",coverURL:"https://cdn.intechopen.com/books/images_new/10630.jpg",editedByType:null,editors:[{id:"13038",title:"Prof.",name:"Antoni",surname:"Grau",slug:"antoni-grau",fullName:"Antoni Grau"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9734",title:"Chromatin Organization in Health and Disease",subtitle:null,isOpenForSubmission:!0,hash:"ad6935289971d793d26ff2584f57143b",slug:null,bookSignature:"Associate Prof. Jehane Eid",coverURL:"https://cdn.intechopen.com/books/images_new/9734.jpg",editedByType:null,editors:[{id:"325814",title:"Associate Prof.",name:"Jehane",surname:"Eid",slug:"jehane-eid",fullName:"Jehane Eid"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10404",title:"Evapotranspiration - Recent Advances and Applications",subtitle:null,isOpenForSubmission:!0,hash:"babca2dea1c80719111734cc57a21a4c",slug:null,bookSignature:"Dr. Amin Talei",coverURL:"https://cdn.intechopen.com/books/images_new/10404.jpg",editedByType:null,editors:[{id:"335732",title:"Dr.",name:"Amin",surname:"Talei",slug:"amin-talei",fullName:"Amin Talei"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10488",title:"Renin-Angiotensin Aldosterone System",subtitle:null,isOpenForSubmission:!0,hash:"5815b21958b2b2d5b653771c3f0cc35c",slug:null,bookSignature:"Prof. Samy I. McFarlane",coverURL:"https://cdn.intechopen.com/books/images_new/10488.jpg",editedByType:null,editors:[{id:"53477",title:"Prof.",name:"Samy I.",surname:"McFarlane",slug:"samy-i.-mcfarlane",fullName:"Samy I. McFarlane"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10323",title:"Osteoporosis - Recent Advances, New Perspectives and Applications",subtitle:null,isOpenForSubmission:!0,hash:"08e07eb8b6c4997a39a2d04b99ac2ffc",slug:null,bookSignature:"Prof. Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/10323.jpg",editedByType:null,editors:[{id:"73208",title:"Prof.",name:"Luis",surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10013",title:"Geothermal Energy",subtitle:null,isOpenForSubmission:!0,hash:"a5f5277a1c0616ce6b35f4b44a4cac7a",slug:null,bookSignature:"Dr. Basel I. Ismail",coverURL:"https://cdn.intechopen.com/books/images_new/10013.jpg",editedByType:null,editors:[{id:"62122",title:"Dr.",name:"Basel",surname:"Ismail",slug:"basel-ismail",fullName:"Basel Ismail"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10221",title:"Bacteriophages",subtitle:null,isOpenForSubmission:!0,hash:"96b799aada07c6e98864f2d8e5780bac",slug:null,bookSignature:"Dr. Sonia Bhonchal Bhardwaj",coverURL:"https://cdn.intechopen.com/books/images_new/10221.jpg",editedByType:null,editors:[{id:"178566",title:"Dr.",name:"Sonia Bhonchal",surname:"Bhardwaj",slug:"sonia-bhonchal-bhardwaj",fullName:"Sonia Bhonchal Bhardwaj"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10332",title:"Mitochondrial Diseases",subtitle:null,isOpenForSubmission:!0,hash:"5a8e118ff6bdf4923a8e6e1d91b8397e",slug:null,bookSignature:"Prof. Angel Catala",coverURL:"https://cdn.intechopen.com/books/images_new/10332.jpg",editedByType:null,editors:[{id:"196544",title:"Prof.",name:"Angel",surname:"Catala",slug:"angel-catala",fullName:"Angel Catala"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9577",title:"Confocal Laser Scanning Microscopy",subtitle:null,isOpenForSubmission:!0,hash:"d0f227eb9f3fc8c85c7757257b6e966a",slug:null,bookSignature:"Dr. Natalia Yu. Grigoryeva",coverURL:"https://cdn.intechopen.com/books/images_new/9577.jpg",editedByType:null,editors:[{id:"239430",title:"Dr.",name:"Natalia",surname:"Grigoryeva",slug:"natalia-grigoryeva",fullName:"Natalia