Mercy Hospital St Louis In-HOSPITAL Therapeutic Hypothermia Protocol
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These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\\n\\n\\n\\n\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"9353",leadTitle:null,fullTitle:"Ginger Cultivation and Its Antimicrobial and Pharmacological Potentials",title:"Ginger Cultivation and Its Antimicrobial and Pharmacological Potentials",subtitle:null,reviewType:"peer-reviewed",abstract:"Ginger is well known as a spice and flavor. It has been a traditional medical plant in many cultures for thousands of years. To uncover the miraculous plant, this book not only gives you the plant's origins, where the plant is grown now, but also provides current studies on its utilization, cultivation, breeding, and therapeutic benefits.",isbn:"978-1-83880-030-7",printIsbn:"978-1-83880-029-1",pdfIsbn:"978-1-83880-407-7",doi:"10.5772/intechopen.83688",price:119,priceEur:129,priceUsd:155,slug:"ginger-cultivation-and-its-antimicrobial-and-pharmacological-potentials",numberOfPages:162,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"b0f597104b548a6b922696409ab891fa",bookSignature:"Haiping Wang",publishedDate:"February 19th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9353.jpg",numberOfDownloads:9544,numberOfWosCitations:3,numberOfCrossrefCitations:16,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:24,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:43,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 20th 2019",dateEndSecondStepPublish:"August 29th 2019",dateEndThirdStepPublish:"October 28th 2019",dateEndFourthStepPublish:"January 16th 2020",dateEndFifthStepPublish:"March 16th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"280406",title:"Dr.",name:"Haiping",middleName:null,surname:"Wang",slug:"haiping-wang",fullName:"Haiping Wang",profilePictureURL:"https://mts.intechopen.com/storage/users/280406/images/system/280406.jpeg",biography:"Haiping Wang holds BSc in Plant protection (1998), MSc in Plant breeding (2001) and PhD in Vegetable science (2001) from Graduate School of Chinese Academy of Agricultural Sciences. Since 2001 he has been a full-time research scientist and professor of Horticulture at the Department of Vegetables Germplasm, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences (IVFCAAS). His research interests include vegetable genetic resources and preservation of the diversity of Midterm Gene-Bank of Vegetables Genetic Resources in China. Also research on vegetable genetics and breeding is conducted to improve the crop for growers and consumers. His key areas of interest include garlic, ginger, radish, and cucumber genetics and the development of genomic tools. His outreach activities include interaction with the garlic and ginger production and with consumers. Dr. Wang is the author and co-author of seventy publications in scientific journals and thirteen book chapters in Chinese and English. He has reviewed numerous publications for more than ten international scientific journals.",institutionString:"Chinese Academy of Agricultural Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Chinese Academy of Agricultural Sciences",institutionURL:null,country:{name:"China"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"41",title:"Plant Biology",slug:"agricultural-and-biological-sciences-plant-biology"}],chapters:[{id:"69831",title:"Introductory Chapter: Studies on Ginger",doi:"10.5772/intechopen.89796",slug:"introductory-chapter-studies-on-ginger",totalDownloads:978,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Haiping Wang",downloadPdfUrl:"/chapter/pdf-download/69831",previewPdfUrl:"/chapter/pdf-preview/69831",authors:[{id:"280406",title:"Dr.",name:"Haiping",surname:"Wang",slug:"haiping-wang",fullName:"Haiping Wang"}],corrections:null},{id:"68980",title:"Utilisation and Functional Components Evaluation of Ginger",doi:"10.5772/intechopen.88940",slug:"utilisation-and-functional-components-evaluation-of-ginger",totalDownloads:912,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Ginger is a Zingiberaceae plant having different purposes in the community and industry. The important parameters of quality of ginger are the functional components so the aims of this chapter are to review the utilisation of ginger in the community and industry and to evaluate the functional components of ginger and its products. Ginger (Zingiber officinale Roscoe) has at least three types, i.e. big ginger, small ginger and red ginger. Fresh, dried and preserved ginger and also its extract, oleoresin and volatile oil were considered as basic products of the utilisation of ginger. Different formulas have been developed for drinks, culinary purposes, flavouring desert and herbal medicines. In folk medicines, ginger is used as remedy for warming body, gastritis and fracture condition. Based on scientific researches, ginger has been developed as anti-emetic, anti-inflammatory, analgesic and anti-influenza. Evaluation of chemical constituents of ginger and its products can be done qualitatively for authentication and quantitatively for standardization. This chapter consists of the utilisation of ginger based on empirical and scientific data, and the functional components evaluation consisting of authentication and standardization.",signatures:"Suwijiyo Pramono",downloadPdfUrl:"/chapter/pdf-download/68980",previewPdfUrl:"/chapter/pdf-preview/68980",authors:[{id:"304365",title:"Prof.",name:"Suwijiyo",surname:"Pramono",slug:"suwijiyo-pramono",fullName:"Suwijiyo Pramono"}],corrections:null},{id:"69314",title:"Biotechnology and Crop Improvement of Ginger (Zingiber officinale Rosc.)",doi:"10.5772/intechopen.88574",slug:"biotechnology-and-crop-improvement-of-ginger-em-zingiber-officinale-em-rosc-",totalDownloads:1191,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Ginger is the third most important spice used for its medicinal properties in day to day life. Ginger is one of the widely studied plants for its biochemical and medicinal properties. Biotechnological tools have played a pivotal role in the improvement of this plant species. Many in vitro techniques namely micropropagation techniques, somatic embryogenesis, somatic hybridization, germplasm conservation, transgenics and mutation breeding have been widely studied whereas less studied for haploid production, and cryogenic in ginger. Many of these have been used in the recent times for the improvement of ginger mainly because of the vegetative mode of propagation. Most varietal improvement programs of this species are confined to evaluation and selection of naturally occurring clonal variations. Problems faced in ginger breeding have so far been the very low genetic variation in ginger plant. Wide genetic variation is needed in plant breeding in order to search ideal plant types during the process of selection. Although traditional mutation breeding has lost its preeminent position, induced mutations continue to be in great demand with the assistance of various biotechnological tools. In vitro culture techniques provide an alternative means of plant propagation and a tool for varietal improvement. Here, is an attempt made to collect the information on the studies made in this regard and present the current status of research in ginger.",signatures:"Neeta Shivakumar",downloadPdfUrl:"/chapter/pdf-download/69314",previewPdfUrl:"/chapter/pdf-preview/69314",authors:[{id:"299119",title:"Dr.",name:"Neeta",surname:"Shivakumar",slug:"neeta-shivakumar",fullName:"Neeta Shivakumar"}],corrections:null},{id:"68348",title:"Cultivation of Ginger in Sikkim under an Organic System",doi:"10.5772/intechopen.87049",slug:"cultivation-of-ginger-in-sikkim-under-an-organic-system",totalDownloads:911,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Ginger is grown extensively throughout India due to its high value and ginger is used for wide range of purposes like in confectionery, traditional medicine for stomach ache, food additives and pickles. The major ginger-producing states include Kerala, Assam, Gujarat, Orissa, Sikkim, Meghalaya, Arunachal Pradesh and Mizoram. It is one of the main cash crops in Himalayan state of Sikkim. In Northeast India, especially in Sikkim, ginger serves as a source of income for small and marginal farmers. It is cultivated in a varying degree of altitude, but the elevation of 1500 above msl is found to be more suitable. Ginger is a tropical plant, and warm, humid climate is the most ideal for ginger cultivation; it grows best in rich soil and shady places. Sikkim has its own indigenous cultivars of ginger, and the prominent varieties that are being cultivated in Sikkim are Bhaise, Gorubathane, Majhaule, Tange, Patle and Jorethang. November to January after 8–9 months of sowing is the optimum time for harvesting ginger; however, this follows the market demand dynamics in Sikkim. Under organic conditions, farmers normally get a yield of 90–100 q/ha depending on ginger cultivation practices. Progressive farmers by adopting improved method of ginger cultivation get on an average of Rs. 150,000 per hectare (benefit-cost ratio varied from 3.50 to 3.80).",signatures:"Vijayan A.K., B.A. Gudade, Ashutosh Gautam, T.N. Deka, S.S. Bora, K. Dhanapal and A.B. Remashree",downloadPdfUrl:"/chapter/pdf-download/68348",previewPdfUrl:"/chapter/pdf-preview/68348",authors:[{id:"299779",title:"Dr.",name:"Vijayan",surname:"Alavoor Keloth",slug:"vijayan-alavoor-keloth",fullName:"Vijayan Alavoor Keloth"}],corrections:null},{id:"69227",title:"Diseases of Ginger",doi:"10.5772/intechopen.88839",slug:"diseases-of-ginger",totalDownloads:1525,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:1,abstract:"Ginger is one of the earliest known oriental spices grown for its edible rhizome, which is widely used as a fresh vegetable, spice, and as a popular folk medicine. Ginger crop is being affected by insect pests, and pathogenic and non-pathogenic diseases cause production constraints. Severely, various pathogenic diseases of viral, bacterial, fungal, and nematode origin reduce its potential yields drastically. Among the various diseases, soft rot, yellows, Phyllosticta leaf spot, storage rot, bacterial wilt, mosaic, and chlorotic fleck are important. The present chapter includes the symptoms, causative agent, disease cycle, epidemiology and host resistance, cultural, biological, chemical, and integrated management of these diseases.",signatures:"Gupta Meenu and Tennyson