These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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\r\n\tDespite increasing evidence of the health benefits of Tai Chi as an exercise form for various chronic diseases, there is a lack of a unified volume reviewing the science and basis of this ancient modality for improving modern health. This book intends \r\n\tto cover major health conditions that may benefit from Tai Chi, including neurodegenerative diseases, cardiopulmonary rehabilitation, psychosocial benefits, chronic fatigue and fibromyalgias, osteoporosis ad bone metabolism, and other chronic degenerative conditions that plague modern health. We seek to include reviews of underlying basic science as well as clinical trial data that demonstrate that multiplicity of benefits of this ancient exercise form to advance evidence-based understanding of Tai Chi exercise as an adjunct treatment.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"4d83cf3e19d5ba6dea45cba1386b5f27",bookSignature:"Dr. Wei-Zen Sun and Dr. Raymond Chang",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10125.jpg",keywords:"fibromyalgia, pain, balance, falling, cognition, dementia, Osteoporosis, Osteopenia, chronic obstructive pulmonary disease, pulmonary rehabilitation, Tai Chi, Depression",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 29th 2019",dateEndSecondStepPublish:"December 31st 2019",dateEndThirdStepPublish:"May 30th 2020",dateEndFourthStepPublish:"July 31st 2020",dateEndFifthStepPublish:"November 30th 2020",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"310791",title:"Dr.",name:"Wei-Zen",middleName:null,surname:"Sun",slug:"wei-zen-sun",fullName:"Wei-Zen Sun",profilePictureURL:"https://mts.intechopen.com/storage/users/310791/images/system/310791.jpg",biography:null,institutionString:"National Taiwan University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:{id:"310792",title:"Dr.",name:"Raymond",middleName:null,surname:"Chang",slug:"raymond-chang",fullName:"Raymond Chang",profilePictureURL:"https://mts.intechopen.com/storage/users/310792/images/system/310792.jpg",biography:null,institutionString:"Institute of East West Medicine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"177731",firstName:"Dajana",lastName:"Pemac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/177731/images/4726_n.jpg",email:"dajana@intechopen.com",biography:"As a Commissioning Editor at IntechOpen, I work closely with our collaborators in the selection of book topics for the yearly publishing plan and in preparing new book catalogues for each season. This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. I am responsible for developing and maintaining strong relationships with all collaborators to ensure an effective and efficient publishing process and support other departments in developing and maintaining such relationships."}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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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:"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:"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:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53682",title:"Imidazolium-Based Ionic Liquid Binary Solvent System as an Extraction Medium in Enhancing the Rotenone Yield Extracted from Derris elliptica Roots",doi:"10.5772/66777",slug:"imidazolium-based-ionic-liquid-binary-solvent-system-as-an-extraction-medium-in-enhancing-the-roteno",body:'\n
\n
1. Introduction
\n
The destructive effects of numerous pests from the time immemorial led to a large decline in crop yield. Through the advent of chemical pesticides, this crisis was resolved to a great extent. However, an overdose, overdependence on and uncontrolled usage of synthetic pesticides eventually created pest resistance which simultaneously led to frequent applications, application of bulk quantity of pesticide and a high cost [1]. In addition, the violative pesticides’ residues had contributed to food safety concern among consumers. Therefore, an eco-friendly alternative is needed to overcome the drawbacks of synthetic pesticides. As agricultural-industrial tools, biopesticides demonstrate exemplary benefits over chemically synthesized pesticides through harnessing the natural capabilities of organisms and their molecular constituents in minimizing the crop and plant damages from pests, affording the opportunity for protection, maintenance of biodiversity, and commerce-strengthening alternatives for organic farming and safe guarding of human health. Rotenone is one of the biopesticides that can be extracted from Derris andLonchocarpus plants’ roots [2]. It exhibits a strong pesticidal activity due to its strong paralysis action (knock-down effect) on cold-blooded animals. Besides, its high degradability, exceptionally selective and poor absorption across the gut and skin of humans enhances its eco-friendly usage [3–7]. In accordance with that, the extraction process plays a major role in optimizing the extraction of the yield of rotenone compound. Conventionally, organic solvents were used as an extraction medium and the selection of solvent systems largely depended on the specific nature of the bioactive compound from natural products. Rotenone is an isoflavonoid and it does not dissolve in water but it dissolves in organic solvents. According to John and Ron [4], the solubility of pure rotenone in acetone is 0.066 g/ml, ethanol, 0.002 g/ml and chloroform, 0.47 g/ml. However, a research completed by Zubairi [8] showed that acetone extracted more rotenone and other bioactive constituents compared to a high-polarity solvent as it could extract rotenone from from 39.5% up to 72.8% compared to chloroform and ethanol.
\n
Although conventional organic solvents have been used for so long as the extraction medium, their drawbacks such as volatility, toxicity, and flammability that lead to several human risks and environmental problems, limit its usage as an extractant. Taking all these into account, there have been several studies conducted on the exploration of ionic liquids (ILs) compatibility as green solvents for plant extraction. According to Fu et al. [9], ILs can be used as an alternative green solvent to replace volatile organic solvents. ILs are organic salts in the liquid state under ambient temperature that comprise a normally charge-stabilized organic cation paired with an organic or inorganic anion. They display a wide range of unique properties such as high thermal stability, nonflammability, insignificant vapor pressure, and low chemical reactivity. In addition to that, they also have fine tunable density, viscosity, polarity, and miscibility with other common solvents through the change of the cation and anion [10]. Some of ILs are also immiscible with organic solvents which define their polar alternative with nonaqueous nature for two-phase systems and ILs can be recycled that this enhances their green properties. The viscosity of ILs also plays a crucial role in the extraction and separation of bioactive compounds from plants. Their viscosity is affected by a range of intermolecular interactions such as electrostatic, van der Waals forces, and hydrogen bonding interaction [11]. The increase in temperature and asymmetry of ILs’ anions lead to the decrease in their viscosity. For instance, using the imidazolium cationic species, the viscosity can be intensified by increasing the substituted alkyl chain length or branching due to more van der Waals interactions between the ions themselves [11–14]. Some ILs also are immiscible in water (formation of biphasic systems) and the organic species have a high solubility in these ILs, making them ideal solvents for bioactive compound extraction from plants and as mobile phase modifiers to improve liquid chromatography separation of bioactive targets. The usage of ILs as plant bioactive constituent extractants has a great impact and potential as they alleviate the environmental pollution and improve the selectivity and extraction yields of interesting compounds in sample pretreatment process compared to conventional organic solvents.
\n
However, due to their charged and asymmetric structures, ILs have a relatively high polarity [15], as they do not have a good affinity with weak-polar compounds, thus causing a reduction in the distribution of weak-polar compounds in the IL phase. The viscosity of ILs increases with longer alkyl chain of ILs in accordance with the strong electrostatic and hydrogen bonding interaction between ions [16, 17]. The high viscosity of ILs will hinder the mixing and transferring of properties in the extraction process by influencing the dissolution of the compounds in ILs. In exchange, the mixture of ILs and polar molecular solvents as an extraction medium could be an effective approach to solve their flaws. Besides creating a wide-adjusted range of solvent polarity, hydrophobicity, hydrogen-bond acidity, and basicity [18, 19], the addition of miscible molecular solvents as co-solvents helps to break the microscopic hydrogen-bond network and the aggregation of ILs, which significantly reduces the viscosity and improves the mixing and transferring process in their mediated extraction [20, 21]. The rotenone compound is an acidic isoflavonoid compound that consists of ketonic chemical groups (R−C(=O)−R) [22] which has the potential of interacting with intermediate-polar solvents. It can be easily dissolved in moderate-polar organic solvents (e.g., methanol, chloroform, and acetone) [23] and is sparingly soluble in water [24]. For that reason, a combination of any ILs with a moderate polarity of organic solvents would perhaps increase the chances of extracting a high rotenone content due to its low viscosity and mediate polarity property and the high tendency of interaction between rotenone compound with the anion and cation of ILs. The previous study indicated that solubility of flavonoids and their derivatives can be increased by using ILs as the of flavonoids are greatly anion-dependent [25]. The anionic potency of both organic solvents and ILs in extracting a large amount of bioactive compounds (e.g., rotenone) and moving into solvent systems is significantly undeniable as both chemicals facilitate the extraction process via salvation power and multiple interactions (e.g., hydrogen bonding, polarity, ionic/charge-to-charge, and π-π, π-n) with the analytes [26, 27].
\n
\n
\n
2. Imidazolium-based ionic liquids as a green extraction medium
\n
\n
2.1. Structural features of ionic liquids
\n
Ionic liquids (ILs) are organic salts in the liquid state under ambient temperature that comprise a normally charged stabilized organic cation paired with an organic or inorganic anion. The widely used cations (\nFigure 1\n) are ammonium, sulfonium, imidazolium, pyridinium, pyrrolidinium, tetraalkylammonium, phosphonium, picolinium, and the functionalized cations with different substitutions [28, 29]. On the other hand, anions are weakly basic inorganic or organic compounds that have a diffuse or protected negative charge [28]. ILs based on halides such as [BF4]−, or [PF6]− ions are not preferred due to their unfavorable properties and they are also strongly hygroscopic [26]. The most preferred anions are the ones which are more complex, perfluorated anions such as bis(trifluoromethane sulfonyl) amide or trifluoromethanesulfonate or halogen-free ions such as dicyandiamide, tosylate, or n-alkyl sulfates (\nFigure 1\n) [30]. The environment constituted by ionic liquids is completely different from that of polar and nonpolar molecular solvents. In addition to the existing interactions in conventional organic solvents such as hydrogen bonding, dipole-dipole, and van der Waals interactions, ionic liquids have strong electrostatic interactions.
Among all ionic liquids, the ionic liquid based on imidazolium cation is widely used and studied due to the stability of the imidazolium ring and its excellent liquescency [31] which is resulted from its electronic structure of the aromatic cation. With delocalized 3-centre-4-electron configuration across the N1-C2-N3 moiety, a double bond between C4 and C5 at the opposite side of the ring, and a weak delocalization in the central region (\nFigure 2\n) [32], the hydrogen atoms C2-H, C4-H and C5-H carry almost the same charge but carbon C2 is positively charged owing to the electron deficit in the C=N bond, whereas C4 and C5 are practically neutral. The resulting acidic proton or hydrogen on the C2 carbon is the key for understanding the properties of the ionic liquids (ILs) and it is presented that the hydrogen on the C2 carbon (C2-H) binds specifically with solute molecules [33, 34] or its counter ion [35] as a good hydrogen bond donor.
\n
Figure 2.
Electronic structure of 1,3-dialkylimidazolium cation.
\n
\n
\n
2.3. Structural organization of imidazolium-based ionic liquids
\n
Long-range coulomb interaction may play a major role in ionic liquids which are composed solely of ions by creating the structure and dynamics that are unique to ionic liquids without being associated with molecular liquids [36]. From macroscopic point of view, ionic liquids can be considered as a continuum system characterized by their macroscopic constants such as boiling point, vapor pressure, density, and surface tension. However, from microscopic point of view, they are a discontinuum system consisting of individual, mutually interacting molecules characterized by molecular properties such as dipole moment, electronic polarizability, hydrogen-bond donor (HBD), and hydrogen bond acceptor (HBA) capability, electron pair donor (EPD) and electron pair acceptor (EPA). The types and degrees of these interactions control and determine the macroscopic properties of ionic liquids and their possibilities for various applications. Specifically, the ionic liquids’ structure exhibits a unique spatial heterogeneity due to their inherent polar/nonpolar phase separation. The underlying reason for the microphase segregation resulted from the interplay between electrostatic interaction (between polar imidazolium ring and anion) and van der Waals interaction with the nonpolar alkyl tails of the cation [37]. In fact, charge-charge distribution and anion size affect the nanostructural segregation of ionic liquids. As the ions’ size increases, the charge becomes more delocalized and the cation-anion interaction is reduced resulting in less charge ordering and nanostructural segregation [38]. On the other hand, divalent anions such as sulfate (SO4\n2−), thiosulfate (S2O3\n2−), chromate (CrO4\n2−), dichromate (Cr2O7\n2−), carbonate (CO3\n2−), and oxalate (C2O4\n2−) increase the electrostatic interaction between cation and anion and enhance intermolecular structuring. Besides, it was observed that the size of structural heterogeneities depended on alkyl chain length [37, 39].
\n
\n
\n
2.4. Physicochemical properties of imidazolium-based ionic liquids
\n
Ionic liquids are constituted exclusively by ions and hence they experience a strong interionic interaction that yield a long-lived association of ions [40]. The nature and types of cation-anion interactions and intermolecular forces in bulk ionic liquids affect their physical and chemical properties and how they interact with other solutes [41]. The examples of conformational heterogeneity of cations and anions are the coexisting trans-trans and trans-gauche conformations of n-butyl chain in 1-butyl-3-methylimidazolium cation and bisimide [Tf2N] anion conformational which forms trans- and cis conformers and this seems to be crucial in lowering their ionic liquid melting point [42]. Ionic liquids which comprise a low symmetry cation possess a low melting point than the one with a higher symmetry due to weak intermolecular interactions and good distribution of charge in the cation.