Grigoryeva"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9504",title:"Evidence-Based Approaches to Effectively Respond to Public Health Emergencies",subtitle:null,isOpenForSubmission:!0,hash:"355f26e9a65d22c4de7311a424d1e3eb",slug:null,bookSignature:"Dr. Erick Guerrero",coverURL:"https://cdn.intechopen.com/books/images_new/9504.jpg",editedByType:null,editors:[{id:"294761",title:"Dr.",name:"Erick",surname:"Guerrero",slug:"erick-guerrero",fullName:"Erick Guerrero"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10547",title:"Physiology and Disorders of Adipose Tissue",subtitle:null,isOpenForSubmission:!0,hash:"b423df09d9aaf08881b015f129af27d0",slug:null,bookSignature:"Dr. Hassan M. Heshmati",coverURL:"https://cdn.intechopen.com/books/images_new/10547.jpg",editedByType:null,editors:[{id:"313921",title:"Dr.",name:"Hassan M.",surname:"Heshmati",slug:"hassan-m.-heshmati",fullName:"Hassan M. Heshmati"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:9},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:16},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:6},{group:"topic",caption:"Computer and Information Science",value:9,count:10},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:4},{group:"topic",caption:"Engineering",value:11,count:15},{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:4},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:56},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:6},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:3},{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:2}],offset:12,limit:12,total:151},popularBooks:{featuredBooks:[{type:"book",id:"7802",title:"Modern Slavery and Human Trafficking",subtitle:null,isOpenForSubmission:!1,hash:"587a0b7fb765f31cc98de33c6c07c2e0",slug:"modern-slavery-and-human-trafficking",bookSignature:"Jane Reeves",coverURL:"https://cdn.intechopen.com/books/images_new/7802.jpg",editors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9961",title:"Data Mining",subtitle:"Methods, Applications and Systems",isOpenForSubmission:!1,hash:"ed79fb6364f2caf464079f94a0387146",slug:"data-mining-methods-applications-and-systems",bookSignature:"Derya Birant",coverURL:"https://cdn.intechopen.com/books/images_new/9961.jpg",editors:[{id:"15609",title:"Dr.",name:"Derya",middleName:null,surname:"Birant",slug:"derya-birant",fullName:"Derya Birant"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8686",title:"Direct Torque Control Strategies of Electrical Machines",subtitle:null,isOpenForSubmission:!1,hash:"b6ad22b14db2b8450228545d3d4f6b1a",slug:"direct-torque-control-strategies-of-electrical-machines",bookSignature:"Fatma Ben Salem",coverURL:"https://cdn.intechopen.com/books/images_new/8686.jpg",editors:[{id:"295623",title:"Associate Prof.",name:"Fatma",middleName:null,surname:"Ben Salem",slug:"fatma-ben-salem",fullName:"Fatma Ben Salem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5143},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9376",title:"Contemporary Developments and Perspectives in International Health Security",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"b9a00b84cd04aae458fb1d6c65795601",slug:"contemporary-developments-and-perspectives-in-international-health-security-volume-1",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, Sagar C. Galwankar, Ricardo Izurieta and Thomas Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/9376.jpg",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7769",title:"Medical