Jebasingh",downloadPdfUrl:"/chapter/pdf-download/69227",previewPdfUrl:"/chapter/pdf-preview/69227",authors:[{id:"301506",title:"Dr.",name:"Jebasingh",surname:"Tennyson",slug:"jebasingh-tennyson",fullName:"Jebasingh Tennyson"},{id:"308870",title:"Dr.",name:"Meenu",surname:"Gupta",slug:"meenu-gupta",fullName:"Meenu Gupta"}],corrections:null},{id:"70485",title:"Harnessing the Therapeutic Properties of Ginger (Zingiber officinale Roscoe) for the Management of Plant Diseases",doi:"10.5772/intechopen.90464",slug:"harnessing-the-therapeutic-properties-of-ginger-em-zingiber-officinale-em-roscoe-for-the-management-",totalDownloads:735,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Ginger (Zingiber officinale Roscoe) is one of the most widely used spices in the world. The therapeutic benefits of ginger are mainly due to the presence of volatile oils, phenols, alkaloid, and high oleoresin content. Ginger extracts have been extensively studied for a broad range of biological activities including antibacterial, antifungal, antiviral, anticonvulsant, analgesic, antiulcer, gastric antisecretory, and antitumor. This is all the more necessary because ginger is of plant origin, specifically more biodegradable, readily available, cheaper, and environmentally friendlier than synthetic chemicals. Since, some farmers in developing countries use ginger extracts as traditional medicine in the treatment of human diseases, it will be easy for them to adopt these extracts as biopesticides for the management of plant diseases. This book chapter seeks to outline the bioactive compounds and therapeutic benefits of ginger in plant disease management, and the mechanisms of action are also discussed.",signatures:"Elias Nortaa Kunedeb Sowley and Frederick Kankam",downloadPdfUrl:"/chapter/pdf-download/70485",previewPdfUrl:"/chapter/pdf-preview/70485",authors:[{id:"296475",title:"Dr.",name:"Elias",surname:"Sowley",slug:"elias-sowley",fullName:"Elias Sowley"},{id:"310656",title:"Dr.",name:"Frederick",surname:"Kankam",slug:"frederick-kankam",fullName:"Frederick Kankam"}],corrections:null},{id:"69729",title:"Ginger (Zingiber officinale) Antimicrobial Potential: A Review",doi:"10.5772/intechopen.89780",slug:"ginger-em-zingiber-officinale-em-antimicrobial-potential-a-review",totalDownloads:1170,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:1,abstract:"Zingiber officinale Roscoe, commonly known as gengibre, ajengibre, jengibre dulce (Brazil, Argentina, and Spain), ginger (United States and England), and gingembre (France), is a perennial herbaceous plant that produces a fleshy and articulated rhizome, with rough brownish epidermis. As a medicinal plant, ginger is one of the oldest and most popular in the world. Several properties of the ginger have been verified in scientific experiments, with emphasis to the antimicrobial activity. Ginger essence oil has been investigated by several in vitro microbiological techniques, in which most of its essential oils presented antimicrobial activity against all selected bacteria. The antimicrobial effect is attributed mainly to several phytochemicals, such as camphene, phellandrene, zingiberene, and zingerone. This review provides an overview of the experimental evidence for the antimicrobial potential of Z. officinale.",signatures:"Amanda Mara Teles, Bianca Araújo dos Santos, Cleidiane Gomes Ferreira, Adenilde Nascimento Mouchreck, Kátia da Silva Calabrese, Ana Lucia Abreu-Silva and Fernando Almeida-Souza",downloadPdfUrl:"/chapter/pdf-download/69729",previewPdfUrl:"/chapter/pdf-preview/69729",authors:[{id:"223173",title:"Dr.",name:"Ana Lucia",surname:"Abreu-Silva",slug:"ana-lucia-abreu-silva",fullName:"Ana Lucia Abreu-Silva"},{id:"287290",title:"Dr.",name:"Fernando",surname:"Almeida-Souza",slug:"fernando-almeida-souza",fullName:"Fernando Almeida-Souza"},{id:"294926",title:"MSc.",name:"Amanda",surname:"Mara Teles",slug:"amanda-mara-teles",fullName:"Amanda Mara Teles"},{id:"294927",title:"Prof.",name:"Adenilde Nascimento",surname:"Mouchrek",slug:"adenilde-nascimento-mouchrek",fullName:"Adenilde Nascimento Mouchrek"},{id:"294930",title:"Dr.",name:"Kátia Da Silva",surname:"Calabrese",slug:"katia-da-silva-calabrese",fullName:"Kátia Da Silva Calabrese"}],corrections:null},{id:"69184",title:"A Review of the Antidiabetic Activities of Ginger",doi:"10.5772/intechopen.88899",slug:"a-review-of-the-antidiabetic-activities-of-ginger",totalDownloads:1091,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:1,abstract:"Diabetes mellitus, a chronic metabolic disorder with major health care burden worldwide, is increasing, with 173 million adults being diabetic and over 8 million deaths recorded annually. Undesirable pathological conditions and high rates of secondary failure limit the use of current antidiabetic agents, thus, the need for more effective antidiabetic agents. Medicinal plants such as spices, rich in bioactive components that promote prevention and treatment of chronic conditions such as heart disease, cancer and Type-2 diabetes, are inexpensive with no side effects. The Zingiberaceae family, of which ginger is a member, consists of many species frequently cited for their antidiabetic and hypoglycemic properties. All important scientific literatures from 2000 to 2018 on the antidiabetic potentials of Zingiber officinale were evaluated. According to these studies, ginger exerts its antidiabetic effects through restorative effects on pancreatic β-cells, increasing insulin sensitivity, action and peripheral utilization of glucose. Other mechanisms include increased synthesis of hepatic glycogen through the enhancement of glycogen regulatory enzyme expression in the liver, inhibition of carbohydrate metabolizing enzymes, stimulation of pancreatic insulin release and inhibition of hepatic glucose production. Further studies, especially in humans are needed, more so, since ginger is one of the spices generally regarded as safe.",signatures:"Gloria Aderonke Otunola and Anthony Jide Afolayan",downloadPdfUrl:"/chapter/pdf-download/69184",previewPdfUrl:"/chapter/pdf-preview/69184",authors:[{id:"303199",title:"Dr.",name:"Gloria",surname:"Otunola",slug:"gloria-otunola",fullName:"Gloria Otunola"},{id:"303201",title:"Prof.",name:"Anthony",surname:"Afolayan",slug:"anthony-afolayan",fullName:"Anthony Afolayan"}],corrections:null},{id:"68833",title:"Pharmacological Potentials of Ginger",doi:"10.5772/intechopen.88848",slug:"pharmacological-potentials-of-ginger",totalDownloads:1034,totalCrossrefCites:5,totalDimensionsCites:6,hasAltmetrics:1,abstract:"Zingiber officinale, belonging to the family Zingiberaceae, is a popular spice and herb used as delicacy and to manage numerous diseases such as diabetes, hypertension, cancer, ulcer, diarrhea, cold, cough, spasm, vomiting, etc. in folk medicine from China, India, and Arabia Peninsula to other continents of the world including Africa (Nigeria, Egypt, and so on). Though this review is aimed at summarizing the pharmacological potentials of this well-endowed spice, interestingly, we found out that these reported ethnobotanical uses are attributed to a number of inherent chemical constituents including gingerol, 6-, 8-, 10-gingerol, 6-shogaol, 6-hydroshogaol, oleoresin, etc., eliciting various pharmacological effects, not limited to antioxidant, antitumor/anticancer, anti-inflammatory, antihyperglycemic, antihypertensive, anticholesterolemic, antibiotic/antimicrobial, neuroprotective, antiulcer/gastroprotective, antiemetic, hepatoprotective, and antiplatelet aggregation, safety profiles established through a number of studies (in vitro, in vivo, and cell lines), though some of these potentials are yet to be explored. Sadly, even few of these established effects are yet to be experimented in clinical trials, and only until these are intensified would there be prospect toward drug development for preventive and curative treatments. In conclusion, we are able to highlight and sum up the therapeutic implications of ginger and its related derivatives in the management of ailments confronting humanity.",signatures:"Fatai Oladunni Balogun, Esther Tayo AdeyeOluwa and Anofi Omotayo Tom Ashafa",downloadPdfUrl:"/chapter/pdf-download/68833",previewPdfUrl:"/chapter/pdf-preview/68833",authors:[{id:"200124",title:"Dr.",name:"Fatai Oladunni",surname:"Balogun",slug:"fatai-oladunni-balogun",fullName:"Fatai Oladunni Balogun"},{id:"267700",title:"Dr.",name:"Anofi",surname:"Ashafa",slug:"anofi-ashafa",fullName:"Anofi Ashafa"},{id:"309473",title:"Mrs.",name:"Temitayo Esther",surname:"Adeyeoluwa",slug:"temitayo-esther-adeyeoluwa",fullName:"Temitayo Esther Adeyeoluwa"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9704",title:"Cucumber Economic Values and Its Cultivation and Breeding",subtitle:null,isOpenForSubmission:!1,hash:"779dad6540f8023acf09657acf0b5da8",slug:"cucumber-economic-values-and-its-cultivation-and-breeding",bookSignature:"Haiping Wang",coverURL:"https://cdn.intechopen.com/books/images_new/9704.jpg",editedByType:"Edited by",editors:[{id:"280406",title:"Dr.",name:"Haiping",surname:"Wang",slug:"haiping-wang",fullName:"Haiping Wang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6277",title:"Physical Methods for Stimulation of Plant and Mushroom Development",subtitle:null,isOpenForSubmission:!1,hash:"33dff71e3489403e273057ae36bd0dbd",slug:"physical-methods-for-stimulation-of-plant-and-mushroom-development",bookSignature:"Mohamed El-Esawi",coverURL:"https://cdn.intechopen.com/books/images_new/6277.jpg",editedByType:"Edited by",editors:[{id:"191770",title:"Dr.",name:"Mohamed A.",surname:"El-Esawi",slug:"mohamed-a.-el-esawi",fullName:"Mohamed A. 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\r\n\tCopper is a metal that is widely used in different applications resulting from thermal and electrical conductivities, together with the use derived from the corrosion resistance, in particular when it is alloyed. This book intends to be a compendium of works related to all the points of the copper manufacture, from the ores (new alternative copper ores) to the processes (new copper production processes or improvements in them) and the final products and applications (new alloys and potential applications of copper and copper alloys). Environmental issues are also welcomed in this book, including improvements in the efficiency of the production processes, recovery of copper from slag, or reutilization of wastes. Therefore, copper, copper alloys, and copper products become attractive materials in making various products.