\n
Generally, ionic liquids (ILs) are denser than water. The density (ρ) of ionic liquids (ILs) decreases with the increase in organic cation bulkiness and anion selection affects ILs’ density. Normally, the density of ILs varies in the range of 1.05–1.36 g/cm3 at ambient temperature [43, 44]. In terms of ILs’ thermal stability, a research conducted had observed that thermal stability was dependent on both the cation and the anion of ILs. Ngo et al. [45] reported that imidazolium-based cations exhibited a higher thermal stability than tetraalkylammonium cations based on thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). In addition, imidazolium-based ILs have a thermal stability that increases in the following order: [Cl]−, [Br]−, [I]−<[BF4]−<[CF3SO3]−<[NTf2]−<[PF6]−and Ngo et al. [45] also reported that IL-based organic anions have a higher thermal stability than that of those based on inorganic anions.
\n
The viscosity of ILs also plays a crucial role in the extraction and separation of bioactive compounds from plants. Their viscosity is affected by a range of intermolecular interactions such as electrostatic, van der Waals forces, and hydrogen bonding interaction [11]. The increase in temperature and asymmetry of IL anions leads to the decrease in their viscosity. For instance, using imidazolium cationic species, the viscosity can be increased by increasing the substituted alkyl chain length or branching due to higher van der Waals interactions between the ions themselves [12–14]. Ionic liquids also have their own polarity values according to Kamlet-Taft parameters such as dipolarity or polarizability (π*), hydrogen bond basicity (ß), and hydrogen bond acidity (α) [46]. Although measurement has not been made for a large number of ionic liquids, the general trend suggests that the π* values for ionic liquids are higher than that of alkyl chain alcohol, while the α values are less than those of water and alkyl chain alcohols and also the magnitude of ß is determined by the anion of ionic liquids. \nTables 1\n and \n2\n display the summary of some physicochemical properties of ILs and Kamlet-Taft parameters for some ionic liquids.
\n
\n
\n
\n
\n
\n\n
\n
ILs
\n
\n
\n
\n
\n
\n
\n
Cation
\n
Anion
\n
Density (g/ml)
\n
Viscosity (cP)
\n
\n\n\n
\n
[EMIM]+\n
\n
[BF4]−\n
\n
1.248
\n
66
\n
\n
\n
[PF6]−\n
\n
1.373
\n
450
\n
\n
\n
[BMIM]+\n
\n
[BF4]−\n
\n
1.208
\n
233
\n
\n
\n
[PF6]−\n
\n
1.373
\n
400
\n
\n
\n
[Br]−\n
\n
1.134
\n
Solid
\n
\n
\n
[Cl]−\n
\n
1.12
\n
Solid
\n
\n
\n
[CF3SO3]−\n
\n
1.29
\n
90
\n
\n
\n
[(CF3SO3)2N]−\n
\n
1.42
\n
52
\n
\n
\n
[NTf2]−\n
\n
1.404
\n
48
\n
\n
\n
[AMIM]+\n
\n
[BF4]−\n
\n
1.213
\n
321
\n
\n
\n
[HMIM]+\n
\n
[BF4]−\n
\n
1.075
\n
211
\n
\n
\n
[PF6]−\n
\n
1.304
\n
800
\n
\n
\n
[OMIM]+\n
\n
[BF4]−\n
\n
1.11
\n
440
\n
\n
\n
[Cl]−\n
\n
1
\n
16,000
\n
\n
\n
[MPPyr]+\n
\n
[NTf2]−\n
\n
1.44
\n
39
\n
\n
\n
[C2H5NH3]+\n
\n
[HCOO]−\n
\n
0.99
\n
11.5
\n
\n
\n
[BMPyrrol]+\n
\n
[NTf2]-\n
\n
1.4
\n
71
\n
\n\n
Table 1.
Summary of some physicochemical properties of ILs at 25°C.
Kamlet-Taft parameters for some imidazolium-based ionic liquids.
\n
\n
\n
2.5. Ionic liquid binary solvent system as phytochemical extractant
\n
The usage of ILs as plant bioactive constituents’ extractants has a great impact and potential as they alleviate the environmental pollution and improve the selectivity and extraction yields of interesting compounds in the sample pre-treatment process compared to conventional organic solvents. However, ILs have a relatively high polarity due to their charged and asymmetric structures [15], which cause them not to have a good affinity with weak-polar compounds and thus this gives rise to a reduction in the distribution of weak-polar compounds in the IL phase. Although a longer alkyl chain of ILs has a lower polarity, their viscosity is large in accordance with the strong electrostatic and hydrogen bonding interaction between the ions [16, 17]. This drawback impairs the mixing and transferring properties in the extraction process by influencing the dissolution of the compounds in ILs. In exchange, the mixture of ILs and organic molecular solvents as an extraction medium could be an effective approach to solve their flaws. Besides creating a wide-adjusted range of solvent polarity, hydrophobicity, hydrogen-bond acidity, and basicity [18, 19], the addition of miscible molecular solvents as cosolvents helps to break the microscopic hydrogen-bond network and the aggregation of ILs, which significantly reduces the viscosity of ILs and improves the mixing and transferring process in their mediated extraction [20, 21].
\n
\n
\n
\n
3. Materials and methods
\n
\n
3.1. Sample collection and preparation
\n
\nDerris elliptica roots were first collected from Ladang 2, Faculty of Agriculture, Universiti Putra Malaysia, UPM, Malaysia. The collected roots (\nFigure 3a\n) were cleaned and cut into smaller parts prior to rapid drying. The cleaned parts of the roots were placed in the freezer to maintain their freshness and dried using a vacuum oven at the temperature of 28 ± 2°C for 24 hours. Once dried, the roots were ground into smaller particles of the size of approximately 0.86 ± 0.20 mm (\nFigure 3b\n). The selected sieved, ground samples were weighed prior to the normal soaking extraction process (NSE).
\n
Figure 3.
(a) Derris elliptica roots and (b) ground fine roots.
\n
\n
\n
3.2. Preparation of binary solvent system
\n
The binary solvent system comprises five selected ILs which are listed as follows: (1) 1-butyl-3-methylimidazolium chloride, [BMIM] Cl; (2) 1-butyl-3-methylimidazolium acetate, [BMIM] OAc; (3) 1-butyl-3-methylimidazolium bis(trifluorosulfonyl)imide, [BMIM] NTf2; (4) 1-butyl-3-methylimidazolium trifluoromethanesulfonate, [BMIM] OTf; and (5) 1-butyl-1-methylpyrrolidinium chloride, [BMPy] Cl. The binary solvent systems were prepared by adding 2 ml of respective ILs into a round bottom flask (with stopper) containing 18 ml of organic solvent (acetone) with the ratio of 1: 9. To avoid any moisture absorption due to the hygroscopic properties of some ILs, the ILs’ collection was carried out in the glove box. The mixtures were stirred by using a magnetic stirrer for 5–6 hours to homogenize the combined solvents. The ratio of 1:9 was based on the exploratory experiment results (data not shown). The mixing of the ILs in acetone was considered homogeneous if no apparent residue appeared in the flask.
\n
\n
\n
3.3. Normal soaking extraction (NSE)
\n
The extraction process was conducted at room temperature (28 ± 2°C) by using a combination of five different types of ILs and acetone with a mixing ratio of 1:9. The optimized parameters were utilized in accordance to protocols of Zubairi et al. [52, 53] as presented in \nTable 3\n. The extraction process was carried out by soaking 0.50 g of dried roots in 10 ml of the solvent systems for 24 hours with the solvent-to-solid ratio of 10 ml/g (n = 3). The liquid crude extract was collected twice at the 14th hour and 24th hour prior to the reversed-phase high-performance liquid chromatography (RP-HPLC) and thin-layer chromatography (TLC) analysis.
\n
\n
\n
\n\n
\n
Solvent-to-solid ratio (mg/ml)
\n
10
\n
\n
\n
Weight of raw material (g)
\n
0.50
\n
\n
\n
Raw material particle size (mm)
\n
0.86 ± 0.20
\n
\n
\n
Temperature (°C)
\n
28 ± 2
\n
\n
\n
ILs-to-acetone ratio
\n
1:9
\n
\n
\n
Extraction time (hour)
\n
14
\n
\n\n
Table 3.
Processing parameters used in the rotenone extraction process.
\n
\n
\n
3.4. Liquid crude extract collection
\n
The liquid crude extracts were collected at the 14th hour and 24th hour and placed in the labeled vials. There were 18 samples in total of five different types of solvent system used in three replicates (n = 3). Acetone was used as a control solvent. Later, the collected samples were placed in a freezer (−18°C) to prevent any thermal degradation.
\n
\n
\n
3.5. Preparation of fine debris-free liquid crude extract
\n
The collected liquid crude extracts were diluted using analytical grade acetonitrile, Sigma-Aldrich, 95% (v/v) with the dilution factor (DF) of 20. Then, the extracts were filtered by using polytetrafluoroethylene (PTFE—0.45 µm pore size) vacuum filtration to remove any fine debris. A 2-ml vial was used to store the extracts prior to the qualitative and quantitative analyses.
\n
\n
\n
3.6. Qualitative analysis using thin-layer chromatography
\n
MERCK Silica gel 60 F254 TLC aluminum sheet was used as a stationary phase to observe the presence of rotenone in the liquid crude extracts (n = 3). The migrations of rotenone markers were compared with rotenone standard. The markers and their migrated distance were visualized and determined under UV light of 254 and 365 nm wavelengths, respectively. In the development chamber, chloroform and n-hexane were combined and utilized as a mobile phase system with the ratio of 70:30. The retardation factors (R\n\nf\n) of each extract were calculated by using Eq. (1).
\n
\n\n\n\nRetardation\n\nfactor\n\n(\n\nR\nf\n\n)\n=\n\n\nMigration distance of substance\n\n\nMigration distance of solvent front\n\n\n\n\n\n\nE1
\n
\n
\n
3.7. Quantitative analysis using reversed-phase high-performance liquid chromatography
\n
Approximately 21.80 mg of rotenone standard Dr. Ehrenstorfer GmbH, 93.80% (w/w) was diluted with 50 ml of acetonitrile in a volumetric flask. The stock solution was filtered using Whatman™ filter paper no. 2 with 8 µm pore size. The quantitative analysis was completed by using Symmetry® C18 5 µl column, Waters with the internal diameter of 4.6 and 150 mm in length. The physical parameters involved in the RP-HPLC are as follows: (1) 0.7 ml/min flow rate; (2) injection volume of 20 µl; (3) mobile phase of acetonitrile and deionized water with the ratio of 60:40 and (4) photodiode array detector (PDA) wavelength of 294 nm.
\n
\n
\n
\n
4. Results and discussion
\n
\n
4.1. Solubility of ionic liquids (ILs) in acetone
\n
To enhance the rotenone extraction capacity, several ionic liquids were selected preliminarily. However, there was a drawback with regard to their solubility in organic solvents. The solubility of the selected ILs in acetone was observed by conducting a normal mixing with the ratio of 1:9. An exploratory experiment implemented revealed that the higher the amount of ILs used in the mixture, the higher the tendency of the ILs to produce undissolved solid residue (data not shown). Of the five selected ILs, only 1-butyl-3-methylimidazolium acetate, [BMIM] OAc, 1-butyl-3-methylimidazolium bis(trifluorosulfonyl)imide, [BMIM] NTf2,and 1-butyl-3-methylimidazolium trifluoromethanesulfonate, [BMIM] OTf could be easily homogenized. In contrast, 1-butyl-3-methylimidazolium chloride, [BMIM] Cl and 1-butyl-1-pyrrolidinlium chloride, [BMPy] Cl required a longer time to be homogenized (with the aid of heating at 80°C prior to mixing with acetone) which this could be possibly due to their physical properties (solid form at ambient temperature) and a specific range of organic solvent polarity, so that the solubility of the ILs in the organic solvent could be achieved. Theoretically, ionic liquids are miscible with an organic solvent of a medium to a high dielectric constant (Ɛ) and they become immiscible with a low dielectric constant (Ɛ) [54, 55]. Thus, the solubility of all of the selected ILs was considered satisfactory as there was no apparent residue appeared in the flask due to the high dielectric constant of acetone that aided the solubility of both chemicals.
\n
\n
\n
4.2. Qualitative analysis of rotenone
\n
The qualitative analysis of thin-layer chromatography (TLC) was performed to identify the existence of rotenone in the extracts of all of the binary solvent systems used. \nFigure 4\n displays the images of rotenone markers visualized under the UV light of 254 nm. All samples exhibited the presence of rotenone markers in the extracts. On the other hand, \nTable 4\n shows the migration distance (cm) and retardation factor (R\n\nf\n) of rotenone in a standard solution and liquid crude extracts. The results indicated that the rotenone’s R\n\nf\n value in a standard solution and all extracts (including control) were determined to be insignificantly different when compared to each other (p > 0.05). However, there were still a lot of impurities (unknown markers left behind rotenone) as presented in \nFigure 4\n. For that reason, a purification process of the liquid crude extracts via high-vacuum pressure liquid chromatography (VLC) is highly recommended as to increase the accuracy of rotenone and its derivative compounds’ identification [54, 56].