Isotopes",subtitle:null,isOpenForSubmission:!1,hash:"f8d3c5a6c9a42398e56b4e82264753f7",slug:"medical-isotopes",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9279",title:"Concepts, Applications and Emerging Opportunities in Industrial Engineering",subtitle:null,isOpenForSubmission:!1,hash:"9bfa87f9b627a5468b7c1e30b0eea07a",slug:"concepts-applications-and-emerging-opportunities-in-industrial-engineering",bookSignature:"Gary Moynihan",coverURL:"https://cdn.intechopen.com/books/images_new/9279.jpg",editors:[{id:"16974",title:"Dr.",name:"Gary",middleName:null,surname:"Moynihan",slug:"gary-moynihan",fullName:"Gary Moynihan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7807",title:"A Closer Look at Organizational Culture in Action",subtitle:null,isOpenForSubmission:!1,hash:"05c608b9271cc2bc711f4b28748b247b",slug:"a-closer-look-at-organizational-culture-in-action",bookSignature:"Süleyman Davut Göker",coverURL:"https://cdn.intechopen.com/books/images_new/7807.jpg",editors:[{id:"190035",title:"Associate Prof.",name:"Süleyman Davut",middleName:null,surname:"Göker",slug:"suleyman-davut-goker",fullName:"Süleyman Davut Göker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editedByType:"Edited by",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9569",title:"Methods in Molecular Medicine",subtitle:null,isOpenForSubmission:!1,hash:"691d3f3c4ac25a8093414e9b270d2843",slug:"methods-in-molecular-medicine",bookSignature:"Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9569.jpg",editedByType:"Edited by",editors:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7802",title:"Modern Slavery and Human Trafficking",subtitle:null,isOpenForSubmission:!1,hash:"587a0b7fb765f31cc98de33c6c07c2e0",slug:"modern-slavery-and-human-trafficking",bookSignature:"Jane Reeves",coverURL:"https://cdn.intechopen.com/books/images_new/7802.jpg",editedByType:"Edited by",editors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8063",title:"Food Security in Africa",subtitle:null,isOpenForSubmission:!1,hash:"8cbf3d662b104d19db2efc9d59249efc",slug:"food-security-in-africa",bookSignature:"Barakat Mahmoud",coverURL:"https://cdn.intechopen.com/books/images_new/8063.jpg",editedByType:"Edited by",editors:[{id:"92016",title:"Dr.",name:"Barakat",middleName:null,surname:"Mahmoud",slug:"barakat-mahmoud",fullName:"Barakat Mahmoud"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10118",title:"Plant Stress Physiology",subtitle:null,isOpenForSubmission:!1,hash:"c68b09d2d2634fc719ae3b9a64a27839",slug:"plant-stress-physiology",bookSignature:"Akbar Hossain",coverURL:"https://cdn.intechopen.com/books/images_new/10118.jpg",editedByType:"Edited by",editors:[{id:"280755",title:"Dr.",name:"Akbar",middleName:null,surname:"Hossain",slug:"akbar-hossain",fullName:"Akbar Hossain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editedByType:"Edited by",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9961",title:"Data Mining",subtitle:"Methods, Applications and Systems",isOpenForSubmission:!1,hash:"ed79fb6364f2caf464079f94a0387146",slug:"data-mining-methods-applications-and-systems",bookSignature:"Derya Birant",coverURL:"https://cdn.intechopen.com/books/images_new/9961.jpg",editedByType:"Edited by",editors:[{id:"15609",title:"Dr.",name:"Derya",middleName:null,surname:"Birant",slug:"derya-birant",fullName:"Derya Birant"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8686",title:"Direct Torque Control Strategies of Electrical Machines",subtitle:null,isOpenForSubmission:!1,hash:"b6ad22b14db2b8450228545d3d4f6b1a",slug:"direct-torque-control-strategies-of-electrical-machines",bookSignature:"Fatma