\r\n\r\n\tThe book chapters intend to provide scientific understanding and knowledge to scholars, students, researchers, and laboratory and industry workers of the subject of copper.
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Postdoctoral Researcher (Juan de la Cierva-Formación, granted by the Spanish Ministry of Science and Innovation) in the Nanomaterials and Nanotechnology Research Center of the Spanish National Research Council. Author of 6 full-length books and 28 articles in indexed journals. His research focuses on the application of concentrated solar energy in materials science and metallurgy (recovery of valuable elements from slags, ferroalloys, and other processes), ferrous and non-ferrous metallurgy, agglomeration of materials (ceramic or non-ceramic) using conventional and advanced sintering processes (spark plasma sintering or laser sintering) and recycling-valorization of metallurgical wastes.",institutionString:"Spanish National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Spanish National Research Council",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:{id:"212958",title:"Dr.",name:"Luis Felipe",middleName:null,surname:"Verdeja González",slug:"luis-felipe-verdeja-gonzalez",fullName:"Luis Felipe Verdeja González",profilePictureURL:"https://mts.intechopen.com/storage/users/212958/images/system/212958.png",biography:"Luis Felipe Verdeja González holds a Ph.D. in Chemical Sciences from the University of Oviedo, where he is a Professor of Materials Science and Head of the Siderurgy, Metals and Materials Group (Sid-Met-Mat) and Head of the Department of Materials Science and Metallurgical Engineering at the University of Oviedo. 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Hypothermia is any body temperature below 36 degree C.
Therapeutic Hypothermia is induced hypothermia and can be mild (34-35.9 degree C), moderate (32-33.9 degree C), moderately deep (30.1-31.9 degree C) or deep (less than 30degree C)
Current indications for induced therapeutic hypothermia
Despite advances in ICU care, cardiac arrest remains a significant cause of death in many countries. Mortality reports vary from 65 to 95% for out-of hospital cardiac arrest.I is a class –I recommendation now that after return of spontaneous circulation in out-of-hospital VF cardiac arrest, patients that remain comatose should be subjected to hypothermia at 32°C to 34°C for 12 to 24 hours. This may also be applied to comatose adult patients with spontaneous circulation after OHCA from a non VF rhythm or in-hospital cardiac arrest.1
Several unanswered questions however remain, due to lack of randomized studies. These in part, relate to time from initiation of therapy to achieving target temperature, and whether this is a significant predictor of outcome. The optimal rate of cooling is also an unanswered question, so is the optimal duration of TH in some settings, albeit in the setting of cardiac arrest, improved outcomes have been demonstrated with 12 and 24 hrs of TH at 32°C to 34°C. Hypothermia for neonatal asphyxia is commonly performed for 72 hrs, while hypothermia for cerebral edema associated with liver failure has been reported for as long as 5 days. 2
Traumatic brain injury (TBI) is a leading cause of death and disability in young people in Western countries. The neuroprotectant effects are thought to be related to decreased metabolic rate, cerebral blood flow, decreased release of excitatory neurotransmitters, decreased apoptosis, cerebral edema, decreased cytokine response etc.3
While studies have shown that Hypothermia is clearly effective in controlling intracranial hypertension (level of evidence: class I); it has been difficult to show that lowering ICP definitely improves outcomes. Few positive studies with regard to survival and improved neurological outcome have been shown mainly in tertiary referral centers with experience in use of hypothermia. Here again, as in cardiac arrest, more unanswered questions remain- duration, time of cooling and rewarming, type of rewarming. Currently, most centers perform it for at least 48 hours. Rewarming is typically done slowly, over at least 24 h (level of evidence: class IIa).4 If there is evidence of ICP elevation during rewarming, again no definite recommendations are available, but most experts will proceed with repeat cooling. It could be that in traumatic brain injury, other therapies, including cerebrospinal fluid drainage, osmolar therapies, sedation, barbiturate coma, and decompressive craniectomy may confer additional benefits that may make it more difficult to prove that Therapeutic hypothermia is superior.
Similar to Cardiac arrest and TBI there is evidence from animal studies that show benefits of therapeutic hypothermia in stroke. Use of hypothermia in stroke remains experimental, until large prospective randomized human clinical trials using hypothermia in acute stroke are completed. 5
Hypothermia may decrease infarct size in patients with acute myocardial infarction after emergency percutaneous coronary intervention
Intraoperative hypothermia is used during neurological surgery but without strong evidence from randomized controlled trials. Indications are being studied in the areas of SAH, Neurosurgery, liver failure, Spinal cord injury.
Both Invasive and non invasive cooling methods have been developed and used to induce hypothermia. The ideal cooling technique should offer efficacy, speed of cooling for target organs, and offer ease of use and transport.It should also have the ability to provide controlled rewarming.
Surface cooling as a noninvasive method to induce hypothermia is easy to use, on the other hand requires more time to achieve the target temperature. There are two described methods: generalized cooling, and selective brain cooling.
Generalized cooling is achieved through the use of cooling blankets, ice packs, and cooling pads. Care should be paid to prevent cold injury to the patient’s skin. This method has variability in time to cooling, ranging from 0.03 to 0.98 °C per hour and difficulty in titration of temperature.
Pads that provide direct thermal conduction through the skin are also used; these are unlike conventional water blankets or wraps where heat transfer is by convection. The cooling rate is reported to be 1.5°C/hour or more. Hydrogel-coated pads in these circulate temperature-controlled water under negative pressure, and are placed usually on the patient’s abdomen, back and thighs.
Selective brain cooling is another non invasive method. The most commonly used methods are cooling caps and helmets that contain a solution of aqueous glycerol to facilitate heat exchange. Helmet devices do not appear to provide particularly significant protection to the brain, but they reduce core temperature slowly.
Several other limitations exist in surface cooling methods. Through vasoconstriction, shivering, redirection of blood flow away from extremities, they create thermal energy. Overcooling occurs. In a study involving 32 patients where surface cooling was used to induce hypothermia, 63% of patients were overcooled, increasing the risk for adverse events. Another problem with surface cooling is cold injury, causing pressure ulcers and skin breakdown. Surface cooling is less efficient in reducing the temperature of target organs, such as the brain and heart6
30 ml/kg Lactated Ringers solution that has been chilled to 4°C can be infused over 30 minutes. No adverse effects of the rapid infusion of this volume of IV crystalloid fluid in a study by Bernard. This is followed by another method to maintain hypothermia. Different types of fluids can be used, including 0.9% sodium chloride injection, lactated Ringer\'s injection, and albumin. Studies have reported cooling rates of 0.8–1.2 °C per liter of fluid infused. Some experts caution that in patients unable to handle the fluid challenge, infusion of large volumes of intravenous fluids in the presence of pulmonary edema or chronic renal failure requiring dialysis may increase adverse events. However, several studies have shown that this process has not been associated with worsening pulmonary edema.7
Endovascular cooling is another invasive method used. This is achieved by inserting central venous catheters, with an external heat exchange-control device that circulates cold intravenous fluid. The user sets a target temperature, and the device appropriately adjusts the fluid /water temperature. These devices can reduce temperatures at rates close to 4 °C per hour. In a study by Holzer and colleagues, looking at post cardiac arrest patients, endovascular cooling was found to improve survival and short-term neurologic recovery without higher rates of adverse events, compared with standard treatment. Furthermore, the constant rate of rewarming prevents elevations in ICP. As with any central venous catheters, insertion risks and infectious, bleeding complications may occur. The placement of catheters with associated risks and, and costs of placing them need to be factored. 8
Other methods for invasive cooling that are reported include cold carotid infusions, single carotid artery perfusion with extracorporeal cooled blood, ice water nasal lavage, cold peritoneal and lung lavage and nasogastric and rectal lavage
Temperature must be monitored continuously and accurately during TH. Peripheral and core temperatures may not always correlate, so two methods of monitoring are usually recommended. A true core temperature is obtained from a pulmonary artery catheter. Tympanic temperatures poorly reflect core temperature. Bladder temperatures are easily obtained by temperature-sensing indwelling urinary catheters. Studies have shown that bladder temperatures are continuous, safe and reliable, correlate well with fluctuations in core temperature. Clinicians must be mindful that in oliguric patients, bladder temperature may poorly reflect core temperature, and other monitoring sites should be used. There is also a delay in reflecting core temperature changes, before bladder temperature also changes, especially the more rapid the cooling rate. This is more of a problem with rectal temperatures. Education of the caregivers about this helps prevent undercooling or overcooling the patient, thereby helps to mitigate the risk of adverse events. Stone, Gilbert J et al
Temperature modulation during therapeutic hypothermia may be broken down into four phases: induction, maintenance, rewarming/ decooling, and normothermia. Each of these phases requires monitoring for and prevention of associated complications.(please refer to Figure 2 for an example of a therapeutic hypothermia protocol used in our institution for cardiac arrest patients).