\n
\n
\n
\n
\n
\n
\n\n
\n
Binary solvent system
\n
Rotenone migration distance, Ds (cm)
\n
Retardation factor (R\n\nf\n)
\n
\n
\n
14 hour
\n
24 hour
\n
14 hour
\n
24 hour
\n
\n\n\n
\n
Rotenone standarda\n
\n
1.80 ± 0.05
\n
2.60 ± 0.03
\n
0.45 ± 0.04
\n
0.65 ± 0.03
\n
\n
\n
Control (acetone)
\n
2.03 ± 0.06
\n
2.60 ± 0.01
\n
0.51 ± 0.02
\n
0.65 ± 0.04
\n
\n
\n
[BMIM] Cl + acetone
\n
1.93 ± 0.06
\n
2.20 ± 0.02
\n
0.49 ± 0.01
\n
0.55 ± 0.01
\n
\n
\n
[BMIM] Oac + acetone
\n
1.53 ± 0.06
\n
1.40 ± 0.04
\n
0.39 ± 0.01
\n
0.35 ± 0.01
\n
\n
\n
[BMIM] NTF2 + acetone
\n
3.20 ± 0.01
\n
2.17 ± 0.06
\n
0.80 ± 0.01
\n
0.54 ± 0.01
\n
\n
\n
[BMIM] OTF + acetone
\n
3.20 ± 0.08
\n
1.70 ± 0.07
\n
0.80 ± 0.08
\n
0.43 ± 0.06
\n
\n
\n
[BMP] Cl + acetone
\n
3.10 ± 0.00
\n
2.93 ± 0.06
\n
0.78 ± 0.00
\n
0.74 ± 0.01
\n
\n\n
Table 4.
Qualitative analysis of rotenone via TLC on varied binary solvent systems.
\na Rotenone standard was prepared in acetone + ILs.
\n
Figure 4.
Visualization of rotenone migration markers of five different types of binary solvent systems used at the 14th hour of extraction. The markers were visualized on the alumina-based TLC plate under the UV light of 254 nm. (a) Acetone; (b) [BMIM] Cl; (c) [BMIM] Oac; (d) [BMIM] NTF2; (e) [BMIM] OTF and (f) [BMP] Cl. The dark circled markers of STD and R (R1, R2, and R3) represent the rotenone standard and replication of each of the binary solvent systems used.
\n
\n
\n
4.3. Quantitative analysis of rotenone content
\n
\n\nTable 5\n, \nFigures 5 and \n6show the concentration (mg/ml) and yield of rotenone, % (w/w), respectively, from five different types of binary solvent systems extracted at the 14th hour and 24th hour. The dependent variables were calculated based on the external standard method of RP-HPLC. The retention times of the rotenone in the standard solution (8.83 mins) and liquid crude extract (8.82 mins) are shown in \nFigures 7 and \n8\n, respectively. Overall, it was observed that the binary solvent system of 1-butyl-3-methylimidazolium trifluoromethanesulfonate, [BMIM] OTf produced the highest rotenone concentration of 4.04 ± 0.34 and 4.19 ± 0.48 mg/ml as compared to the others ionic liquids and control solvent (acetone) (p < 0.05) at the 14th hour and 24th hour, respectively. The highest yield of rotenone ((2.69 ± 0.21% (w/w) and 2.03 ± 0.11% (w/w) in dried roots) was also determined in the 1-butyl-3-methylimidazolium trifluoromethanesulfonate, [BMIM] OTf solvent system at the 14th hour and 24th hour, respectively. However, both of the optimized processing parameters and the control extract (acetone) reported in the previous study resulted in only 2.44 ± 0.02% (w/w) [8] and 2.44 ± 0.09% (w/w) with the concentration of 3.65 ± 0.13 mg/ml respectively. The results were approximately 10.25% lower than that of the yield of rotenone extracted using a combination of [BMIM] OTf:acetone (p < 0.05).
\n
\n
\n
\n
\n
\n
\n\n
\n
Solvent system type
\n
Concentration (mg/ml) (±SD)
\n
Yield (%, w/w) (±SD)
\n
\n
\n
14 hour
\n
24 hour
\n
14 hour
\n
24 hour
\n
\n\n\n
\n
Acetone (control)
\n
3.65 ± 0.13
\n
3.50 ± 0.02
\n
2.44 ± 0.09
\n
1.73 ± 0.09
\n
\n
\n
[BMIM] Cl:Acetone
\n
2.73 ± 0.00
\n
2.57 ± 0.02
\n
2.00 ± 0.06
\n
1.55 ± 0.01
\n
\n
\n
[BMIM] OAc:Acetone
\n
2.51 ± 0.02
\n
2.69 ± 0.14
\n
1.60 ± 0.01
\n
1.18 ± 0.06
\n
\n
\n
[BMIM] NTf2:Acetone
\n
3.70 ± 0.11
\n
3.80 ± 0.03
\n
2.42 ± 0.14
\n
2.07 ± 0..07
\n
\n
\n
[BMIM] OTf:Acetone
\n
4.04 ± 0.34
\n
4.19 ± 0.48
\n
2.69 ± 0.21
\n
2.03 ± 0.11
\n
\n
\n
[BMPy] Cl:Acetone
\n
2.66 ± 0.20
\n
2.37 ± 0.26
\n
1.78 ± 0.08
\n
1.27 ± 0.16
\n
\n\n
Table 5.
Rotenone quantitative analysis using RP-HPLC using different binary solvent systems at the 14th hour and 24th hour of extraction time.
\n
Figure 5.
Concentration of rotenone (mg/ml) with respect to five different types of binary solvent systems. Ψ\np < 0.05—[BMIMI] OTf: acetone was the best binary solvent system to procure the highest rotenone concentration (mg/ml) (n = 3). *p < 0.05—[BMIM] NTf2: acetone and acetone extract produced a high concentration as compared to the [BMIM] OAc, [BMPy] Cl and [BMIM] Cl.
\n
Figure 6.
Yield of rotenone, % (w/w) in dried roots with respect to five different types of binary solvent systems. *p < 0.05—[BMIMI] OTf : acetone was the best binary solvent system to procure the highest rotenone content in dried roots (n = 3).
\n
Figure 7.
Chromatogram of rotenone standard.
\n
Figure 8.
Chromatogram of [BMIM] OTf: acetone binary solvent system at the 14th hour.
\n
This phenomenon can be explained from the perspective of the types of ILs. Of the five different ILs, four of them have the same cation but different anions ([BMIM] OTf, [BMIM] OAc, [BMIM] NTf2, [BMIM] Cl), and one with the same anion but a different cation ([BMPy] Cl). The increase of the rotenone yield is related to the anion and cation of ILs as ILs have different polarities depending on the anion and cation presence. ILs’ polarity is referred to Kamlet-Taft parameters such as polarity (π*), hydrogen bond basicity (ß) and hydrogen bond acidity (α) [46]. ILs’ hydrogen bond basicity (ß) depends on anion, while hydrogen bond acidity (α) depends on the cation. [BMIM] OTf has lower hydrogen bond basicity compared to [BMIM] OAc and [BMIM] Cl, but higher than that of [BMIM] NTf2 ([OAc]−>[Cl]−>[OTf]−>[NTf2]−) and has hydrogen bond acidity higher than that of [BMPy] Cl.
\n
The rotenone compound is an acidic isoflavonoid compound that consists of ketonic chemical groups (R−C(=O) −R) [22] which has the potential of interacting with intermediate-polar solvents. It can be easily dissolved in moderate-polar organic solvents (e.g., methanol, chloroform, and acetone) [23] and sparingly soluble in water [24]. These are the factors that lead to the increase in the rotenone yield extracted when [BMIM] OTf with mid polarities is used as the extraction medium. The abundant presence of anion [OTf]− helped to attract more hydroxyl groups of rotenone to form more hydrogen bonds [25, 26]. With respect to the impact of the ILS’ cation, [BMIM] Cl and [BMPy] Cl on rotenone extraction, it was discovered that the rotenone yield extracted was high when the cation [BMIM]+ was used. This was due to the presence of an acid proton in the imidazole ring [32], which had the potential to form the hydrogen bond with oxygen of the rotenone compounds. The significant increase in the rotenone content can be explained in relation to several aspects as follows: (1) the trend of functional groups of rotenone toward foreign charge and (2) the capacity of the IL in the vicinity of various charges. For that reason, any combination of ionic liquids and middle-polar organic solvents does not only optimize the absorption of solute into the solvent due to the low viscosity but is also even able to increase the opportunities for extracting higher rotenone compounds.
\n
The previous study also revealed that the solubility of flavonoids and their derivatives could be increased by using ILs, as the components were greatly an anion-dependent [25]. The anionic potency of both organic solvent and ILs in extracting a large amount of bioactive compounds (e.g., rotenone) and moving into the solvent systems was significantly undeniable as both chemicals facilitated the extraction process via salvation power and multiple interactions (e.g., hydrogen bonding, polarity, ionic charge-to-charge, and π-π, π-n) with the analysis [26, 27].
\n
\n
\n
\n
5. Conclusion
\n
In conclusion, the best ionic liquid to assist the organic solvent (acetone) extraction system was 1-butyl-3-methylimidazolium trifluoromethanesulfonate, [BMIM] OTf. The selected binary solvent system had contributed to the highest rotenone content of 2.69 ± 0.21% (w/w) with a concentration of 4.04 ± 0.34 mg/ml at the 14th hour (the time of the exhaustive extraction as reported in the previous study). The rotenone content was 10.25% higher than the optimized parameter of the acetone extract (control) (p < 0.05). Therefore, the addition of certain ionic liquids to the organic solvent will potentially give rise to a significant increase in the amount of bioactive constituent in the phytochemical extraction process. Further study is required to optimize several processing parameters especially on the mixing ratio between the ILs and organic solvent in order to verify the increase in the rotenone content as the solubility problem between both chemicals, is relatively prominent.
\n
\n
Acknowledgments
\n
We would like to thank the Ministry of Higher Education (MOHE), Malaysia for providing financial support to this project (FRGS/2/2013/TK04/UKM/03/1 and GGPM-2013-078).