Ben Salem",coverURL:"https://cdn.intechopen.com/books/images_new/8686.jpg",editedByType:"Edited by",editors:[{id:"295623",title:"Associate Prof.",name:"Fatma",middleName:null,surname:"Ben Salem",slug:"fatma-ben-salem",fullName:"Fatma Ben Salem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"3",title:"Health Sciences",slug:"health-sciences",parent:null,numberOfBooks:1613,numberOfAuthorsAndEditors:41759,numberOfWosCitations:18267,numberOfCrossrefCitations:12350,numberOfDimensionsCitations:31381,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"health-sciences",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"9569",title:"Methods in Molecular Medicine",subtitle:null,isOpenForSubmission:!1,hash:"691d3f3c4ac25a8093414e9b270d2843",slug:"methods-in-molecular-medicine",bookSignature:"Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9569.jpg",editedByType:"Edited by",editors:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editedByType:"Edited by",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editedByType:"Edited by",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8468",title:"Sheep Farming",subtitle:"An Approach to Feed, Growth and Health",isOpenForSubmission:!1,hash:"838f08594850bc04aa14ec873ed1b96f",slug:"sheep-farming-an-approach-to-feed-growth-and-health",bookSignature:"António Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/8468.jpg",editedByType:"Edited by",editors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9018",title:"Some RNA Viruses",subtitle:null,isOpenForSubmission:!1,hash:"a5cae846dbe3692495fc4add2f60fd84",slug:"some-rna-viruses",bookSignature:"Yogendra Shah and Eltayb Abuelzein",coverURL:"https://cdn.intechopen.com/books/images_new/9018.jpg",editedByType:"Edited by",editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9523",title:"Oral and Maxillofacial Surgery",subtitle:null,isOpenForSubmission:!1,hash:"5eb6ec2db961a6c8965d11180a58d5c1",slug:"oral-and-maxillofacial-surgery",bookSignature:"Gokul Sridharan",coverURL:"https://cdn.intechopen.com/books/images_new/9523.jpg",editedByType:"Edited by",editors:[{id:"82453",title:"Dr.",name:"Gokul",middleName:null,surname:"Sridharan",slug:"gokul-sridharan",fullName:"Gokul Sridharan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9585",title:"Advances in Complex Valvular Disease",subtitle:null,isOpenForSubmission:!1,hash:"ef64f11e211621ecfe69c46e60e7ca3d",slug:"advances-in-complex-valvular-disease",bookSignature:"Michael S. Firstenberg and Imran Khan",coverURL:"https://cdn.intechopen.com/books/images_new/9585.jpg",editedByType:"Edited by",editors:[{id:"64343",title:null,name:"Michael S.",middleName:"S",surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7703",title:"Ocular Surface Diseases",subtitle:"Some Current Date on Tear Film Problem and Keratoconic Diagnosis",isOpenForSubmission:!1,hash:"3dcf967eb2f185930ce7fb7ae462d4e0",slug:"ocular-surface-diseases-some-current-date-on-tear-film-problem-and-keratoconic-diagnosis",bookSignature:"Dorota Kopacz",coverURL:"https://cdn.intechopen.com/books/images_new/7703.jpg",editedByType:"Edited by",editors:[{id:"271261",title:"Dr.",name:"Dorota",middleName:null,surname:"Kopacz",slug:"dorota-kopacz",fullName:"Dorota Kopacz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9376",title:"Contemporary Developments and Perspectives in International Health Security",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"b9a00b84cd04aae458fb1d6c65795601",slug:"contemporary-developments-and-perspectives-in-international-health-security-volume-1",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, Sagar