DO NOT SUBSTITUTE | |||||
| |||||
DATE | TIME | ||||
NS - 30 mL/kg IV of cold injection at a target of 4° Celsius | |||||
| |||||
Apply pads appropriate for patient weight(Apply Universal pads if Wt"/>= 220 LBs) | |||||
The Arctic Sun is preset to 33° Celsius | |||||
Start Magnesium Sulphate 4 Gm IV (in 100 ml injectable water ) over 4 hours | |||||
Continuous cardiac monitoring with pulse oximetry - monitor vital signs and record every hour | |||||
Consider target MAP ≥ 90mmHg or mmHg to maintain Cerebral Perfusion Pressure (CPP) of ____ | |||||
Goal CVP 8-12mmHg or mmHg Maintain ScvO2 "/> 70%.(if available) | |||||
Obtain bedside glucose every 1 hour. (See Adult Insulin order sheet if already initiated.)Maintain Accuchecks q 1 Hr until T=37° Celsius.(maintain BS=110-150) | |||||
ABG every hour(s) | |||||
CBC, BMP, Magnesium, Phosphorus, PT/PTT every 6 hours | |||||
Consider blood cultures 12 hours after initiation of cooling | |||||
Initiate VAP Bundle Order Set, if not already begun | |||||
No sedation vacation if patient is receiving neuromuscular blockade infusion or in cooling phase | |||||
Consider Empiric Antimicrobial therapy if sepsis or immunosuppression is suspected(ex: neutropenia..) | |||||
Bedrest | |||||
Skin assessment should be performed and documented every 4 hours | |||||
Turn patient every two hours unless contraindicated and ordered | |||||
PT/OT consults and treatment if not already ordered | |||||
Propofol (DIPRIVAN) drip initiated at 10mcg/kg/min. - titrate by 5mcg/kg/min for Ramsay of _____ to a max. of 80mcg/kg/min | |||||
Midazolam (VERSED) drip initiated at mg/hour - titrate by 1mg/hr for Ramsay of _____ | |||||
Fentanyl infusion at mcg/hour - titrate to mcg/hour | |||||
Morphine infusion at mg/hour - titrate to mg/hour | |||||
Buspar 10mg/ 20mg PT TID(circle dose) | |||||
DATE | TIME | ||||
Start with PRN dosing as ordered for shivering If patient still shivering, consider continuous infusion. Place “Neuromuscular Blockade in use” sign at head of bed. | |||||
Atracurium | Intermittent dosing__________________________(dose/route/interval) Loading dose (0.5 mg/kg) = ________ mg IV x one dose now Infusion – begin at 4 mcg/kg/min IV to a max. of 12 mcg/kg/min | ||||
Vecuronium | Intermittent dosing__________________________(dose/route/interval) Loading dose (0.1 mg/kg) = ________ mg IV x one dose now Infusion – begin at 1 mcg/kg/min IV to a max. of 2 mcg/kg/min | ||||
Monitor patient for ventilator compliance and shivering | |||||
Start now and D/C when patient is rewarmed to 37° Celsius - page EEG tech | |||||
Start in am and D/C when patient is rewarmed to 37° Celsius - page EEG tech | |||||
Maintain O2 Sats=95% Maintain pCO2=40mmHg | |||||
Artificial tears ophthalmic ointment (LACRILUBE or equivalent) – one ribbon in each eye every 12 hours. | |||||
Maintenance IV Fluids: at ml/hr.- | |||||
Continuous EKG for dysrhythmias | |||||
Stop all potassium infusions | |||||
Rewarm at 0.25° Celsius to 0.33° Celsius per hour - Keep patient in goal temperature range of 36° Celsius to 37° Celsius for next 48 hours | |||||
May discontinue paralytic(if used) once goal temperature is obtained | |||||
Begin daily sedation vacation once paralytic has been discontinued | |||||
Mercy Hospital St Louis In-HOSPITAL Therapeutic Hypothermia Protocol
In the setting of cardiac arrest, based on animal and human data, initiation of cooling should be done as soon as possible after return of spontaneous circulation (ROSC). The induction phase can be initiated in the prehospital or in hospital setting. There are ongoing studies involving prehospital cooling. One should be mindful that if prehospital cooling is not followed by in hospital cooing, outcomes could be considerably worse, especially if patients are rewarmed quickly
The maintenance phase usually occurs in an intensive care unit and hemodynamic parameters, electrolytes should be watched closely. For example, hypokalemia is a common occurrence, and can precipitate further arrests, so replacement is essential. Secondary insults such as hypercarbia, hypoxemia, glycemic shifts should be avoided. It is important to recognize that drug metabolism is altered in hypothermia, meticulous attention to medication dosing is needed and aggressive treatment of shivering, with sedation and neuromuscular blockade is often needed
Fever in the first 72 hrs after ROSC is associated with poor outcome. Although unproven, an increasing body of evidence supports the cautious prevention and treatment of fever in the setting of critical neurological illness, and many clinicians attempt to maintain a core temperature of 36°C to 37.5°C until at least 72 hrs after ROSC
Rewarming /Decooling is associated with electrolyte shifts, vasodilation, and the “post resuscitation” syndrome, many deaths occur in this phase due to hemodynamic instability and other complications. Rewarming / Decooling should not be treated casually.
The “post resuscitation” syndrome which is characterized by elevated inflammatory cytokine levels, vasodilatory shock, intracranial hypertension, and thereby decreased cerebral perfusion pressure often compounds the myocardial dysfunction related to acute myocardial infarction, defibrillation injury or cardiomyopathy. The duration of cooling and rewarming may vary depending on the indication, for instance, in post cardiac arrest, rewarming is usually begun 24 hours after the initiation of cooling, in intracranial hypertension, this is typically done later, after 48 hours. Patients should be rewarmed slowly so that it avoids rapid hemodynamic alterations, while preserving the neuroprotectant effects of hypothermia. The usual rate of rewarming is a goal rate of 0.2°C to 0.33°C per hour, in ICP elevations; the rate is sometimes slower, at 0.05 to 0.1 degrees C per hour. While the optimal rewarming rate remains unknown; the process usually takes about 8 hours. Careful hemodynamic monitoring is needed, patients may require additional hemodynamic support with fluid boluses, inotropes, and vasopressors to maintain adequate cerebral perfusion pressures, and mean arterial pressures during decooling, Sometimes, if significant hemodynamic instability or signs of elevated ICP occur, it may become necessary to slow or stop the temperature decooling process.Rewarming is typically achieved through active or passive means through the use of heated-air blankets, or the removal of cooling methods allowing the patient\'s body temperature to increase over time. Paralysis and sedation should be maintained until the patient\'s temperature reaches 35 °C. Patients must be monitored closely, and all electrolyte infusions must be discontinued to avoid dangerous electrolyte shifts
Hypothermia affects many intracellular processes. While some of these are directly related to its protective effects, hypothermia therapy is also known to be associated with a number of potential adverse events. These adverse effects generally do not pose a problem until core body temperatures are< 35°C.
Many physiological, laboratory changes occur with induction of hypothermia. Education of caregivers is key, so there is not only timely recognition of adverse events, but unnecessary interventions are minimized in case of routine changes that are seen. It is possible that in many studies especially in traumatic brain injury and hypothermia, the results may have been negatively impacted by adverse events related to hypothermia and /or failure to recognize and treat the physiological effects.
Example, mild hypothermia is associated leucopenia, thrombocytopenia. Hyperglycemia is common due to decreased insulin sensitivity and increased insulin resistance. Decreases in cardiac output may be seen, also an increase in lactate levels and levels of serum transaminases, amylase. A common occurrence is increased urinary output (cold diuresis). These effects of hypothermia depend on the degree of hypothermia, age, comorbidities. A significant risk for severe arrhythmias occurs at temperatures below 28–30_C. These low temperatures are not typically used in current practice; the target temperature is usually mild –moderate hypothermia, although they are still practiced in major vascular and other neurosurgical procedures.4
Hypothermia leads to a decrease in the metabolic rate. Metabolism is reduced by between 5% and 7% per Celsius degree reduction in body temperature. Cerebral blood flow is decreased, but, this is offset by the decrease in metabolism. It decreases cerebral edema, decreases the excessive influx of Ca2+ into the cell, decreases the accumulation of glutamate, an excitatory neurotransmitter. It thereby is thought to decrease apoptosis.
Hypothermia inhibits neutrophil and macrophage function, suppresses inflammatory reactions and inhibits the release of pro-inflammatory cytokines. While this may help contribute to hypothermia’s neuroprotective effects, this may occur at the expense of an increased the risk of infections.
Adverse events of Hypothermia, prevention and management strategies:
Shivering is the body’s physiological response to hypothermia. Both in the induction and maintenance of hypothermia, this can pose challenges, and shivering is sometimes more an issue when normothermia is the goal temperature. Shivering generates heat and increases the oxygen consumption and metabolic demands of tissues.
Shivering is especially important in the extremes of age. It has been associated with a higher risk of adverse cardiac events and poor outcomes in the perioperative setting. The threshold for shivering is slightly higher in females. The process is regulated via the preoptic nucleus of the anterior hypothalamus. Through positive and negative feedback loops this helps minimize fluctuations, maintains core body temperature within 0.1°C– 0.2°C. 4
Typically a shivering response is seen when core temperature decreases below 35.5°C, the “shivering threshold.” However, in febrile patients, and in brain injured patients, this regulation is altered and both the temperature “set point” and the shivering threshold increase. The hypothalamus then makes attempts to maintain the higher temperatures as it does to maintain normal temperature or normothermia. This causes an increase in oxygen consumption, metabolic rate, and increases carbon dioxide production. At temperatures lower than 33-34°C, the shivering response decreases, therefore sedation and paralytics can be decreased at this point, if the clinical situation allows it.