\n
\n',keywords:"rotenone, Derris sp., binary solvent system, imidazolium-based, ionic liquids",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/53682.pdf",chapterXML:"https://mts.intechopen.com/source/xml/53682.xml",downloadPdfUrl:"/chapter/pdf-download/53682",previewPdfUrl:"/chapter/pdf-preview/53682",totalDownloads:1793,totalViews:266,totalCrossrefCites:0,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:71,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"March 30th 2016",dateReviewed:"November 9th 2016",datePrePublished:null,datePublished:"February 22nd 2017",dateFinished:"December 28th 2016",readingETA:"0",abstract:"Rotenone, is a biopesticide which can be isolated from Derris species roots. However, procuring significant amount of rotenone using green alternative solvent rather than harmful organic solvents for commercialization is a challenge to be faced. Therefore, an approach using imidazolium-based ionic liquids (ILs) as an extraction medium was employed in this study. Five different types of binary solvent systems comprising a combination of acetone and five respective ionic liquids (ILs) of (1) [BMIM] Cl; (2) [BMIM] OAc; (3) [BMIM] NTf2; (4) [BMIM] OTf; and (5) [BMPy] Cl were used in the normal soaking extraction (NSE) of rotenone for a 24-hour extraction. The yield of the rotenone, % (w/w), and its concentration (mg/mL) in the dried roots was quantitatively determined by means of the reversed-phase high-performance liquid chromatography (RP-HPLC) and thin-layer chromatography (TLC). The results showed that a binary solvent system of [BMIM] OTf:acetone was the best solvent system combination compared to other solvent systems (p < 0.05). It contributed to the highest rotenone content of 2.69 ± 0.21% (w/w) (4.04 ± 0.34 mg/ml) at the 14th hour of the exhaustive extraction time. In conclusion, a combination of certain ILs with a selective organic solvent has been proven to be able to increase a significant amount of bioactive constituents in the phytochemical extraction process.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/53682",risUrl:"/chapter/ris/53682",book:{id:"5381",slug:"progress-and-developments-in-ionic-liquids"},signatures:"Zetty Shafiqa Othman, Nur Hasyareeda Hassan and Saiful Irwan\nZubairi",authors:[{id:"187652",title:"Dr.",name:"Saiful",middleName:null,surname:"Zubairi",fullName:"Saiful Zubairi",slug:"saiful-zubairi",email:"saiful-z@ukm.edu.my",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/187652/images/system/187652.jfif",institution:{name:"University Kebangsaan Malaysia Medical Centre",institutionURL:null,country:{name:"Malaysia"}}},{id:"189285",title:"Ms.",name:"Zetty",middleName:null,surname:"Shafiqa Othman",fullName:"Zetty Shafiqa Othman",slug:"zetty-shafiqa-othman",email:"zetsha789@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"189286",title:"Dr.",name:"Nur Hasyareeda",middleName:null,surname:"Hassan",fullName:"Nur Hasyareeda Hassan",slug:"nur-hasyareeda-hassan",email:"syareeda@ukm.edu.my",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Imidazolium-based ionic liquids as a green extraction medium",level:"1"},{id:"sec_2_2",title:"2.1. Structural features of ionic liquids",level:"2"},{id:"sec_3_2",title:"2.2. Imidazolium-based ionic liquid characterization",level:"2"},{id:"sec_4_2",title:"2.3. Structural organization of imidazolium-based ionic liquids",level:"2"},{id:"sec_5_2",title:"2.4. Physicochemical properties of imidazolium-based ionic liquids",level:"2"},{id:"sec_6_2",title:"2.5. Ionic liquid binary solvent system as phytochemical extractant",level:"2"},{id:"sec_8",title:"3. Materials and methods",level:"1"},{id:"sec_8_2",title:"3.1. Sample collection and preparation",level:"2"},{id:"sec_9_2",title:"3.2. Preparation of binary solvent system",level:"2"},{id:"sec_10_2",title:"3.3. Normal soaking extraction (NSE)",level:"2"},{id:"sec_11_2",title:"3.4. Liquid crude extract collection",level:"2"},{id:"sec_12_2",title:"3.5. Preparation of fine debris-free liquid crude extract",level:"2"},{id:"sec_13_2",title:"3.6. Qualitative analysis using thin-layer chromatography",level:"2"},{id:"sec_14_2",title:"3.7. Quantitative analysis using reversed-phase high-performance liquid chromatography",level:"2"},{id:"sec_16",title:"4. Results and discussion",level:"1"},{id:"sec_16_2",title:"4.1. Solubility of ionic liquids (ILs) in acetone",level:"2"},{id:"sec_17_2",title:"4.2. Qualitative analysis of rotenone",level:"2"},{id:"sec_18_2",title:"4.3. Quantitative analysis of rotenone content",level:"2"},{id:"sec_20",title:"5. Conclusion",level:"1"},{id:"sec_21",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\nStoll, G. Natural Crop Protection Based on Local Farm Resources in the Tropics and Subtropics, Weikersheim, Margraf Publishers Scientific Books, Germany. 1988.\n'},{id:"B2",body:'\nGingerich, W. H. Tissue distribution and elimination of rotenone in rainbow trout. 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Inorganic Chemistry. 1996; 35(5): 1168–1178.\n'},{id:"B13",body:'\nHandy, S. T. Room temperature ionic liquids: different classes and physical properties. Current Organic Chemistry. 2005; 9(10): 959–988.\n'},{id:"B14",body:'\nRooney, D., Jacquemin, J. and Gardas, R. Thermophysical properties of ionic liquids. Topics in Current Chemistry 2009; 290: 185–212.\n'},{id:"B15",body:'\nReichardt, C. Polarity of ionic liquids determined empirically by means of solvatochromic pyridinium N-phenolate betaine dyes. Green Chemistry. 2005; 7(5): 339–351.\n'},{id:"B16",body:'\nHuddleston, J. G., Visser, A. E., Reichert, W. M., Willauer, H. D., Broker, G. A. and Rogers, R. D. Characterization and comparison of hydrophilic and hydrophobic room temperature ionic liquids incorporating the imidazolium cation. Green Chemistry. 2001; 3(4): 156–164.\n'},{id:"B17",body:'\nXie, L.-L., Favre-Reguillon, A., Wang, X.-X., Fu, X., Pellet-Rostaing, S., Toussaint, G., Geantet, C., Vrinat, M. and Lemaire, M. Selective extraction of neutral nitrogen compounds found in diesel feed by 1-butyl-3-methyl-imidazolium chloride. Green Chemistry.\n 2008; 10(5): 524–531.\n'},{id:"B18",body:'\nMancini, P. M., Fortunato, G. G. and Vottero, L. R. Molecular solvent/ionic liquid binary mixtures: designing solvents based on the determination of their microscopic properties. Physics and Chemistry of Liquids.\n 2004; 42(6): 625–632.\n'},{id:"B19",body:'\nMellein, B. R., Aki, S. N., Ladewski, R. L. and Brennecke, J. F. Solvatochromic studies of ionic liquid/organic mixtures. The Journal of Physical Chemistry B.\n 2007;111(1): 131–138.\n'},{id:"B20",body:'\nHeintz, A. Recent developments in thermodynamics and thermophysics of non-aqueous mixtures containing ionic liquids. A review. The Journal of Chemical Thermodynamics. 2005. 37(6): 525–535.\n'},{id:"B21",body:'\nGómez, E., González, B., Domínguez, Á., Tojo, E. and Tojo, J. Dynamic viscosities of a series of 1-alkyl-3-methylimidazolium chloride ionic liquids and their binary mixtures with water at several temperatures. Journal of Chemical and Engineering Data. 2006; 51(2): 696–701.\n'},{id:"B22",body:'\nAhmad, F. and Raji, H. Kimia hasilan semula jadi dan tumbuhan ubatan. Dewan Bahasa dan Pustaka. 1993.\n'},{id:"B23",body:'\nCabizza, M., Angioni, A., Melis, M., Cabras, M., Tuberoso, C. V. and Cabras, P. Rotenone and rotenoids in cube resins, formulations, and residues on olives. Journal of Agricultural and Food Chemistry. 2004; 52(2): 288–293.\n'},{id:"B24",body:'\nDhaouadi, A., Monser, L. and Adhoum, N. Removal of rotenone insecticide by adsorption onto chemically modified activated carbons. Journal of Hazardous Materials. 2010; 181(1): 692–699.\n'},{id:"B25",body:'\nGuo, Z., Lue, B.-M., Thomasen, K., Meyer, A. S. and Xu, X. Predictions of flavonoid solubility in ionic liquids by COSMO-RS: experimental verification, structural elucidation, and solvation characterization. Green Chemistry.\n 2007; 9(12): 1362–1373.\n'},{id:"B26",body:'\nAnderson, J. L., Ding, J., Welton, T. and Armstrong, D. W. Characterizing ionic liquids on the basis of multiple solvation interactions. Journal of the American Chemical Society. 2002; 124(47): 14247–14254.\n'},{id:"B27",body:'\nDu, F.-Y., Xiao, X.-H. and Li, G.-K. Application of ionic liquids in the microwave-assisted extraction of trans-resveratrol from Rhizma Polygoni Cuspidati. Journal of Chromatography A. 2007; 1140(1): 56–62.\n'},{id:"B28",body:'\nGonfa, G., Bustam, M., Man, Z. and Mutalib, M. A. Unique structure and solute–solvent interaction in imidazolium based ionic liquids: A review. Asian Transactions on Engineering. 2011; 1: 24–34.\n'},{id:"B29",body:'\nGeetanjali S. and Anil K. Ionic liquids: Physico-chemicals, solvent properties and their applications in chemical processes. Indian Journal of Chemistry. 2008; 47A: 495–503.\n'},{id:"B30",body:'\nWeingärtner, H. Understanding ionic liquids at the molecular level: facts, problems, and controversies. Angewandte Chemie International Edition\n. 2008; 47(4): 654–670.\n'},{id:"B31",body:'\nNobuoka, K., Kitaoka, S., Iio, M., Harran, T. and Ishikawa, Y. Solute–solvent interactions in imidazolium camphorsulfonate ionic liquids. Physical Chemistry Chemical Physics. 2007; 9(44): 5891–5896.\n'},{id:"B32",body:'\nHunt, P. A., Kirchner, B. and Welton, T. Characterising the electronic structure of ionic liquids: An examination of the 1‐butyl‐3‐methylimidazolium chloride ion pair. Chemistry: A European Journal.\n 2006; 12(26): 6762–6775.\n'},{id:"B33",body:'\nAggarwal, A., Lancaster, N. L., Sethi, A. R. and Welton, T. The role of hydrogen bonding in controlling the selectivity of Diels–Alder reactions in room-temperature ionic liquids. Green Chemistry. 2002; 4(5): 517–520.\n'},{id:"B34",body:'\nZnamenskiy, V. and Kobrak, M. N. Molecular dynamics study of polarity in room-temperature ionic liquids. The Journal of Physical Chemistry B. 2004; 108(3): 1072–1079.\n'},{id:"B35",body:'\nDieter, K. M., Dymek, C. J., Heimer, N. E., Rovang, J. W. and Wilkes, J. S. Ionic structure and interactions in 1-methyl-3-ethylimidazolium chloride-aluminium chloride molten salts. Journal of the American Chemical Society. 1988; 110(9): 2722–2726.\n'},{id:"B36",body:'\nIwata, K., Okajima, H., Saha, S. and Hamaguchi, H.O. Local structure formation in alkyl-imidazolium-based ionic liquids as revealed by linear and nonlinear Raman spectroscopy. Accounts of Chemical Research. 2007; 40(11): 1174–1181.\n'},{id:"B37",body:'\nRaju, S. and Balasubramanian, S. Molecular dynamics simulation of model room temperature ionic liquids with divalent anions. Indian Journal of Chemistry-Section A: Inorganic, Physical, Theoretical and Analytical Chemistry. 2010; 49(5-6): 721–726.\n'},{id:"B38",body:'\nDeetlefs, M., Hardacre, C., Nieuwenhuyzen, M.,. Padua, A. A, Sheppard, O. and Soper, A. K. Liquid structure of the ionic liquid 1,3-dimethylimidazolium bis {(trifluoromethyl) sulfonyl} amide. The Journal of Physical Chemistry B. 2006; 110(24): 12055–12061.\n'},{id:"B39",body:'\nTriolo, A., Russina, O., Bleif, H.-J. and Di, C. E. Nanoscale segregation in room temperature ionic liquids. The Journal of Physical Chemistry B. 2007; 111(18): 4641–4644.\n'},{id:"B40",body:'\nZhao, W., Leroy, F., Heggen, B., Zahn, S., Kirchner, B., Balasubramanian, S. and. Müller-Plathe, F. Are there stable ion-pairs in room-temperature ionic liquids? Molecular dynamics simulations of 1-n-butyl-3-methylimidazolium hexafluorophosphate. Journal of the American Chemical Society. 2009; 131(43): 15825–15833.\n'},{id:"B41",body:'\nFernandes, A. M., Rocha, M. A., Freire, M. G., Marrucho, I. M., Coutinho, J. A. and Santos, L. M. Evaluation of cation−anion interaction strength in ionic liquids. The Journal of Physical Chemistry B. 2011; 115(14): 4033–4041.\n'},{id:"B42",body:'\nHamaguchi, H. O., Saha, S., Ozawa, R. and Hayashi, S. Raman and X-ray Studies on the Structure of [bmim] X. In ACS Symposium Series Oxford University Press. 2005; 901: 68–78.\n'},{id:"B43",body:'\nPringle, J. M., Golding, J., Baranyai, K., Forsyth, C. M., Deacon, G. B., Scott, J. L. and MacFarlane, D. R. The effect of anion fluorination in ionic liquids—physical properties of a range of bis (methanesulfonyl) amide salts. New Journal of Chemistry. 2003; 27(10): 1504–1510.\n'},{id:"B44",body:'\nXu, W., Wang, L.-M., Nieman, R. A. and Angell, C. A. Ionic liquids of chelated orthoborates as model ionic glassformers. The Journal of Physical Chemistry B. 2003; 107(42): 11749–11756.\n'},{id:"B45",body:'\nNgo, H. L., LeCompte, K., Hargens, L. and McEwen, A. B. Thermal properties of imidazolium ionic liquids. Thermochimica Acta. 2000; 357: 97–102.\n'},{id:"B47",body:'\nKamlet, M.J., Abboud, J. L. M., Taft, R. W. Progress in Physical Organic Chemistry. 1981; 13: 485.\n'},{id:"B48",body:'\nColeman, S., Byrne, R., Minkovska, S. and Diamond, D. Thermal reversion of spirooxazine in ionic liquids containing the [NTf2]− anion. Physical Chemistry. 2009; 11(27): 5608–5614.\n'},{id:"B49",body:'\nChiappe, C. and Pieraccini, D. Determination of ionic liquids solvent properties using an unusual probe: The electron donor-acceptor complex between 4,4′-bis (dimethylamino)-benzophenone and tetracyanoethene. The Journal of Physical Chemistry A. 2006; 110(14): 4937–4941.\n'},{id:"B50",body:'\nJeličić, A., García, N., Löhmannsröben, H.-G. and Beuermann, S. Prediction of the ionic liquid influence on propagation rate coefficients in methyl methacrylate radical polymerizations based on Kamlet-Taft solvatochromic parameters. Macromolecules. 2009; 42(22): 8801–8808.\n'},{id:"B51",body:'\nDoherty, T. V., Mora-Pale, M., Foley, S. E., Linhardt, R. J. and Dordick, J. S. Ionic liquid solvent properties as predictors of lignocellulose pretreatment efficacy. Green Chemistry. 2010; 12(11): 1967–1975.\n'},{id:"B52",body:'\nWu, Y., Sasaki, T., Kazushi, K., Seo, T. and Sakurai, K. Interactions between spiropyrans and room-temperature ionic liquids: photochromism and solvatochromism. The Journal of Physical Chemistry B. 2008. 112(25): 7530–7536.\n'},{id:"B53",body:'\nZubairi, S. I., Sarmidi, M. R. and Aziz, R. A. The effects of raw material particles size, types of solvents and solvent-to-solid ratio on the yield of rotenone extracted from Derris elliptica roots. Sains Malaysiana. 2014; 43(5): 707–713.\n'},{id:"B54",body:'\nZubairi, S. I., Sarmidi, M. R. and Aziz, R. A. A preliminary study of rotenone exhaustive extraction kinetic from Derris elliptica dried roots using normal soaking extraction (NSE) method. Advances in Environmental Biology. 2014; 8(4): 910–915.\n'},{id:"B55",body:'\nTouchstone, J. C. Practice of Thin Layer Chromatography. John Wiley & Sons. 1992.\n'},{id:"B56",body:'\nPoole, C. F. and Poole, S. K. Extraction of organic compounds with room temperature ionic liquids. Journal of Chromatography A. 2010; 1217(16): 2268–2286.\n'},{id:"B57",body:'\nZubairi, S. I., Sarmidi, M. R. and Aziz, R. A. Identification of bio-active constituents from Derris elliptica liquid crude extract using liquid chromatographic method coupled with high vacuum pressure. Advances in Environmental Biology. 2014; 8(2): 437–440.\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Zetty Shafiqa Othman",address:null,affiliation:'
Faculty of Science and Technology, School of Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, Malaysia
Faculty of Science and Technology, School of Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, Malaysia
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1. Introduction
The label ‘enteric fever’ suggests a febrile illness arising out of infection of the gut, however it is restricted to infections with Salmonella enterica typhi and paratyphi [Salmonella enterica serovar typhi and paratyphi] [1] rather than the family- enterobacteriacae itself. The nosology of ‘enteric’ suggests early and predominant involvement of the ileum and other parts of the gastrointestinal and biliary system in typhoid and paratyphoid fever [2]. The term typhoid is derived from the [3] Greek word typhus, in 1829 by a French Pathologist Louis Pierre [4]. He wanted to describe the disease by one of its prominent manifestations in those days. Typhus means ‘hazy’ or ‘smoky’ and typhoid means ‘Typhus like’, differentiating it from the typhus group of fevers. The ‘hazy’ could have been a reference to the CNS manifestation where the patient is often delirious.