C. Galwankar, Ricardo Izurieta and Thomas Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/9376.jpg",editedByType:"Edited by",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1613,mostCitedChapters:[{id:"19013",doi:"10.5772/21983",title:"Cell Responses to Surface and Architecture of Tissue Engineering Scaffolds",slug:"cell-responses-to-surface-and-architecture-of-tissue-engineering-scaffolds",totalDownloads:9614,totalCrossrefCites:106,totalDimensionsCites:222,book:{slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",title:"Regenerative Medicine and Tissue Engineering",fullTitle:"Regenerative Medicine and Tissue Engineering - Cells and Biomaterials"},signatures:"Hsin-I Chang and Yiwei Wang",authors:[{id:"45747",title:"Dr.",name:"Hsin-I",middleName:null,surname:"Chang",slug:"hsin-i-chang",fullName:"Hsin-I Chang"},{id:"53659",title:"Ms.",name:"Yiwei",middleName:null,surname:"Wang",slug:"yiwei-wang",fullName:"Yiwei Wang"}]},{id:"46479",doi:"10.5772/57353",title:"Floating Drug Delivery Systems for Eradication of Helicobacter pylori in Treatment of Peptic Ulcer Disease",slug:"floating-drug-delivery-systems-for-eradication-of-helicobacter-pylori-in-treatment-of-peptic-ulcer-d",totalDownloads:1936,totalCrossrefCites:65,totalDimensionsCites:150,book:{slug:"trends-in-helicobacter-pylori-infection",title:"Trends in Helicobacter pylori Infection",fullTitle:"Trends in Helicobacter pylori Infection"},signatures:"Yousef Javadzadeh and Sanaz Hamedeyazdan",authors:[{id:"94276",title:"Prof.",name:"Yousef",middleName:null,surname:"Javadzadeh",slug:"yousef-javadzadeh",fullName:"Yousef Javadzadeh"},{id:"98229",title:"Dr.",name:"Sanaz",middleName:null,surname:"Hamedeyazdan",slug:"sanaz-hamedeyazdan",fullName:"Sanaz Hamedeyazdan"}]},{id:"43874",doi:"10.5772/55925",title:"Residual Transmission of Malaria: An Old Issue for New Approaches",slug:"residual-transmission-of-malaria-an-old-issue-for-new-approaches",totalDownloads:4208,totalCrossrefCites:59,totalDimensionsCites:141,book:{slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",title:"Anopheles mosquitoes",fullTitle:"Anopheles mosquitoes - New insights into malaria vectors"},signatures:"Lies Durnez and Marc Coosemans",authors:[{id:"152754",title:"Prof.",name:"Marc",middleName:null,surname:"Coosemans",slug:"marc-coosemans",fullName:"Marc Coosemans"},{id:"169018",title:"Dr.",name:"Lies",middleName:null,surname:"Durnez",slug:"lies-durnez",fullName:"Lies Durnez"}]}],mostDownloadedChaptersLast30Days:[{id:"43758",title:"Anxiety Disorders in Pregnancy and the Postpartum Period",slug:"anxiety-disorders-in-pregnancy-and-the-postpartum-period",totalDownloads:29552,totalCrossrefCites:11,totalDimensionsCites:20,book:{slug:"new-insights-into-anxiety-disorders",title:"New Insights into Anxiety Disorders",fullTitle:"New Insights into Anxiety Disorders"},signatures:"Roberta Anniverno, Alessandra Bramante, Claudio Mencacci and Federico Durbano",authors:[{id:"157077",title:"Dr.",name:"Federico",middleName:null,surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"},{id:"166382",title:"Dr.",name:"Roberta",middleName:null,surname:"Anniverno",slug:"roberta-anniverno",fullName:"Roberta Anniverno"}]},{id:"58891",title:"Cognitive-Behavioral Psychotherapy for Couples: An Insight into the Treatment of Couple Hardships and