The Bedside Shivering Assessment Scale (BSAS) is a simple scale that was developed as a means to detect and quantify shivering and guide therapeutic interventions. The scale has 4 levels. 9
Score | Description or observation | Severity |
0 | Absence of shivering on palpation of neck or pectoralis muscles | None |
1 | Localized to the neck and/or thorax | Mild |
2 | Involvement of the upper extremities with or without neck | Moderate |
3 | Generalized, whole-body involvement | Severe |
Bedside Shivering assessment Scale
A non pharmacologic measure that has been shown to decrease shivering in some studies, mainly in healthy volunteers is called Surface counter warming. Studies have shown decreased shivering and improved metabolic profiles, and that is safe and effective, easy to use. Theoretically, an increase of 4°C in skin temperature could compensate for a 1°C decrease in core temperature, reducing the shivering response.9
Numerous pharmacologic strategies have been used to control shivering. In the operating room, volatile anesthetics, including halothane, isoflurane and enflurane, are used to control post anesthetic shivering. In the intensive care unit, other agents are of more practical use. These agents are thought to be effective by various mechanisms. The agents act though serotonin manipulation, or are N-methyl-D-aspartate Antagonists, α2-agonists, Opioids, and others. Most studies involving these agents have been conducted in healthy volunteers.
Buspirone is a serotonin (5-HT) 1A partial agonist that has been shown to be a good anti shivering agent.At a 60-mg dose, buspirone – a 5-HT1a partial agonist – reduced the shivering threshold by 0.7ºC. A study in volunteers found that a 30-mg dose combined with low-dose meperidine produced a similar reduction in shivering threshold compared to a large dose of meperidine alone (2.3ºC).Buspirone provides a good synergistic therapy when combined with other antishivering interventions. The main disadvantage of buspirone is that it needs to be administered enterally, no IV formulation is available. Bioavailability in the critically ill may not be reliable.10
Meperidine is an opioid analgesic. Meperidine is probably the single most useful antishivering drug, but has significant adverse events. Meperidine acts on both mu and kappa receptors, is considered the most effective antishivering agent among the opioids. The mechanism behind meperidine’s antishivering action is not clearly known. It is thought that activation of [kappa]-opioid receptors, anticholinergic action, and N-methyl-d-aspartate antagonism all play a role. In studies, plasma concentrations near 1.3 µg/mL have been required to induce moderate hypothermia with meperidine alone, which could increase the risk of side effects.Meperidine is effective for postoperative shivering and, it inhibits shivering twice as much as vasoconstriction.
Meperidine has major side effects; the more significant of them is lowering of seizure threshold. Other reported adverse events include arrhythmias, hyperreflexia, and myoclonus. The metabolite Normeperidine accumulates in patients with renal failure and could potentiate these adverse events.
Fentanyl, morphine are pure mu opioid receptor agonists, and have had mixed results in studies. High doses may be needed to achieve this effect, and this may potentiate side effects11.
The alpha2-receptor agonists are another important class of drugs used as pharmacologic measures to control shivering. Bradycardia and hypotension are the main adverse events with this class of drugs.Important to remember, they may also exacerbate the bradycardia induced by hypothermia.
Clonidine decreases the vasoconstriction and shivering thresholds. Prophylactic use of clonidine lowered the threshold of vasoconstriction in healthy volunteers. 12, 13 In a trial comparing clonidine and meperidine, the average onset of action for meperidine and clonidine were 2.7 and 3.1 minutes, respectively. At least from these data, clonidine appears to be as effective as meperidine for postanesthetic shivering14
Dexmedetomidine is another agent that has been shown to decrease postanesthetic shivering when compared to both placebo and Meperidine. In studies with dexmedetomidine in healthy volunteers, it showed a decrease in the vasoconstriction and shivering thresholds by similar amounts.15
A small study looked at healthy volunteers and found that Meperidine and Dexmedetomidine were synergistic as well. 16, 17
Magnesium is another anti shivering agent. It is thought to act as an antagonist of the NMDA receptors. In addition, hypothermia causes hypomagnesaemia commonly, and magnesium replacement is often required. Results on magnesium as a neuroprotectant have been variable. In a study of healthy volunteers, despite reducing the shivering threshold, the authors concluded that it was not clinically significant in counteracting the shivering effect of therapeutic hypothermia. 18 In another study, magnesium shortened the time to achieve target temperature and improved patient comfort.
In this small study, 22 volunteers were randomly assigned to one of four therapies: meperidine monotherapy; meperidine plus buspirone; meperidine plus ondansetron; or meperidine, ondansetron, and magnesium sulfate. In this study, Magnesium was shown to decrease time to target temperature and increase patient comfort. Although the presence of shivering was recorded in this investigation, these data were not reported. 19
Dantrolene is another agent that has been used for malignant hyperthermia. It acts on the skeletal muscle and interferes with the release of calcium from the sarcoplasmic reticulum, and inhibits the excitation-contraction coupling of skeletal muscles. It is a good adjunctive antishivering agent. In a study with healthy volunteers, dantrolene decreased the gain of shivering. Dantrolene had no effect on the vasoconstriction threshold.Hepatitis is a complication of dantrolene, especially in people older than 35 years. The reaction can be dose dependent or idiosyncratic.20
Propofol has been widely studied in Shivering control. It has been compared to Thiopental and isoflurane.Patients on propofol experienced less shivering compared to thiopental alone or thiopental plus isoflurane. Like other drugs, during hypothermia, the plasma concentration of propofol is increased by 30% due to reduced clearance. Clinicians should also be aware of propofol infusion syndrome.21\n\t\t\t\t\t22 Propofol infusion syndrome is a rare complication of propofol infusion. Risk factors include administration of high doses (greater than 3-5 mg/kg per) and prolonged use, more than 48 hours, patients on catecholamines for vasopressor support, steroids. Additional proposed risk factors include a young age, critical illness, high fat and low carbohydrate intake, inborn errors of mitochondrial fatty acid oxidation. Patients present with cardiac dysrhythmias, metabolic acidosis, rhabdomyolysis, and renal failure. It can be associated with a high mortality.
There is limited data on the use of other agents such as Ketamine, methylphenidate and doxapram as anti shivering agents in hypothermia.
By redistributing blood flow away from muscle, skin, and fat, hypothermia alters drug pharmacokinetics. Drugs with a large volume of distribution, in the setting of hypothermia distribute to reduced volume and thereby produce higher plasma concentrations. Due to reduced blood flow, these drugs may initially be sequestered in tissue, but subsequently with rewarming and vasodilation, these drugs now redistribute from tissues, leading to high plasma concentrations, thereby increasing the risk of toxicity.23
Cardiac output decreases, but this is offset by the decreased metabolic rate
Common electrocardiographic findings during hypothermia include prolonged P-R and Q-T intervals and widening of the QRS complex as well as altered T waves and appearance of the J wave. (Osborne). These usually do not require interventions.
Arrhythmias: Initially, hypothermia causes tachycardia, and then bradycardia ensues. The arrhythmias depend on the severity of hypothermia, more severe commonly occur at temperatures of < 28C.The bradycardia may be severe enough to warrant discontinuing hypothermia. This is compounded by the fact that the anti arrhythmics become less effective, and so does electrical defibrillation. Attempts at electrical defibrillation can initiate malignant arrhythmias.
In the setting of a cardiac arrest, the myocardium in a deeply hypothermic patient is easily susceptible to manipulations such as CPR, defibrillation, and can predispose to arrhythmias. While mild hypothermia can be protective by stabilizing membranes, severe hypothermia increases risk of malignant arrhythmias.
Limited data exist on the efficacy of various antiarrhythmics. Bretylium, the most commonly studied agent, has been recommended as the drug of choice during moderate-to-severe hypothermia
Observational data from humans and experimental animal models have looked at Bretylium. Bretylium is a parenteral Class III antiarrhythmic agent. However, Bretylium is no longer available in the US secondary to lack of availability of raw materials needed to produce the drug, as well as declining usage in clinical practice. Amiodarone has been studied in an animal model. Stoner et al looked at thirty anesthetized dogs and induced hypothermic VF. They compared defibrillation rates after drug therapy with amiodarone, bretylium, and placebo. In this study, neither amiodarone nor bretylium was significantly better than placebo in improving the resuscitation rate.24, 25.The benefits of amiodarone during hypothermia have not been clearly established in humans. In the Bernard study looking at hypothermia after cardiac arrest, Lidocaine was administered for 24 hrs. Clinically significant cardiac arrhythmias occurred with less frequency in the Australian study compared to the European study, where no lidocaine was employed. 6
Coronary blood flow has been shown to decrease during mild hypothermia in patients with coronary artery disease. Evidence from animal studies has shown a 10% reduction in myocardial infarct size for every 1°C decrease in body temperature. 26
Dixon et al looked at a randomized study of 42 patients with acute myocardial infarction and where cooling was maintained for 3 hours after reperfusion (core temperature target 33 degrees C.)There were no significant adverse hemodynamic events with cooling; however, the median infarct size was not significantly smaller in those that were cooled compared with the control group27
Other clinical studies of therapeutic hypothermia in patients with acute myocardial infarction who are undergoing primary PCI have not shown any beneficial effects.