Clinical manifestations: Typhoid fever to this day institutes a very significant proportion of diarrheal and febrile illnesses, especially in the developing world [5]. It has been reduced to very low levels in countries with good sanitation and accessibility to hygienic drinking water [6]. Cases in developed nations often are patients who have traveled to nations where enteric fever is endemic and these patients may have a drug resistance pattern similar to the originating country or locality [7, 8, 9].
Classical clinical features in the form of fever in a step ladder pattern, rose-spots and relative bradycardia may be less commonly seen and recognized. Typical fever patterns and classical signs may help to consider Salmonella typhi infection early in the disease, however, they are often not recognized [3, 10]. Enteric manifestations are common, with diarrhea, vomiting, abdominal pain and abdominal tenderness are present in most patients. Non-enteric manifestations are common as well, and central nervous system manifestations are discussed in this chapter.
Nervous system manifestations: The nervous system manifestations usually occur later in the disease, usually by the second week. CNS manifestations are often associated with severe disease and other toxic manifestation including septicemia and septic shock. Fever with any central manifestations, always raises the possibility of meningitis, if the febrile illness has not been diagnosed earlier. Empirical antibiotics given early in the disease, impacts culture results.
Microbiological diagnosis becomes imperative to decide choice of antibiotics. Appropriate diagnostic facilities are often not available in areas where typhoid infection is common. These patients are often treated with empirical antibiotics [11]. If the choice, duration and doses are incorrect, patients are likely to develop multi-drug resistant infection, and often present late when they become toxic and have signs of severe disease. Antibiotic resistance to fluoroquinolones has become common. Resistance to third generation cephalosporins is rising as well [12, 13]. Inappropriate antibiotic usage also interferes with cultures, hence microbiological diagnosis becomes incorrect, and hence all the more risk of drug resistance and poorer clinical outcomes [14]. Incidence of multi-drug and extensively drug resistant salmonella infections, that includes resistance to extended spectrum penicillin, and carbapenems like meropenem has been reported [15, 16]. This makes it necessary for clinicians to be alert to the possibility of patients presenting with typhoid fever in all its manifestations including the eponymous one.
The earliest possible description which possibly can be typhoid fever was made by the historian Thucydides [17]. He describes ‘the plague of Athens’ in his writings of the Peloponnesian war in 430 BC and probably later again. The description is that of a slowly rising fever, weakness, diarrhea, muscle pain, rash of flat spots, and in extreme illness, intestinal bleeding, memory loss, and confused behavior.
Clinical studies with large patient cohorts have been described since the end of the nineteenth century and recently as well. Descriptions of neuropsychiatric manifestations, behavior and association with fever along with other classic manifestations have been described. Quite a few classic authors in the field of neurology have dabbled with typhoid and its CNS involvement. In their classic book “On peripheral neuritis- A treatise” James Ross and Judson S Bury describe ‘Paralysis after typhoid fever” in detail, amongst other infective and non-infective causes of neuropathies [18]. Adolphe Gubler of Millard-Gubler syndrome fame has described patients with palatal paresis and limb paresis after presumably a bout of typhoid fever. Hermann Nothnagel has described patients with typhoid fever developing ulnar nerve palsies [19]. Even William Osler has attempted to describe and name a syndrome called ‘Typhoid spine’ which apparently had been used until the 1980s, however, has fallen out of use [20]. Wallenberg had reported 4 cases out of 160 cases of hemiplegia were secondary to typhoid fever. Hemiplegia was also reported by Smithies and Osler [21, 22].
Many large descriptive cohort studies have been conducted, since the beginning of the twentieth century, and later in the post-antibiotic era. CNS manifestations range from 5 to 35% in various studies [10, 23, 24, 25, 26].
Psychiatric manifestations in the form of delirium, altered behavior are the commonest CNS manifestations. It may be difficult to differentiate from encephalopathy of sepsis and may have similar pathogenesis. Older authors describe ‘scared’ ‘frightful’ patients who worsen to become comatose and develop focal deficits. Aggressive behavior is less commonly described [19]. Memory disturbances are common and may remain persistent after the acute encephalopathy wanes off. Behavioral disturbances generally improve, however often do not resolve completely. Hallucinations, delusions and other psychotic symptoms have been described, and are less common. Low mood and fatigue out of proportion to fever is common, and has been demonstrated in chimpanzees, who develop excessive fatigue without fever, hinting that fever and fatigue may have different pathogeneses [27].
Other less common manifestations that have been reported are stroke like presentations, cerebellar involvement, reversible extrapyramidal syndrome, myelopathy and optic neuropathy. These presentations are more commonly late presentations. Other peripheral nervous system involvement in the form of Guillain Barre syndrome has been reported. Cases of Salmonella brain abscess have been reported [28, 29, 30].
Diagnosis of typhoid fever, when CNS involvement is significant, can be delayed. In Mozambique, an outbreak of fever with often patients developing neurological complications was reported. Typhoid was not suspected immediately, however, later investigations revealed it to be the cause. Around 13% of patients had some neurological abnormality, with similar profile as other series, with addition. Vitamin B6 deficiency was also described to be low, however, direct comparison with patients without neurological manifestations was not done [25].
Patients who develop salmonella infection-related CNS complications generally have a more severe form of illness. Older patients, dehydration, lung involvement, thrombocytopenia and low blood counts have been found to be high risk factors for development of encephalopathy. Widal levels were found to be higher in patients with encephalopathy as compared to patients without CNS involvement [26].
Neurological manifestations have largely been reported to occur in the second week of fever, however, can be seen early in the disease as well. Early and empirical use of antibiotics may be one reason for reduced CNS manifestations of typhoid fever. However, cultures must be taken, and an appropriate microbiological diagnosis must be made.
CNS manifestations generally wane with the initiation of early antibiotics. However, some studies have noted features of encephalopathy after the patient has been treated with antibiotics. The mechanism proposed for this is endotoxin release, however, it has not been substantiated adequately. Another possible mechanism is immune mediated disease. Encephalopathy occurring after initiating antibiotics may confound the treating physician. Treatment consists of steroids as discussed later.
Non-typhoidal salmonellosis can cause CNS involvement in the form of encephalopathy and meningitis as well. This has even been reported from developed nations. Minimal brain edema, microvesicular fatty liver and severe enterocolitis was seen in the patients that expired. Focal encephalitis with seizures with frontal intermittent rhythmic delta activity (FIRDA) on electro-encephalography (EEG) has been described. Rare manifestations like cerebellar ataxia, cranial nerve palsies and Guillain Barre Syndrome have been reported [31, 32]. Non-typhoidal Salmonella associated meningitis has a very high mortality of around 60%.
2. Immune response to salmonellae
Innate immune response is the first wall in the defense at places where the body is exposed to microorganisms. One important such site is the gastroenteric tract where a balance has to be maintained to enable absorption of nutrients and protection from plethora of organisms residing or invasive organisms [33].
The acidic pH is the one of the initial steps to reduce infections arising in the gastro-intestinal tract. Thus, conditions in which acidic pH is impaired can give rise to higher risk of contracting salmonella or severe salmonella. This includes achlorhydria, proton pump inhibitor therapy or previous gastrectomy. Additionally, salmonellae also show increased acid tolerance, especially if previously exposed to a moderately acidic environment such as ponds or soils [34].
After passing the stomach salmonellae arrive in the intestine. The intestinal flora is one of the luminal barriers to prevent invasion. Antibiotic usage, especially ones that destroy the intestinal flora, increase chances of infection as well as give rise to a risk of severe infection [35]. Also, during an outbreak, patients who developed salmonella infection were significantly more likely to have taken antibiotics in the last one month as compared to individuals who had not taken [36, 37]. The intestinal flora provide competition for nutrients, as well as reduce pH in the intestines and increase volatile fatty acids. However, salmonella use a specific nutrient called ethanolamine, which is especially present when the intestines are inflamed. Therefore, a mild inflammation induced by salmonella increased chances of further infection. Additionally, inflammatory bowel diseases like Crohn’s disease provide an additional risk factor for development of salmonella infection.
Salmonella enters the gut by means of antigen presenting cells or direct invasion of the epithelial cells [38, 39]. Entry is partially gained via the cystic fibrosis transmembrane conductance regulator protein, that is abnormal is cystic fibrosis. Indeed, homozygous and heterozygous mutations in this gene may have some protection against salmonella infections.
Salmonella can survive and replicate intracellularly, with a capacity to divide in different tissues. Entry into the enteric cells and later survival in macrophages and that too especially macrophages in the liver and spleen may be essential for it to gain virulence as well as seed to different organs, including the central nervous system. This stage of reticuloendothelial infection gives rise to the common clinical findings of rising fever after complaints of loose stools, and mild hepatosplenomegaly [40].
Salmonella virulence in the gut has been identified in studies that it arises from the Salmonella pathogenicity island loci [SPI] placed on the Salmonella chromosome. They produce amongst others a protein called Type-III secretion system (TTSS-1) that modulates the intracellular milieu to aid Salmonella uptake into the cells and replication [41, 42]. Whether the same mechanism is enough or essential is a topic of many studies. Salmonellae evade the initial response as they can survive in the macrophages. This is mediated by the Salmonella pathogenicity Island – 2 [SPI-2] encoding type three secretion system that blocks movement of reactive oxygen and nitrogen species inside the phagosome, where the salmonella survives. This initial survival against the innate immune responses is the key to systemic infection. Once the salmonellae survive in the macrophages, they can travel and multiply in other sites [33, 43]. Developing a mouse model and demonstrating Salmonella bacteria in the brain after oral feeding, was amongst the initial steps to study brain infections [44]. Crossing the blood–brain barrier is difficult, however eventual invasion of the neurons and later multiplication of the bacteria in the CNS is a relatively rapid process as has been demonstrated in vitro models by Debolina et al. [45, 46].
In the central nervous system, the presence of blood brain barrier poses an extra line of defense to most organisms including Salmonella. How S. typhi get around this is not clearly known. Most of the studies of central nervous system infection with Salmonella have been done with S typhimurium, as S. Typhi itself is an exclusive human pathogen. Van Sorge et al. used human brain microvascular endothelial cells to demonstrate binding and intracellular uptake of Salmonella typhimurium as a substitute to blood brain-barrier [45]. They showed that entry via blood–brain barrier may have additional pathogenic factors apart from the SPI associated proteins. Additionally, it has been studied in septicemia secondary to gram-negative bacteria there are structural and functional deficits in the blood–brain barrier which may give rise to sepsis-associated encephalopathy. This is a complex state with multiple players, including circulatory and microcirculatory dysfunction, cytokine storm, free radical release and oxidative damage amongst other metabolic derangements.