Struggles",slug:"cognitive-behavioral-psychotherapy-for-couples-an-insight-into-the-treatment-of-couple-hardships-and",totalDownloads:6453,totalCrossrefCites:2,totalDimensionsCites:3,book:{slug:"cognitive-behavioral-therapy-and-clinical-applications",title:"Cognitive Behavioral Therapy and Clinical Applications",fullTitle:"Cognitive Behavioral Therapy and Clinical Applications"},signatures:"Caroline Dugal, Gaëlle Bakhos, Claude Bélanger and Natacha\nGodbout",authors:[{id:"57536",title:"Prof.",name:"Claude",middleName:null,surname:"Belanger",slug:"claude-belanger",fullName:"Claude Belanger"}]},{id:"70405",title:"Hemostasis in Cardiac Surgery: How We Do it with Limited Resources",slug:"hemostasis-in-cardiac-surgery-how-we-do-it-with-limited-resources",totalDownloads:1444,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:null,title:"Biosurgicals - The Next Frontier in Operative Approaches",fullTitle:"Biosurgicals - The Next Frontier in Operative Approaches"},signatures:"Fevzi Sarper Türker",authors:null},{id:"57717",title:"In Vitro Cytotoxicity and Cell Viability Assays: Principles, Advantages, and Disadvantages",slug:"in-vitro-cytotoxicity-and-cell-viability-assays-principles-advantages-and-disadvantages",totalDownloads:12177,totalCrossrefCites:30,totalDimensionsCites:57,book:{slug:"genotoxicity-a-predictable-risk-to-our-actual-world",title:"Genotoxicity",fullTitle:"Genotoxicity - A Predictable Risk to Our Actual World"},signatures:"Özlem Sultan Aslantürk",authors:[{id:"211212",title:"Dr.",name:"Özlem Sultan",middleName:null,surname:"Aslantürk",slug:"ozlem-sultan-aslanturk",fullName:"Özlem Sultan Aslantürk"}]},{id:"64851",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:9475,totalCrossrefCites:10,totalDimensionsCites:16,book:{slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"64762",title:"Mechanism and Health Effects of Heavy Metal Toxicity in Humans",slug:"mechanism-and-health-effects-of-heavy-metal-toxicity-in-humans",totalDownloads:5883,totalCrossrefCites:21,totalDimensionsCites:47,book:{slug:"poisoning-in-the-modern-world-new-tricks-for-an-old-dog-",title:"Poisoning in the Modern World",fullTitle:"Poisoning in the Modern World - New Tricks for an Old Dog?"},signatures:"Godwill Azeh Engwa, Paschaline Udoka Ferdinand, Friday Nweke Nwalo and Marian N. Unachukwu",authors:[{id:"241837",title:"Mr.",name:"Godwill Azeh",middleName:null,surname:"Engwa",slug:"godwill-azeh-engwa",fullName:"Godwill Azeh Engwa"},{id:"274194",title:"BSc.",name:"Paschaline Ferdinand",middleName:null,surname:"Okeke",slug:"paschaline-ferdinand-okeke",fullName:"Paschaline Ferdinand Okeke"},{id:"286975",title:"Dr.",name:"Friday",middleName:null,surname:"Nweke Nwalo",slug:"friday-nweke-nwalo",fullName:"Friday Nweke Nwalo"},{id:"286976",title:"Dr.",name:"Marian",middleName:null,surname:"Unachukwu",slug:"marian-unachukwu",fullName:"Marian Unachukwu"}]},{id:"56223",title:"Volunteering in Palliative Care in France: “A Tough Job”; Patient, Family, Caregiver, and Volunteer Perspectives",slug:"volunteering-in-palliative-care-in-france-a-tough-job-patient-family-caregiver-and-volunteer-perspec",totalDownloads:2327,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"highlights-on-several-underestimated-topics-in-palliative-care",title:"Highlights on Several Underestimated Topics in Palliative Care",fullTitle:"Highlights on Several Underestimated Topics in Palliative Care"},signatures:"Yaël Tibi-Lévy and Martine Bungener",authors:[{id:"88839",title:"Dr.",name:"Martine",middleName:null,surname:"Bungener",slug:"martine-bungener",fullName:"Martine Bungener"},{id:"205065",title:"Ph.D.",name:"Yaël",middleName:null,surname:"Tibi-Levy",slug:"yael-tibi-levy",fullName:"Yaël