Despite these data, hypothermia can potentially cause hypotension and myocardial dysfunction. It induces a cold diuresis and induces hypovolemia. This is through increased venous return, stimulation of atrial natriuretic peptide, decreased anti diuretic hormone levels, and renal tubular dysfunction.
Patients with severe Traumatic brain injury may also receive mannitol for hyperosmolar therapy for raised intracranial pressures or may have diabetes insipidus, which can further contribute to hypovolemia.4
Infectious complications occur frequently in ICU patients, especially after cardiac arrest. The increasing use of therapeutic hypothermia has raised awareness about increased infectious complications. In a retrospective review of a single institution cohort, Mongardon et al found that pneumonia as the most common source, and Staphylococcus aureus was the main causative agent. Duration of hypothermia was associated with increased infection rates. ICU survival and neurologic outcome were not affected. 28A numbers of studies, especially in patients with stroke or TBI, have reported higher risks of pneumonia when therapeutic hypothermia is used over longer periods of time (48–72 h) However, other studies using hypothermia for prolonged periods in patients with TBI reported no increase in infection rates.
Evidence from clinical and in vitro studies shows that hypothermia can impair immune function. Hypothermia inhibits the release of various pro-inflammatory cytokines, inhibit neutrophil and macrophage function. Kimura and colleagues found that the peak release of interleukin-6, interleukin-1, and other proinflammatory cytokines was significantly delayed at 33 °C compared with 37 °C 29, 30 Hypothermia reduces gastrointestinal motility, and cardiac dysfunction in post arrest patients, therefore, it may increase risk of mucosal ischemia and breakdown. This may cause bacterial translocation. The insulin resistance and hyperglycemia associated with hypothermia may further predispose the patient to infection. The normal host responses to infection like leukocytosis may not be noted in hypothermic patients, so careful surveillance is needed. The threshold to initiate antibiotic treatment should be low. Fever in these patients should be treated aggressively to prevent further neurologic injury.
Many institutions perform blood cultures and sputum cultures at the time of initiation of hypothermia, and periodic surveillance cultures to detect early bacteremia. In patients developing infections after hypothermia treatment, fever should be treated aggressively, to mitigate new or additional neurological injuries
In a retrospective observational study involving neonates, moderate cooling decreased seizures recorded by EEG.31 Seizures after cardiac arrest and TBI are common; the detection of seizures is an important aspect of a neurointensivist in the care of therapeutic hypothermia patients. Many of these patients are under neuromuscular blockade, and convulsive movements are absent. The incidence of seizures after cardiac arrest is around 24%, with some studies showing a higher incidence than others. Continuous EEG monitoring should be used when available over intermittent EEG, because seizures could be no convulsive as well as convulsive in these patients. The disadvantage of continuous EEG is that is not always available, is expensive, labor intensive, and subject to misinterpretation. No clear guidelines exist to guide therapy of EEG findings like PLEDS.
Intravenous benzodiazepines are used the initial medical treatment of status epilepticus. If the patient fails first line therapy and is considered to be in refractory status epilepticus, there is no firm data to guide subsequent management. The VA cooperative study showed that early control with a first line agent is important, because, if the first line agent fails, the success of subsequent second and third line agents is marginal. In the VA cooperative trial, the treatment success rate with the first drug was 55% in the overt status group and 15% in the subtle status group.32, 33\n\t\t\t\t
Many experts recommend continuous intravenous antiepileptic drugs at this stage. Midazolam is the safest anesthetic agent in treating SE. Doses as high as 3 to 5 mg/kg/h may be necessary to maintain seizure suppression in the most refractory cases. Tachyphylaxis is often encountered when prolonged infusions are used. The other agents used to treat SE are propofol, and barbiturates (Thiopental or pentobarbital). Barbiturates produce hypotension, and myocardial depression, this may pose further challenges in the post cardiac arrest setting. Other side effects include ileus, hepatotoxicity, increased susceptibility to infections and very prolonged sedation. Propofol can be associated with propofol infusion syndrome as discussed earlier.Valproic acid, levetiracetam, are emerging as alternative agents. Fosphenytoin is an antiepileptic that is often added in these patients. Fosphenytoin is a prodrug of phenytoin and its preparation does not include propylene glycol. It can be administered faster than IV phenytoin, and has less adverse cardiac events with IV infusion compared to phenytoin. It is much less likely to produce local tissue reactions, and it can be infused faster than phenytoin.34 As with status epilepticus from other causes, it is not clear whether burst suppression on EEG is superior to seizure suppression. No data on seizure prophylaxis after hypoxic ischemic encephalopathy are available
Bleeding diatheses occur in the setting of mild therapeutic hypothermia. For every 1 °C decrease in temperature, coagulation-factor function is decreased by 10%. Watts et al showed that in trauma patients, enzyme activity alteration, platelet dysfunction and changes in fibrin pathways occur. Clinically significant bleeding is rarely a significant problem, even in traumatic brain injury patients. Schefold et al. in a prospective observational study of 31 patients with AMI and mild induced hypothermia and primary PCI found no excessive bleeding risk with cooling/PCI.35,36\n\t\t\t
Values of standard coagulation tests such as prothrombin time and partial thromboplastin times are usually normal, because these tests are usually performed at 37_C in the lab. Tests will be prolonged only if they are performed at the patient’s actual core temperature
Skin integrity should be assessed carefully and frequently. The surface cooling, vasoconstrictive response to cooling can increase skin breakdown in hypothermic patients.6
Hypothermia patients have GI dysmotility, ileus. Caution needs to be exercised with promotility agents like Erythromycin, metoclopramide, neostigmine, as they can induce arrhythmias. Increased serum amylase levels are common, but patients rarely have significant pancreatitis. Enteral nutrition can help decrease risk of bacterial translocation. Gaussorgues P, et al. Bacteremia following cardiac arrest and cardiopulmonary resuscitation.
A common problem is severe electrolyte disorders hypokalemia, hypomagnesemia, hypophosphatemia during induction of cooling. These may cause further arrhythmias in post-arrest patients. Hypothermia decreases insulin sensitivity and insulin secretion, which often leads to hyperglycemia. Tight control of glucose levels may decrease morbidity and mortality in ICU patients, but the exact levels at which glycemia needs to be maintained is controversial. During rewarming, glucose levels tend to drop, and therefore, insulin may need to be decreased or discontinued. Likewise, hyperkalemia and hypermagnesemia are common during rewarming, and cardiac arrests have occurred when the clinician s unaware of this phenomenon. Hypothermia also induces a metabolic acidosis by increased synthesis of glycerol, free fatty acids, ketones and lactate. These changes are normal metabolic consequences of hypothermia and should not be attributed to complications such as bowel ischemia.4
Hypotension can occur through hypovolemia, the cold diuresis, that occurs in hypothermia, and the use of agents like mannitol in TBI or diuretics in the setting of cardiomyopathies can further exacerbate this.If this is unrecognized, the problem is worse in the rewarming phase when vasodilatation often occurs, and profound shock ensues. Cueni-Villoz N, et al.\n\t\t\t
In conclusion, hypothermia is becoming increasingly used across many intensive care units, and the applications could expand well beyond the current indications. It is important to use safe, effective cooling methods, recognize, prevent and treat various adverse events that could occur, so we can improve the survival of these patients.
The growing interest in a healthy lifestyle has led the food industry to establish an alliance with the scientific community to create a viable and effective alternative for the consumer, carrying out several studies about the bioactive potential of various compounds present in natural matrices [1].
The recently discovered properties of phenolic compounds have been exploited, and the food industry has launched numerous new functional products whose health functionality is closely connected with their polyphenols content [2].
The scientific community have been developing several studies to determine the presence of phenolic compounds natural matrices, namely the presence of flavonoids. For example, in cereals, several kinds of flavonoids (principally glycosylated flavones) are distributed in these grass crops; in legumes, the presence of a total of 690 isoflavonoids have been reported; and in medicinal plants these molecules are a major constituent in lists of metabolites responsible for the bioactivities [3].
Flavonoids are a subdivision of polyphenols that are abundant in the human diet and can be found in several matrices; specifically, they are commonly found in fruits, vegetables, nuts, teas, dark chocolate, red wine and legumes [3].
These compounds are divided into principal subclasses of flavanols, including flavanol monomers (flavan-3-ols) and flavanol polymers (called proanthocyanidins), flavonols, flavanones, flavones, isoflavones, and anthocyanins (depending on the substitution at the heterocyclic ring (C-ring)) [4]. Regarding their physiological potential, flavonoids have a vast range of bioactivities, namely antioxidant, anti-inflammatory, vasorelaxant, anticoagulant, cardio-protective, anti-obesity and anti-diabetic, chemoprotective, neuroprotective, and antidepressant properties that are progressively being clarified [5]. These beneficial properties are strongly dependent on the polyphenols chemical structure [2].
Flavonols are the most important subgroup of flavonoids. Chemically, these compounds (as other flavonoids) have a characteristic 15-carbon skeleton (C6-C3-C6), two benzene rings constitute its structure (catechol B ring and resorcinol A ring) joined together by a 4-pyrone heterocyclic ring C (Figure 1) [6].