When salmonella interact with the blood brain barrier increased chemokines and a neutrophilic response is noted. Interactions with outer membrane protein A [often a constituent protein of cell membrane of gram negative bacteria] may be involved as ompA deficient strains when injected intraperitoneally have reduced CNS concentration even though liver and spleen concentrations remain the same [47]. OmpA has been incriminated for blood brain penetration by E. coli as well [48]. This additionally brings up the second mode of producing CNS manifestations mediated via non-specific toxins (Figures 1 and 2).
Figure 1.
A page from the classic book on typhoid fever and its manifestations called ‘The Medical Complications, Accidents and Sequelae of Typhoid or Enteric Fever’ by Hobart Amory Hare and F.X. Dercum. [5].
Figure 2.
Basic pathway of salmonella infection to reach the central nervous system.
3. Pathology and pathophysiology
The clinical description of central nervous system manifestations has been described since the end of the nineteenth century. Numerous studies have been done to evaluate the pathogeneses of the same, and they continue into the twenty-first century. The early studies have described clinical manifestations in detail. Multiple mechanisms of CNS manifestations were put forward, including meningitis, toxic-mediated brain damage and dyselectrolytemia being the possible causes. Neuropsychiatric manifestations have been described in good detail by Hare and Foulerton in the late nineteenth century [31]. They document cases and reports of early mania and delusions associated with typhoid fever by multiple physicians. However, they conclude suggesting central nervous system manifestations are not common in the early stages of the disease. Studies by Foulerton and Thompson demonstrated bacterial invasion into the brain, however, attempts to demonstrate a toxin were futile [49].
In their seminal book titled ‘The Medical Complications, Accidents and Sequelae of Typhoid or Enteric Fever’, Hare classifies nervous system related symptoms into those arising from prodrome or early stage of the disease, in the well-developed stage of the disease and those arising in convalescence. Such a division of manifestations pushes one to consider different pathogenic mechanisms for different manifestations. These are described in Table 1.
Period of infection
Manifestations
Early infection or prodrome [First few days]
Confusional state, delusions, mania, meningismus often progress rapidly to coma
4. Hypotheses and evaluation of pathogenic mechanisms
CNS manifestations have been suspected to result out of one or more of the following
Salmonella meningitis or meningoencephalitis: For this, the organism if entering the body orally, requires to be absorbed into the gut, get disseminated, cross the blood–brain barrier and finally cause infection of the cells of the CNS. Direct damage to the cells then causes the clinical syndrome.
Toxin mediated damage: where chemicals are released locally or systemically which impair the neuronal function. The toxin could be Salmonella specific or non-specific, for example, cytokine storm following any gram-negative septicemia.
The role of toxins in pathogenesis of clinical manifestations in Salmonella has been suspected for more than a century. However, the discovery of toxin and mechanism of actions is yet under investigation. A reason for the inability to demonstrate toxins is that toxins are produced intracellularly and causes severe disease only in humans [27, 50]. The toxins have variable effect on humans and chimpanzees. In chimpanzees, despite there being a higher concentration of bacteria, symptoms are only mild, with manifestations being severe in humans. This has been attributed to the differences in sialoglycans in humans and chimpanzees. Additionally, even though the toxin produced only a mild fever in primates, it did produce severe malaise and fatigue that is seen in patients with typhoid fever. As the malaise occurs without the fever, it is expected to probably be a CNS manifestation rather than secondary to a systemic infection [27]. A recent study indicates that typhoid toxin is not essential for typhoid infection nor may be responsible for early manifestations. The study was not adequate to negate attribution to severe manifestations or chronic disease [51]
Electrolyte disturbances: These could arise in typhoid commonly as a result of loose stools or vomiting. Renal impairment in severe infections causing multiple organ dysfunction syndromes can also cause metabolic derangements.
Immune mediated damage: Many reported syndromes can best be explained by immunological involvement, for example, Guillain Barre syndrome, acute disseminated encephalomyelitis like presentation, cerebellitis and late manifestations.
Immune-mediated clinical syndromes associated with typhoid are often suspected and reported [52]. Another reason to suspect immune basis is that the symptoms begin well after the fever subsides, in which case autoimmune mechanisms become very likely. Resolution of symptoms with steroids helps the case further, however, specific antigens have not been conclusively described. A well-known complication of severe typhoid fever is macrophage activation syndrome. In all the series that have studied CNS manifestations, discussion regarding macrophage/microglial activation is surprisingly inadequate. This is one complication that needs further evaluation as a means of encephalopathy. This is especially important as treatment may mandate high dose steroids and carefully follow up till the macrophage activation syndrome reverses.
Micronutrient deficiency: Possibly postulated as secondary to intestinal involvement giving rise to difficulty in the absorption of some nutrients, and anorexia as well along with increased metabolic demand.
5. Diagnosis and evaluation
Clinical evaluation: Like any febrile illness, evaluation begins with a history and circumstantial knowledge. In an area of a high incidence of typhoid fever, there is a chance that the diagnosis will be suspected at the outset. History of any contacts with patients who had salmonella may be beneficial. An astute clinical examination in all patients presenting with acute febrile illnesses should include looking for dehydration, coated tongue, Rose spots, splenomegaly and relative bradycardia. A detailed CNS examination is a must especially in cases of manifestations, including brief cognition testing, evaluation for focal motor, or sensory deficits and neck stiffness, at the bare minimum.
Laboratory evaluation: All patients with an acute febrile illness usually have total blood counts done which may be normal or mildly reduced. Thrombocytopenia may be present. Blood cultures in all patients is mandatory before starting antibiotics. Bone marrow culture is more likely to yield a positive result; however, it is invasive in nature [14]. Stool and urine cultures may be helpful as well in the second and third weeks of fever. Serological tests like Widal or Typhidot can be done in the second week if the fever persists. In addition to getting cultures, it is imperative to check for sensitivity patterns, in view of ever-rising drug resistance. CSF is almost always done when CNS manifestations are present, importantly to rule out bacterial meningitis secondary to common organisms. CSF studies are often found to be normal. Cultures may occasionally show the presence of Salmonella.
Other evaluations for encephalopathy require checking of hydration status, and metabolic disorders including dys-electrolytemias, renal failure, liver disease, or acidosis.
Imaging: In the absence of florid findings on the CSF, other means to chase CNS involvement in typhoid fever is imaging. MRI findings have been described in multiple cases. They include focal white matter edema suggestive of cerebritis or diffuse vasogenic edema. There may be other focal signs in the form of single or multiple Salmonella associated abscesses. Reversible diffusion restriction in the white matter has been described [53, 54, 55]. Often findings of swelling of the splenium of corpus callosum have been reported, however it is a finding that can be seen when imaging is done immediately after seizures.
EEG generally shows nonspecific findings. There can be focal slowing, focal spikes, and one case showing features of FIRDA [56].
Serological testing with WIDAL is commonly conducted, as it is widely available, inexpensive and easy to conduct. A rise in titers may be more important than a single study. Although it is non-specific, patients with CNS involvement often have very high titers of antibodies, as compared to patients without CNS involvement. Also, in the same spirit, patients are often sicker, have systemic inflammatory response syndrome, low blood counts, thrombocytopenia and more likely to have pulmonary or hepatic complications [26].
6. Management
Early diagnosis is essential in cases of salmonella infections which can be difficult especially in a non-endemic clinical setting. In endemic areas blood-cultures commercial kits are often not available or may not be affordable. As the incubation period is around one to two weeks, a history of recent travel must be documented in patients. This has shown to be as much as 60 days. The classic clinical presentations of step ladder pattern fever, with loose stools, and abdominal pain, relative bradycardia, rose spots over the abdomen and occasionally chest, and coated tongue should be carefully evaluated, however, they often may be absent. Soft splenomegaly may be present. Peripheral white blood cell counts are generally on the lower side of normal, and thrombocytopenia is often present.
Definitive diagnosis however entails blood culture, especially in the first week. It can take a long time to show results. Immunological tests including WIDAL become positive only after a period of one week. Imaging and CSF analysis are often done for evaluation of differential diagnosis.
Antibiotic therapy: Antibiotic therapy is generally not as urgent as in other gram-negative septicemia. However as soon as the diagnosis is made, therapy should be initiated with help from a local microbiological guide regarding sensitivity to drugs. Empirical antibiotic therapy is to be generally avoided, however, must be started early in cases when the patient has SIRS or CNS manifestations.
Antibiotic therapy is generally advised for a period of two to three weeks. Ceftriaxone becomes a good choice of therapy especially as it has good CNS penetration. As more often Salmonella resistance is being reported, it is imperative to have a local drug sensitivity profile. Fluoroquinolones were sensitive, and possibly sensitivity to ciprofloxacin may still be present, however gradually increasing NARST [Nalidixic acid-resistant S Typhi] strains may necessitate higher doses or change in therapy. Extensively drug-resistant strains have been reported with resistance to Chloramphenicol, Trimethoprim-sulbactam, ampicillin, third-generation cephalosporin, and fluoroquinolones [57]. Resistance to Azithromycin has been reported in a single case of S. paratyphi who was treated with ceftriaxone [58]. However, if the patient is septic, or is in shock, injectable carbapenems like meropenem may be the treatment of choice at the outset. Therapy can be adjusted later based on drug sensitivity testing.
Steroids: Steroids are indicated in the treatment of patients with severe disease [59, 60]. The two common and most important indications are CNS disease and shock. CNS involvement in the form of encephalopathy, psychiatric manifestations, cerebellar involvement, extrapyramidal involvement, myelopathy or seizures are indications of starting steroids. Hydrocortisone, dexamethasone and pulse doses of methylprednisolone have been tried, with case reports suggesting good outcomes [61]. CNS manifestations have been recorded often to revert quickly with steroids, however, there are only case reports present. Additionally, mechanisms of how steroids help is not explored, as also if steroids have caused poor outcomes. This aspect requires further study.
Steroids are often helpful in presumed immunologically mediated syndromes, for example, ADEM and cerebellitis. Intravenous immunoglobulin (IvIg) may be required in some cases, especially post infectious Guillain Barre syndrome.
Supportive therapy: This includes rehydration and fluid resuscitations. Dyselectrolytemia needs to be corrected promptly. If the patient has had seizures, then anti-epileptic therapy is warranted. The choice of anti-epileptic will vary from patient to patient. Phenytoin is to be avoided if cerebellar signs are present. Valproate and phenytoin are to be avoided if hepatic dysfunction is present and levetiracetam is to be avoided or doses need to be adjusted if renal failure is present.
Early and aggressive treatment with close monitoring is required to avoid long-lasting complications. Long-lasting problems known to persist are psychosis, delusions and spasticity. Extrapyramidal and cerebellar involvement generally reverts completely. Patients can have memory deficits and behavioral symptoms and hence follow up is essential.
7. Public health issues
Salmonella infection being an orally acquired infection, has major public health issues. Any such infection should assume that there is a break in the path for fecal waste disposal or contamination. CNS manifestations are assumed to be severe manifestations and hence they have a special regard.
Severe infections are common in patients who have taken antibiotics in the past one month. Widespread illogical use of broad-spectrum antibiotics should hence be controlled. With a single dose of streptomycin, the bacterial flora of the gut gets altered and leads to higher risks of infection. Additionally, drug resistant infections, especially fluoroquinolone and third generation cephalosporin resistant infections are on the rise and drug resistance to carbapenems has been reported as well. This is a huge implication in terms of management of typhoid fever.
Use of oral vaccine has been slow, but gradually increasing. The protection offered by these vaccines should reduce severe typhoid infections, and additionally so the CNS manifestations, however, this is not clearly known.