Tibi-Levy"}]},{id:"59779",title:"Effective Communication in Nursing",slug:"effective-communication-in-nursing",totalDownloads:6059,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"nursing",title:"Nursing",fullTitle:"Nursing"},signatures:"Maureen Nokuthula Sibiya",authors:[{id:"73330",title:"Dr.",name:"Nokuthula",middleName:null,surname:"Sibiya",slug:"nokuthula-sibiya",fullName:"Nokuthula Sibiya"}]},{id:"42668",title:"Hematopoietic Stem Cells in Chronic Myeloid Leukemia",slug:"hematopoietic-stem-cells-in-chronic-myeloid-leukemia",totalDownloads:3925,totalCrossrefCites:1,totalDimensionsCites:4,book:{slug:"stem-cell-biology-in-normal-life-and-diseases",title:"Stem Cell Biology in Normal Life and Diseases",fullTitle:"Stem Cell Biology in Normal Life and Diseases"},signatures:"Antonieta Chávez-González, Sócrates Avilés-Vázquez, Dafne\nMoreno-Lorenzana and Héctor Mayani",authors:[{id:"159656",title:"Dr.",name:"Antonieta",middleName:null,surname:"Chavez-Gonzalez",slug:"antonieta-chavez-gonzalez",fullName:"Antonieta Chavez-Gonzalez"},{id:"160310",title:"Dr",name:"Dafne",middleName:null,surname:"Moreno-Lorenzana",slug:"dafne-moreno-lorenzana",fullName:"Dafne Moreno-Lorenzana"},{id:"160311",title:"Mr.",name:"Socrates",middleName:null,surname:"Aviles-Vazquez",slug:"socrates-aviles-vazquez",fullName:"Socrates Aviles-Vazquez"},{id:"160312",title:"Dr.",name:"Hector",middleName:null,surname:"Mayani",slug:"hector-mayani",fullName:"Hector Mayani"}]},{id:"61046",title:"Optical Diagnostics to Improve Periodontal Diagnosis and Treatment",slug:"optical-diagnostics-to-improve-periodontal-diagnosis-and-treatment",totalDownloads:3723,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"periodontology-and-dental-implantology",title:"Periodontology and Dental Implantology",fullTitle:"Periodontology and Dental Implantology"},signatures:"Fardad Shakibaie and Laurence Walsh",authors:[{id:"179467",title:"Prof.",name:"Laurence",middleName:null,surname:"Walsh",slug:"laurence-walsh",fullName:"Laurence Walsh"},{id:"235443",title:"Dr.",name:"Fardad",middleName:null,surname:"Shakibaie",slug:"fardad-shakibaie",fullName:"Fardad Shakibaie"}]}],onlineFirstChaptersFilter:{topicSlug:"health-sciences",limit:3,offset:0},onlineFirstChaptersCollection:[{id:"74911",title:"Airway Management in Head and Neck Pathology",slug:"airway-management-in-head-and-neck-pathology",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.94498",book:{title:"Special Considerations in Human Airway Managements"},signatures:"Muayad M. Radi Al-Khafaji, Hossam Makki, Hassan Haider, Furat Abbas and Abhishek Menon"},{id:"74915",title:"Trained Immunity-Based Vaccines: A Ready-to-Act Strategy to Tackle Viral Outbreaks",slug:"trained-immunity-based-vaccines-a-ready-to-act-strategy-to-tackle-viral-outbreaks",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.95765",book:{title:"Viral Outbreaks"},signatures:"Laura Conejero, Paula Saz-Leal and José Luis Subiza"},{id:"74752",title:"Dyslipidemia and Endocrine Disorder",slug:"dyslipidemia-and-endocrine-disorder",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.95756",book:{title:"Dyslipidemia"},signatures:"Mezgebu Legesse Habte, Etsegenet Assefa Beyene and Teka Obsa Feyisa"}],onlineFirstChaptersTotal:551},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/114132/tayeb-merabti",hash:"",query:{},params:{id:"114132",slug:"tayeb-merabti"},fullPath:"/profiles/114132/tayeb-merabti",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)}()