Chemical structure of flavonols. Designed with eMolecules (
Some compounds of this subclass include quercetin, myricetin, kaempferol, galangin, and fisetin [7, 8, 9]. These molecules represent the most ubiquitous and abundant flavonoids in the plant kingdom (dicotyledonous plants, especially flowers and leaves of woody) [10, 11] and occur abundantly in fruits (
The scientific community has widely studied the positive effects of flavonols on human health. These molecules have been reported as important antioxidants due to their abilities to suppress free radical formation, scavenge free radicals, and upregulate or protect antioxidant systems. They also inhibit the enzymes associated with free radical production, reduce lipid peroxidation, and chelate metal ions in reducing free radical generation [10, 11]. In addition to the antioxidant potential, these molecules have shown other target biological activities such as antimicrobial, anti-viral (interruption of virus’s entry and replication cycle) hepatoprotective, nephroprotective (effective for the treatment of chronic kidney disease), anti-inflammatory, vasodilatation effects, and cardiovascular protective effects (preventative role in coronary diseases). They also have been considered as potential anticancer agents [8, 13, 14].
However, despite all the flavonols have a broad spectrum of biological activities, kaempferol, myricetin, and quercetin are the main representatives and have been widely studied due to their health-promoting functions. Both kaempferol and quercetin have unique biological properties as anticarcinogenic, antimicrobial, antidiabetic, anti-viral, anti-allergic, antioxidant, and anti-inflammatory [7, 8, 11].
Flavanols or flavan-3-ols are another flavonoid subclass with a hydroxyl group at position 3 and a fully saturated carbon ring structure (Figure 2) [9].
Chemical structure of flavanol. Designed with eMolecules (
The most common flavan-3-ol monomers are catechin, epicatechin, catechin gallate, epicatechin gallate, gallocatechin, epigallocatechin, gallocatechin gallate and epigallocatechin gallate [2]. These compounds are widely spread in nature and can be found in a wide range of natural matrices as apples, peaches, cocoa powder, nuts, dark chocolate, grapes, berries and beverages (such as red wine, tea, and cider) [9]. Furthermore, they can also be found in certain food plants, such as
Over time, the interest in flavanols has grown, and different studies have reported these compounds’ health benefits. These compounds present several beneficial effects in consumers’ health, acting as antioxidant (scavenging of free radicals, chelation of transition metals, as well as the mediation and inhibition of enzymes), anticarcinogen, cardio-preventive (modulation of vascular homeostasis), anti-microbial, anti-viral, and neuro-protective agents [4, 18]. Besides, dietary intervention studies demonstrated that consuming certain flavanol-containing foods results in improved arterial function, a decrease in blood pressure, positive modulation of hemostasis, and improved insulin sensitivity [15]. In this sense, diets enriched in flavan-3-ol containing foodstuffs may provide beneficial health effects [17].
Flavones are also a subgroup of the flavonoid class based on the backbone of 2-phenylchromen-4-one (2-phenyl-benzopyran-4-one). The molecular formula of the flavone molecule is C15H10O2. It has a three-ring skeleton, C6-C3-C6, and the rings are referred to as A-, C-, and B-rings, respectively (Figure 3). These compounds are also characterized by the presence of three functional groups, including hydroxy, carbonyl, and a conjugated double bond. Consequently, they exhibit characteristic reactions of all three functional groups [19].
Chemical structure of flavones. Designed with eMolecules (
The most abundant types of flavones are luteolin, apigenin and chrysin [20]. These compounds are commonly found in edible vegetables, fruits, nuts, seeds and plant-derived beverages and cereals, which are ingested inadvertently in our daily diet and positively impact consumers’ health without significant side effects [3, 20].
The scientific community has carried out several studies to determine the biological potential of flavones. These molecules have received broad interest for their antioxidant potential [21] and their ability to modulate several enzyme systems involved in many diseases [22]. Also, these compounds have demonstrated to have other biological properties beneficial to health, namely anti-inflammatory activities [23], antibacterial [24], antifungal [25], antiviral [26] and anti-carcinogenic [27]. Furthermore, they also have immunomodulatory effects [28], and they intervene in the reduction of total cholesterol [29]. Recent studies in numerous disease areas (osteoporosis, prostate hyperplasia, endocrinology, and others) have shown that many disorders, specifically in the metabolic area, are multi-factorial and are better treated with combinations of drugs and natural products [19]. However, all these therapeutic actions depend and differ according to the different compounds belonging to the subclass of flavones [30].
Flavones are another subgroup of flavonoids and have a C6-C3-C6 skeleton composed of 3 rings, A-, C-, and B-, respectively, and a chiral carbon at the C-3 position (Figure 4) [31].
Chemical structure of flavanones. Designed with eMolecules (
Formerly, flavanones were considered minor flavonoids, like chalcones, dihydrochalcones, dihydroflavonols and aurones; nevertheless, in the past 15 years, the total number of known flavanones has increased, and they are now considered a major flavonoid class like flavones, isoflavones, flavanols, flavonols and anthocyanidins. Nowadays, in nature, up to 350 flavanone aglycones and 100 flavanone glycosides have been identified [32].
Flavanones are mainly divided into naringenin, hesperetin and eriodicthiol [20]. They are characteristic compounds of citrus fruit, principally lemon, lime, mandarin (tangerine), sweet orange, grapefruit, sour (bitter) orange and tomato [33, 34, 35]. These compounds are also widely distributed in around 42 plant families (
As in the other subgroups of flavonoids, flavanones also exhibit biological properties, which positively affect consumers’ health. Properties associated with flavanone intake include antioxidant [34], anti-inflammatory [36], antitumor, antiviral [37] and antimicrobial activities [38]. Furthermore, flavanones are related to some beneficial effects, such as improved gastrointestinal function [39], decreased blood cholesterol level [38], cardioprotective effect [40] and reduction of inflammatory responses caused by SARS-CoV-2 infection [35].
Some structural variation from flavones are presented in isoflavones, which differs from flavones in the location of the phenyl group’s location at C3 rather than C2 position (Figure 5) [9].
Chemical structure of isoflavones. Designed with eMolecules (
Isoflavones are divided into genistein, daidzein and glycitein [20]. These compounds are naturally-occurring plant compounds and are usually found in legumes from the
Isoflavones have also demonstrated bioactive properties that intervene beneficially in human health. The therapeutic effects of isoflavones are anti-inflammatory, antioxidant [43], anti-obesity [44] and antitumor activities [45]. Besides, several benefits are associated with isoflavones, such as relieving menopausal symptoms [46], hepatoprotective [47], cardiovascular protection [48], therapeutic potential in the control of diabetes [49], osteoporosis prevention and treatment [50], modulatory effect of the intestinal microbiota [51] and studies in rats have reported an improvement in kidney function in obese rats [52].
Anthocyanins belong to the large group of flavonoids, being considered the most revealing water-soluble pigments for extraction from natural matrices [53]. Regarding their chemical characterization, anthocyanins come from a basic structure of 3 rings of the C6-C3-C6 shape, defined as an aglycone portion, called the flavylic cation (Figure 6). When associated with chemical groups in the R positions, it is called anthocyanidin [53, 54].
Chemical structure of anthocyanins. Designed with eMolecules (
The most common types of anthocyanins are cyanidin, delphinidin, pelargonidin, peonidin, malvidin and petunidin [55]. The anthocyanin compounds are present in a composition of a wide range of vegetables (red onion, radish, red cabbage, red lettuce, eggplant, red-skinned potato and purple sweet potato), flowers (red hibiscus, red rose, red pineapple sage, red clover, and pink blossom) and several red fruits, such as: cherries, plums, strawberries, raspberries, blackberries, grapes, and many others [56, 57].
Anthocyanins are involved in many biological activities that positively impact human health. The use of these molecules for medicinal purposes has been long supported by epidemiological evidence. Still, just in recent years, some of the specific, measurable pharmacological properties of isolated anthocyanin pigments have been proven by controlled
The bioactive properties of flavonoids are directly linked to the functions they exert. Flavonoids, present in higher plants’ cells, have a protective role against parasites and other pathogens (participating in allelopathy processes), herbivores, and ultraviolet (UV) radiation [61]. They have a regulatory function like most lipid-soluble vitamins and act as pollinating agents. The varied colors they can have attract pollinators, thus contributing to plant seeds’ dispersion [62]. The following sections display a set of functions attributed to these compounds, seeking to relate their bioactivity to their chemical features and/or possible mechanism of action.