\n',keywords:"Typhoid, brain, CNS",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76635.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76635.xml",downloadPdfUrl:"/chapter/pdf-download/76635",previewPdfUrl:"/chapter/pdf-preview/76635",totalDownloads:302,totalViews:0,totalCrossrefCites:1,dateSubmitted:"April 15th 2019",dateReviewed:"April 7th 2021",datePrePublished:"May 7th 2021",datePublished:"August 25th 2021",dateFinished:"May 7th 2021",readingETA:"0",abstract:"Typhoid fever is a common cause of febrile illness. The causative organism S. Typhi uses special mechanisms to invade the intestines and then disseminates to the reticuloendothelial system. Thereafter, using the immune mechanism to its own advantage, it can reach the nervous system. The nervous system involvement usually occurs around the second week of fever. It usually occurs when the patient has severe sepsis. Neuropsychiatric manifestations are common, and fatigue is out of proportion to the fever. Diagnosis is often delayed, due to lack of diagnostic facilities in developing nations where it is common. In developed nations diagnosis is delayed as well, as often it is not suspected. Antibiotic therapy usually is effective, unless resistance is present, which is gradually becoming common. Early diagnosis and treatment usually leads to complete resolution of symptoms.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76635",risUrl:"/chapter/ris/76635",signatures:"Atif Iqbal Ahmed Shaikh and Appasamy Thirumal Prabhakar",book:{id:"8959",type:"book",title:"Innate Immunity in Health and Disease",subtitle:null,fullTitle:"Innate Immunity in Health and Disease",slug:"innate-immunity-in-health-and-disease",publishedDate:"August 25th 2021",bookSignature:"Shailendra K. 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Hypotheses and evaluation of pathogenic mechanisms",level:"1"},{id:"sec_5",title:"5. Diagnosis and evaluation",level:"1"},{id:"sec_6",title:"6. Management",level:"1"},{id:"sec_7",title:"7. Public health issues",level:"1"}],chapterReferences:[{id:"B1",body:'Stoesser N, Eyre D, Basnyat B, Parry C. Treatment of enteric fever (typhoid and paratyphoid fever) with third and fourth generation cephalosporins. Cochrane Database Syst Rev [Internet]. 2013 [cited 2019 Sep 24];(3). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010452/full'},{id:"B2",body:'Physical Examination - Royal College Surgeons in Ireland [Internet]. [cited 2019 Sep 24]. Available from: https://www.rcsi.ie/index.jsp?p=1452&n=1459'},{id:"B3",body:'Habte L, Tadesse E, Ferede G, Amsalu A. Typhoid fever: clinical presentation and associated factors in febrile patients visiting Shashemene Referral Hospital, southern Ethiopia. BMC Res Notes [Internet]. 2018 Aug 22 [cited 2019 Oct 25];11. 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McCusker, Séamus Fanning and Marta Martins. Salmonella–Host Interactions – Modulation of the Host Innate Immune System. Front. Immunol., 07 October 2014 | https://doi.org/10.3389/fimmu.2014.00481'},{id:"B34",body:'J W Foster. Low pH adaptation and the acid tolerance response of Salmonella typhimurium, Crit Rev Microbiol. 1995;21(4):215-237. doi: 10.3109/10408419509113541.'},{id:"B35",body:'Bohnhoff M, Miller CP, Martin WR, resistance of the mouse’s intestinal tract to experimental salmonella infection. I. Factors which interfere with the initiation of infection by oral inoculation.J Exp Med. 1964;120:805.'},{id:"B36",body:'Tannock GW, Savage DC, Indigenous microorganisms prevent reduction in cecal size induced by Salmonella typhimurium in vaccinated gnotobiotic mice. Infect Immun. 1976;13(1):172.'},{id:"B37",body:'Ryan CA, Nickels MK, Hargrett-Bean NT, Potter ME, Endo T, Mayer L, Langkop CW, Gibson C, McDonald RC, Kenney RT JAMA. 1987;258(22):3269. 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The Lancet. 1900 Apr 21;155(3999):1121-1125.'},{id:"B50",body:'Parkhill J, Dougan G, James KD, Thomson NR, Pickard D, Wain J, et al. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature. 2001 Oct 25;413(6858):848-852.'},{id:"B51",body:'Gibani MM, Jones E, Barton A, Jin C, Meek J, Camara S, et al. Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model. Nat Med. 2019 Jul;25(7):1082-1088.'},{id:"B52",body:'Ktsoyan Z, Budaghyan L, Agababova M, Mnatsakanyan A, Arakelova K, Gevorgyan Z, et al. Potential involvement of Salmonellainfection in autoimmunity. Pathogens [Internet]. 2019 Jul 3 [cited 2019 Oct 27];8(3). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789781/'},{id:"B53",body:'Ahmed M, Sureka J, Mathew V, Jakkani R, Abhilash KPP. Magnetic resonance imaging findings in a fatal case of Salmonella typhi-associated encephalopathy: A case report and literature review. 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J Clin Microbiol. 2010 Dec;48(12):4655-4657.'},{id:"B59",body:'Chisti MJ, Bardhan PK, Huq S, Khan WA, Khan AM, Sharifuzzaman null, et al. High-dose intravenous dexamethasone in the management of diarrheal patients with enteric fever and encephalopathy. Southeast Asian J Trop Med Public Health. 2009 Sep;40(5):1065-1073.'},{id:"B60",body:'Hoffman SL, Punjabi NH, Kumala S, Moechtar MA, Pulungsih SP, Rivai AR, et al. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med. 1984 Jan 12;310(2):82-88.'},{id:"B61",body:'Jain A, Baheti G. Steroid Pulse Therapy in the Management of Neuro-psychiatric Manifestations in an Atypical Presentation of Typhoid Fever. J Med Res Innov. 2019 Jul 1;e000178.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Atif Iqbal Ahmed Shaikh",address:"dr.atifshaikh@gmail.com",affiliation:'
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Dobrzański"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5874",title:"Structural Health Monitoring",subtitle:"Measurement Methods and Practical Applications",isOpenForSubmission:!1,hash:"72f61895d84252f6f5b92b7625741743",slug:"structural-health-monitoring-measurement-methods-and-practical-applications",bookSignature:"Moises Rivas-Lopez, Wendy Flores Fuentes and Oleg Sergiyenko",coverURL:"https://cdn.intechopen.com/books/images_new/5874.jpg",editedByType:"Edited by",editors:[{id:"178178",title:"Dr.",name:"Moises",middleName:null,surname:"Rivas-Lopez",slug:"moises-rivas-lopez",fullName:"Moises Rivas-Lopez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1649",title:"Electrostatics",subtitle:null,isOpenForSubmission:!1,hash:"c0630d15c7e3fc8f85f239750051ef7f",slug:"electrostatics",bookSignature:"Huseyin Canbolat",coverURL:"https://cdn.intechopen.com/books/images_new/1649.jpg",editedByType:"Edited by",editors:[{id:"5887",title:"Dr.",name:"Hüseyin",middleName:null,surname:"Canbolat",slug:"huseyin-canbolat",fullName:"Hüseyin Canbolat"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:8,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"62943",doi:"10.5772/intechopen.80238",title:"Silver Nanoparticles as Multi-Functional Drug Delivery Systems",slug:"silver-nanoparticles-as-multi-functional-drug-delivery-systems",totalDownloads:3434,totalCrossrefCites:24,totalDimensionsCites:53,abstract:"Nanoparticles can surmount some essential problems of conventional small molecules or biomacromolecules (e.g., DNA, RNA, and protein) used in some diseases by allowing targeted delivery and overcome through biological barriers. Recently, silver nanoparticles have been harnessed as delivery vehicles for therapeutic agents, including antisense oligonucleotides, and other small molecules. Silver is the most profit-oriented precious metal used in the preparation of nanoparticles and nanomaterials because of its antibacterial, antiviral, antifungal, antioxidant and unusually enhanced physicochemical properties compared to the bulk material such as optical, thermal, electrical, and catalytic properties. Small silver nanoparticles offer many advantages as drug carriers, including adjustable size and shape, enhanced stability of surface-bound nucleic acids, high-density surface ligand attachment, transmembrane delivery without harsh transfection agents, protection of the attached therapeutics from degradation, and potential for improved timed/controlled intracellular drug-delivery. Plant-mediated synthesis of silver nanoparticles is gaining interest due to its inexpensiveness, providing a healthier work environment, and protecting human health leading to lessening waste and safer products. The chapter presents the essential physicochemical characteristics, antibacterial, and anticancer properties which silver nanoparticles obtained by plant-mediated methods possess, and their application as drug-delivery systems with a critical view on the possible toxicity on the human body.",book:{id:"7437",slug:"nanomedicines",title:"Nanomedicines",fullTitle:"Nanomedicines"},signatures:"Nadezhda Ivanova, Viliana Gugleva, Mirena Dobreva, Ivaylo\nPehlivanov, Stefan Stefanov and Velichka Andonova",authors:[{id:"202958",title:"Dr.",name:"Velichka",middleName:null,surname:"Andonova",slug:"velichka-andonova",fullName:"Velichka Andonova"},{id:"265332",title:"MSc.",name:"Nadezhda",middleName:null,surname:"Ivanova",slug:"nadezhda-ivanova",fullName:"Nadezhda Ivanova"},{id:"265333",title:"MSc.",name:"Viliana",middleName:null,surname:"Gugleva",slug:"viliana-gugleva",fullName:"Viliana Gugleva"},{id:"265334",title:"MSc.",name:"Mirena",middleName:null,surname:"Dobreva",slug:"mirena-dobreva",fullName:"Mirena Dobreva"},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov"},{id:"265336",title:"MSc.",name:"Ivaylo",middleName:null,surname:"Pehlivanov",slug:"ivaylo-pehlivanov",fullName:"Ivaylo Pehlivanov"}]},{id:"63035",doi:"10.5772/intechopen.80225",title:"Biological Function of Exosomes as Diagnostic Markers and Therapeutic Delivery Vehicles in Carcinogenesis and Infectious Diseases",slug:"biological-function-of-exosomes-as-diagnostic-markers-and-therapeutic-delivery-vehicles-in-carcinoge",totalDownloads:2190,totalCrossrefCites:12,totalDimensionsCites:23,abstract:"Exosomes are nano-sized vesicles that are formed during inward budding of multivesicular bodies and the maturation of endosomes. They are secreted by almost all cell types under normal, pathological, and physiological conditions. They are found in mostly all biological fluids, such as breast milk, blood, urine, and semen. Exosomes are involved in cell-to-cell communication through the biological transfer of lipids, proteins, DNAs, RNAs, mRNAs, and miRNAs. Exosomes are enriched in tetraspanins, enzymes, heat shock proteins, and membrane trafficking proteins. There are numerous techniques that are used to isolate, purify, and characterize exosomes from biofluids. Isolation/purification techniques include ultracentrifugation, filtration, sucrose density gradient centrifugation, etc. Characterization techniques include flow cytometry, electron microscopy, NanoSight tracking analysis, Western blot, etc. These techniques are often used to help principal investigators understand the properties and biological functions of exosomes. However, some of these techniques can be very complicated and challenging, resulting in various drawbacks. Exosomes can be used as potential carriers for therapeutics. Thus, they can serve as biomarkers to diagnosis various diseases that are associated with cancer, genetics, viruses, bacteria, parasites, etc. Therefore, with advances in science and technology, many innovative techniques have been established to exploit the biological properties of exosomes.",book:{id:"7437",slug:"nanomedicines",title:"Nanomedicines",fullTitle:"Nanomedicines"},signatures:"Brennetta J. Crenshaw, Brian Sims and Qiana L. Matthews",authors:[{id:"254038",title:"Ph.D.",name:"Qiana",middleName:null,surname:"Matthews",slug:"qiana-matthews",fullName:"Qiana Matthews"},{id:"254039",title:"Ms.",name:"Brennetta",middleName:null,surname:"Crenshaw",slug:"brennetta-crenshaw",fullName:"Brennetta Crenshaw"},{id:"266042",title:"Dr.",name:"Brian",middleName:null,surname:"Sims",slug:"brian-sims",fullName:"Brian Sims"}]},{id:"56634",doi:"10.5772/intechopen.70122",title:"Biomaterials and Stem Cells: Promising Tools in Tissue Engineering and Biomedical Applications",slug:"biomaterials-and-stem-cells-promising-tools-in-tissue-engineering-and-biomedical-applications",totalDownloads:1568,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"Biomaterial sciences and tissue engineering approaches are currently fundamental strategies for the development of regenerative medicine. Stem cells (SCs) are a unique cell type capable of self‐renewal and reconstructing damaged tissues. At the present time, adult SCs isolated from postnatal tissues are widely used in clinical applications. Their characteristics such as a multipotent differentiation capacity and immunomodulatory activity make them a promising tool to use in patients. Modern material technologies allow for the development of innovative biomaterials that closely correspond to requirements of the current biomedical application. Biomaterials, such as ceramics and metals, are already used as implants to replace or improve the functionality of the damaged tissue or organ. However, the continuous development of modern technology opens new insights of polymeric and smart material applications. Moreover, biomaterials may enhance the SCs biological activity and their implementation by establishing a specific microenvironment mimicking natural cell niche. Thus, the synergistic advancement in the fields of biomaterial and medical sciences constitutes a challenge for the development of effective therapies in humans including combined applications of novel biomaterials and SCs populations.",book:{id:"5951",slug:"biomaterials-in-regenerative-medicine",title:"Biomaterials in Regenerative Medicine",fullTitle:"Biomaterials in Regenerative Medicine"},signatures:"Małgorzata Sekuła and Ewa K. Zuba‐Surma",authors:[{id:"202773",title:"Prof.",name:"Ewa",middleName:null,surname:"Zuba-Surma",slug:"ewa-zuba-surma",fullName:"Ewa Zuba-Surma"},{id:"202775",title:"Dr.",name:"Malgorzata",middleName:null,surname:"Sekula",slug:"malgorzata-sekula",fullName:"Malgorzata Sekula"}]},{id:"56100",doi:"10.5772/intechopen.69718",title:"Properties of Co-Cr Dental Alloys Fabricated Using Additive Technologies",slug:"properties-of-co-cr-dental-alloys-fabricated-using-additive-technologies",totalDownloads:1592,totalCrossrefCites:5,totalDimensionsCites:14,abstract:"The aim of the present paper is to make a review of the properties of dental alloys, fabricated using Additive Technologies (AT). The microstructure and mechanical properties of Co-Cr alloys as well as the accuracy and surface roughness of dental constructions are discussed. In dentistry two different approaches can be applied for production of metal frameworks using AT. According to the first one the wax/polymeric cast patterns are fabricated by 3D printing, than the constructions are cast from dental alloy with as-printed patterns. Through the second one the metal framework is manufactured form powder alloy directly from 3D virtual model by Selective Electron Beam Melting (SEBM) or Selective Laser Melting (SLM). The microstructure and mechanical properties of Co-Cr dental alloys, cast using 3D printed patterns, are typical for cast alloys. Their dimensional and adjustment accuracy is higher comparing to constructions, produced by traditional lost-wax casting or by SLM. The surface roughness is higher than that of the samples, cast by conventional technology, but lower comparing to the SLM objects. The microstructure of SLM Co-Cr dental alloys is fine grained and more homogeneous comparing that of the cast alloys, which defines higher hardness and mechanical properties, higher wear and corrosion resistance.",book:{id:"5951",slug:"biomaterials-in-regenerative-medicine",title:"Biomaterials in Regenerative Medicine",fullTitle:"Biomaterials in Regenerative Medicine"},signatures:"Tsanka Dikova",authors:[{id:"205539",title:"Dr.",name:"Tsanka",middleName:null,surname:"Dikova",slug:"tsanka-dikova",fullName:"Tsanka Dikova"}]},{id:"31995",doi:"10.5772/35937",title:"Air-Solids Flow Measurement Using Electrostatic Techniques",slug:"air-solids-flow-measurement-using-electrostatic-techniques",totalDownloads:5001,totalCrossrefCites:6,totalDimensionsCites:11,abstract:null,book:{id:"1649",slug:"electrostatics",title:"Electrostatics",fullTitle:"Electrostatics"},signatures:"Jianyong Zhang",authors:[{id:"106435",title:"Dr.",name:"Jianyong",middleName:null,surname:"Zhang",slug:"jianyong-zhang",fullName:"Jianyong Zhang"}]}],mostDownloadedChaptersLast30Days:[{id:"69398",title:"New Generation Peptide-Based Vaccine Prototype",slug:"new-generation-peptide-based-vaccine-prototype",totalDownloads:1119,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Synthetic peptide-based vaccine prototypes are the future potential vaccination. Antigens, which belong to minimal microbial component and produce antibodies such as peptides and polysaccharides, can promote long-term protection against pathogens that can cause infectious diseases. Production of peptides becomes simple with solid phase peptide synthesis and microwave-assisted solid phase peptide synthesis using automatic synthesizers. The use of synthetic peptides was approved by the health authorities for vaccine design. Peptides are themselves very weak immunogens and need adjuvants to provide an effective autoimmune response. For this reason, peptide antigens are conjugated with biopolymers and loaded with nanoparticles. The toxicity of vaccine prototypes is evaluated in cell culture, and non-toxic prototypes are selected for vaccinating experimental animals. The most effective peptide-based vaccine prototype is determined as the one with the highest antibody level. The goal of this book chapter is to illustrate the use of peptides vaccine systems and present their opportunities with their future development.",book:{id:"9048",slug:"current-and-future-aspects-of-nanomedicine",title:"Current and Future Aspects of Nanomedicine",fullTitle:"Current and Future Aspects of Nanomedicine"},signatures:"Öznur Özge Özcan, Mesut Karahan, Palanirajan Vijayaraj Kumar, Shen Leng Tan and Yi Na Tee",authors:[{id:"305705",title:"Dr.",name:"Mesut",middleName:null,surname:"Karahan",slug:"mesut-karahan",fullName:"Mesut Karahan"},{id:"310005",title:"MSc.",name:"Öznur Özge",middleName:null,surname:"Özcan",slug:"oznur-ozge-ozcan",fullName:"Öznur Özge Özcan"},{id:"310006",title:"Prof.",name:"Palanirajan Vijayaraj",middleName:null,surname:"Kumar",slug:"palanirajan-vijayaraj-kumar",fullName:"Palanirajan Vijayaraj Kumar"},{id:"310008",title:"MSc.",name:"Shen Leng",middleName:null,surname:"Tan",slug:"shen-leng-tan",fullName:"Shen Leng Tan"},{id:"310009",title:"MSc.",name:"Yi Na",middleName:null,surname:"Tee",slug:"yi-na-tee",fullName:"Yi Na Tee"}]},{id:"56614",title:"Systematic Study of Ethylene-Vinyl Acetate (EVA) in the Manufacturing of Protector Devices for the Orofacial System",slug:"systematic-study-of-ethylene-vinyl-acetate-eva-in-the-manufacturing-of-protector-devices-for-the-oro",totalDownloads:1657,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Fracture of facial bones and dental elements, and laceration of soft tissue, have increased in sports over recent years. Dentist is the only professional responsible for the mouth protection design, the knowledge about suitable materials is essential. EVA is a thermoplastic material, available in the market, easy of handling and processing, and low-cost. However, it is important to understand the mechanical properties and ability to absorb and to dissipate the impact energy, when this material is submitted to different environments, such as oral cavity with saliva and different temperatures. This chapter show provides a systematic evaluation of the EVA application in orofacial protectors while focusing on sports. The research comprises two aspects: experimental tests and numerical analyses. During experimental tests, EVA was analyzed in special buccal conditions, concerning temperature and presence of saliva. Regarding the presence of saliva, more specific studies about its influence on the mechanical behavior of EVA were performed. In the numerical analyses of the EVA orofacial protector, the studies focused on its effect on the nasal bone integrity, and in the zygomatic bone protection. However, life cycle should be analyzed, since its performance deteriorates over time. Mainly due to the saliva-originated changes to the EVA mechanical characteristics, it can behave as a rigid material. For facial protection, a better performance is obtained with a combination of rigid and soft EVA material. According to the experimental and numerical results from a systematic study of EVA, its application to orofacial protection can be considered satisfactory.",book:{id:"5951",slug:"biomaterials-in-regenerative-medicine",title:"Biomaterials in Regenerative Medicine",fullTitle:"Biomaterials in Regenerative Medicine"},signatures:"Reinaldo Brito e Dias, Neide Pena Coto, Gilmar Ferreira Batalha and\nLarissa Driemeier",authors:[{id:"204968",title:"Dr.",name:"Neide",middleName:null,surname:"Pena Coto",slug:"neide-pena-coto",fullName:"Neide Pena Coto"}]},{id:"63035",title:"Biological Function of Exosomes as Diagnostic Markers and Therapeutic Delivery Vehicles in Carcinogenesis and Infectious Diseases",slug:"biological-function-of-exosomes-as-diagnostic-markers-and-therapeutic-delivery-vehicles-in-carcinoge",totalDownloads:2189,totalCrossrefCites:12,totalDimensionsCites:23,abstract:"Exosomes are nano-sized vesicles that are formed during inward budding of multivesicular bodies and the maturation of endosomes. They are secreted by almost all cell types under normal, pathological, and physiological conditions. They are found in mostly all biological fluids, such as breast milk, blood, urine, and semen. Exosomes are involved in cell-to-cell communication through the biological transfer of lipids, proteins, DNAs, RNAs, mRNAs, and miRNAs. Exosomes are enriched in tetraspanins, enzymes, heat shock proteins, and membrane trafficking proteins. There are numerous techniques that are used to isolate, purify, and characterize exosomes from biofluids. Isolation/purification techniques include ultracentrifugation, filtration, sucrose density gradient centrifugation, etc. Characterization techniques include flow cytometry, electron microscopy, NanoSight tracking analysis, Western blot, etc. These techniques are often used to help principal investigators understand the properties and biological functions of exosomes. However, some of these techniques can be very complicated and challenging, resulting in various drawbacks. Exosomes can be used as potential carriers for therapeutics. Thus, they can serve as biomarkers to diagnosis various diseases that are associated with cancer, genetics, viruses, bacteria, parasites, etc. Therefore, with advances in science and technology, many innovative techniques have been established to exploit the biological properties of exosomes.",book:{id:"7437",slug:"nanomedicines",title:"Nanomedicines",fullTitle:"Nanomedicines"},signatures:"Brennetta J. Crenshaw, Brian Sims and Qiana L. Matthews",authors:[{id:"254038",title:"Ph.D.",name:"Qiana",middleName:null,surname:"Matthews",slug:"qiana-matthews",fullName:"Qiana Matthews"},{id:"254039",title:"Ms.",name:"Brennetta",middleName:null,surname:"Crenshaw",slug:"brennetta-crenshaw",fullName:"Brennetta Crenshaw"},{id:"266042",title:"Dr.",name:"Brian",middleName:null,surname:"Sims",slug:"brian-sims",fullName:"Brian Sims"}]},{id:"64869",title:"Transethosomes and Nanoethosomes: Recent Approach on Transdermal Drug Delivery System",slug:"transethosomes-and-nanoethosomes-recent-approach-on-transdermal-drug-delivery-system",totalDownloads:1618,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"In the past few decades, an emerging drug delivery system that came into light is transdermal drug delivery system. It has become the talk of the town in the field of drug delivery because of its better and easy accessibility. Though it is one of the attractive routes, transport of drug through the skin has remained a challenge. To overcome the challenge, vesicular system has been adopted so as to have better skin permeation of bioactive agents. Vesicular system like liposome has shown inefficiency to cross the layers of skin. Then transethosomes and nanoethosomes are employed for delivering drug into the deeper layer of skin. Nanoethosomes and transethosomes have same composition that is water, ethanol and phospholipid. Transethosome contains edge activator additionally. Due to the presence of ethanol and edge activator, it displayed enhanced skin permeation. Vesicular system gives a better patient compliance, being a non-invasive method of drug administration. In this chapter, we attempted to provide brief information about methods of preparation, characterization and pharmaceutical uses of nanoethosomes and transethosomes.",book:{id:"7437",slug:"nanomedicines",title:"Nanomedicines",fullTitle:"Nanomedicines"},signatures:"Koushlesh Kumar Mishra, Chanchal Deep Kaur, Shekhar Verma, Anil\nKumar Sahu, Deepak Kumar Dash, Pankaj Kashyap and Saraswati\nPrasad Mishra",authors:[{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu"},{id:"211230",title:"Mr.",name:"Pankaj",middleName:null,surname:"Kashyap",slug:"pankaj-kashyap",fullName:"Pankaj Kashyap"},{id:"221419",title:"Mr.",name:"Koushlesh",middleName:null,surname:"Mishra",slug:"koushlesh-mishra",fullName:"Koushlesh Mishra"},{id:"221420",title:"Mr.",name:"Sarawati Prasad",middleName:null,surname:"Mishra",slug:"sarawati-prasad-mishra",fullName:"Sarawati Prasad Mishra"},{id:"250558",title:"Dr.",name:"Deepak Kumar",middleName:null,surname:"Dash",slug:"deepak-kumar-dash",fullName:"Deepak Kumar Dash"},{id:"270359",title:"Dr.",name:"Chanchal Deep",middleName:null,surname:"Kaur",slug:"chanchal-deep-kaur",fullName:"Chanchal Deep Kaur"},{id:"270998",title:"Prof.",name:"Shekhar",middleName:null,surname:"Verma",slug:"shekhar-verma",fullName:"Shekhar Verma"}]},{id:"68412",title:"Self-Emulsifying Drug Delivery Systems: Easy to Prepare Multifunctional Vectors for Efficient Oral Delivery",slug:"self-emulsifying-drug-delivery-systems-easy-to-prepare-multifunctional-vectors-for-efficient-oral-de",totalDownloads:1106,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Self-emulsifying drug delivery systems (SEDDS) have been mainly investigated to enhance the oral bioavailability of drugs belonging to class II of the Biopharmaceutics Classification System. However, in the past few years, they have shown promising outcomes in the oral delivery of various types of therapeutic agents. In this chapter, we discuss the recent progress in the application of SEDDS for oral delivery of protein therapeutics and genetic materials. The role of SEDDS in enhancing the oral bioavailability of P-glycoprotein and cytochrome P450 3A4 substrate drugs is also highlighted. Also, we discuss the most critical evaluation criteria of SEDDS. Additionally, we summarize various solidification techniques employed to transform liquid SEDDS to the more stable solid self-emulsifying drug delivery systems (s-SEDDS) that are associated with high patient compliance. This chapter provides a comprehensive approach to develop high utility SEDDS and their further transformation into s-SEDDS.",book:{id:"9048",slug:"current-and-future-aspects-of-nanomedicine",title:"Current and Future Aspects of Nanomedicine",fullTitle:"Current and Future Aspects of Nanomedicine"},signatures:"Khaled AboulFotouh, Ayat A. Allam and Mahmoud El-Badry",authors:[{id:"299910",title:"Prof.",name:"Mahmoud",middleName:null,surname:"El-Badry",slug:"mahmoud-el-badry",fullName:"Mahmoud El-Badry"},{id:"299914",title:"MSc.",name:"Khaled",middleName:null,surname:"Abulftooh",slug:"khaled-abulftooh",fullName:"Khaled Abulftooh"},{id:"299916",title:"Dr.",name:"Ayat",middleName:null,surname:"Allam",slug:"ayat-allam",fullName:"Ayat Allam"}]}],onlineFirstChaptersFilter:{topicId:"282",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"May 13th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. 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Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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