The antioxidant properties of flavonoids have been recognized over the years. Given the wide presence of flavonoids in various fruits, vegetables, legumes, grains and nuts, these compounds represent approximately two-thirds of the phenols consumed in the diet, being the class predominantly described [63, 64]. The mechanisms underlying the antioxidant properties of flavonols include eliminating free radicals and the chelating activity of transition metal ions, being the preventive action and chain-breaking mechanisms responsible for the high bioactivity of flavonoids [65, 66]. In fact, flavonoids can eliminate free radicals and reduce their formation and/or their effects. As expected, the chemical structure plays a key role in the antioxidant activity of flavonoids. That is, due to the reducing capacity of the phenolic hydroxyl groups (presence of hydrogen-/electron-donating substituents), flavonoids can donate hydrogen; thanks to the ability to delocalize the unpaired electron leading to the formation of a stable phenoxyl radical, flavonoids can protect against damage caused by reacting oxygen species (ROS), and flavonoids can chelate transition metals capable of promoting the formation of hydroxyl radicals in reduced forms through the Fenton reaction under abnormal conditions. This property is strongly dependent on the arrangement of hydroxyls and carbonyl group around the molecule [66]. Considering these characteristics that underlie the antioxidant potential of flavonoids, studies carried out over the years have shown that the flavonoids with greater antioxidant activity have the following structure features: (i) a certain hydroxylation pattern, particularly in the ring B, namely 3′,4′-dihydroxyl group (
If the abovementioned features favor the antioxidant potential of flavonoids, on the other hand, the presence of saccharide groups seems to reduce the antioxidant properties of these molecules. Still, some studies showed that
However, the abundant consumption of flavonoids, as polyphenols in general, through the daily diet does not always correspond to obtaining the effects observed
The antimicrobial properties of natural products rich in flavonoids have been reported and recognized since antiquity. Of the best-known products, propolis can be highlighted, whose healing properties have been mentioned for thousands of years and used to treat wounds and ulcers. In fact, propolis’s antimicrobial properties have been attributed to its high content of flavonoids, particularly galangin and pinocembrin [72]. As previously mentioned, flavonoids’ bioactivity is related to their function in nature, namely protecting plants against pathogens. In this way, plant-derived flavonoids have different antibacterial mechanisms of action than conventional drugs, and generally, their bioactivity does not confer resistance. In fact, to the best of our knowledge, no report claims to have observed bacteria developing resistance to plant-based antimicrobials. In this way, antibacterial agents based on natural extracts rich in flavonoids represent an important alternative in developing new antibacterial formulations, both from a clinical perspective, as in any other application such as the food sector [73]. The possible mechanisms of antimicrobial action of flavonoids are briefly: (i) cell envelop synthesis inhibition (
Polyphenols’ prebiotic effects have also been explored, with available reports from pre-clinical and clinical studies. Flavonoids have been the most investigated phenolic compounds in terms of their effects on the composition of the intestinal microbiota and the health benefits of the host [75]. It must be highlighted that the current definition of prebiotic recognizes that, in addition to the stimulation of
In clinical trials, anthocyanins consumed in a wild blueberry drink have been studied, in a dose of 25 g/250 mL of water. The study included 20 healthy male individuals, with a 6-week consumption of the drink. After this period, an increase of
Color is the most important sensory perception that defines consumer expectations about foods’ organoleptic properties [80]. Thus, adding or improving food color has been one of the food industry’s commitments to make products more appealing. Although each coloring agent used by the food industry in the European Union is subjected to a rigorous safety assessment, some problems of intolerance and/or allergies or hyperactivity have been related to its consumption [81], which may justify the consumer’s preference for natural additives to the detriment of the artificial counterparts. In this way, the scientific community has been looking for natural alternatives to the artificial colors widely used in the industry. The major natural pigments obtained from nature include chlorophylls, carotenoids, betalains and flavonoids. Among the main classes of flavonoids used as coloring agents, the flavonols and anthocyanins stand out, obtaining a range of colors between cream, yellow, pink, red, blue and black [82]. There is already a natural coloring agent, based on flavonoids, approved by the regulatory authorities for its use in the food sector, namely anthocyanins (E163). The approved anthocyanin extract is obtained from the natural strains of vegetables and edible fruits, including blackcurrant pomace and grape skin [83]. The pH strongly influences the color of anthocyanins. In acidic conditions, anthocyanins are red, while in basic pH, they appear blue, being purple in solutions with neutral pH. Hence, grapes are one of the best sources of this natural red pigment, since their anthocyanins are largely methylated, leading to an increase in color intensity and higher stability [84, 85]. After consulting the literature, we found that most studies on natural food colors based on flavonoids are strongly focused on anthocyanins. Other classes of flavonoids have been studied as copigments. Given the sensitivity of anthocyanins to various factors, not only pH but also temperature, light, oxygen, among others. Copigments or other co-solutes can be added, even when colorless, since they trigger a hyperchromic effect [82]. Copigmentation may occur by forming (in the presence or absence of metal ions) noncovalent complexes involving an anthocyanin or anthocyanin-derived pigment (
Besides the properties previously described, some other bioactivities have been assigned to flavonoids, such as anti-diabetic, anti-inflammatory or anticancer activities. For instance, a new approach to treat diabetes with enhanced antidiabetic activity from a flavonoid nanoparticulate system has been proposed. This system with new biodegradable releasers would increase the solubility of flavonoids and consequently their bioavailability, preventing flavonoid from first-pass metabolism and intestinal absorption in the form of a flavonoid nanoparticulate system. Flavonoids exert their antidiabetic properties by enhancing insulin secretion via regeneration of pancreatic β-cells, enhancing insulin-mediated glucose uptake by target cells, inhibiting aldose reductase and increasing Ca2+ uptake [88]. Antidiabetic activity of flavonoids depends on the chemical criterion (C-2-C-3 double bond and ketonic group at C-4 position on ring B) which is fundamental for the bioactivity of polyphenols [89]. The antioxidant and anti-inflammatory activity of the flavonol fisetin (7, 3′, 4′-flavon-3-ol) has been evaluated, showing that it could improve the plasma insulin and antioxidant levels in diabetic rats and significantly decrease the levels of blood glucose. Therefore, the authors suggested that fisetin could be considered as an adjunct for the treatment of diabetes [90]. Regarding anthocyanins, in addition to their coloring capacity, other studies suggest that these flavonoids also have bioactivity with a potential impact on human health, namely antioxidant activity, chemopreventive potential, anti-inflammatory and immunomodulatory properties [91]. Some of the bioactivities attributed to flavonoids have been specifically pointed to flavonoid glycosides. For example, the
According to the current and continuously increasing demand for new healthy products for a better lifestyle of the population, an increase in the number of techniques used to extract bioactive compounds has occurred. Choose the best extraction technique for each sample is essential in terms of the quality and quantity of the target molecules obtained, that is, flavonoids. Nowadays, there is many extraction techniques that can be employed. These techniques are selected depending on the characteristics of the raw material, which are, in general, plants, food or liquid samples such as wine, tea or olive oil [94]. Independently of the source, the samples must be homogenized. Hence, the most used methods are grinding, milling, filtration, pulverizing and mechanical stirring. Depending on the raw material, before or after homogenization, a pretreatment could be used to facilitate or improve the homogenization and the extraction process. The pretreatments usually used are freezing (in a freezer or by liquid nitrogen), different drying process and freeze-drying [95]. However, the use of these pretreatments can affect the extract characteristics, limiting the optimization of the extraction process [96, 97, 98]. There is no standard for every source of raw material, so selected pretreatments must be chosen depending on the physical and chemical characteristics of the samples. Moreover, depending on the pretreatment and homogenization method, the sample must be stored in the appropriate conditions or perform the extraction immediately before the homogenization and the pretreatment [99, 100]. The extraction techniques can be divided into two groups, conventional and novel approaches.
Conventional extraction techniques are characterized using conventional solvents, with or without heat and usually under agitation. In a standard conventional extraction, the sample is homogenized and submerged in a solvent or a mix of solvents. Using this extraction methodology, flavonoids are obtained through the diffusion and mass-transfer phenomena [101, 102]. The most used methods are maceration and Soxhlet. Nevertheless, other techniques like percolation, hydro-distillation, boiling, reflux and soaking can be used [103, 104]. The advantages of using these techniques are their simplicity and low cost, so they are preferred by companies [102]. On the other hand, these methods have several disadvantages: high volumes of solvent, low extraction yields and long times. Furthermore, due to the sensitivity of flavonoids to high temperature, in extraction assisted by heat, the compounds’ biological properties could be affected [105, 106].
For its simplicity and low cost, extraction by Soxhlet is the most used [106]. The main advantages of this method are three. The first one is that through repeated cycles, the sample is in contact with fresh solvent almost all the time, helping the displacement of the mass transfer equilibrium. In the second place, after the extraction, it is not necessary to filter the sample. Lastly, the amount of sample extracted can be improved easily by simultaneous parallel extraction, which needs very little investment. However, Soxhlet extraction has some disadvantages concerning other conventional extractions. The main disadvantages of this technique are its duration (
Significant differences in the extraction yields between different conventional extractions can be observed. There are also differences between the number of compounds obtained and their bioactivity within the same method. These variations are caused by the parameters directly implicated in the extraction process like temperature, time, number of extractions (cycles), the ratio of solvent to raw material or type of solvent [108]. Table 1 shows diverse examples of extractions carried out under different conditions and different methods to compare the conventional extraction methods.
Type (cycles) | Substrate | Solvent (%) | Temperature (°C) | Time (min) | Yields | References |
---|---|---|---|---|---|---|
Batch | Ethanol | 50 | 50 | 2.04 mg/g dw | [109] | |
HRE | Eth:W (80:20) | — | 150 | 1.16% (Flavonoid extraction yield) | [110] | |
Mac | Eth:W (70:20) | 25 | 2880 | 5.6 mg/g dw | [111] | |
Reflux | Eth:W (70:20) | — | 150 | 6.8 mg/g dw | [111] | |
SAE | Eth:W (52:48) | 30 | 30 | 12.77 ± 0.65 mg/g dw | [112] | |
SBE | Ethanol | 50 | 450 | 48.15 mg RE/g | [109] | |
Soxhlet | Ethanol | 60 | 460 | 67.85 mg RE/g | [109] | |
Soxhlet | Eth:W (80:20) | — | 300 | 1.48% (Flavonoid extraction yield) | [110] | |
Soxhlet | Ethanol | 90 | 180 | 10.67 ± 0.27 mg/g dw | [112] | |
Soxhlet | Eth:W (70:30) | — | 300 | 7.0 mg/g dw | [111] | |
Soxhlet | Methanol | — | 300 | 0.40 ± 0.03 mg QE/g dw | [113] | |
Soxhlet | Ethyl acetate | 77 | 480 | 11.4 ± 0.6 (wt% extract) | [114] | |
Soxhlet | Metanhol | 65 | 480 | 25.8 ± 0.7 (wt% extract) | [114] | |
Soxhlet | N-hexane | 69 | 480 | 6.7 ± 0.2 (wt% extract) | [114] | |
Soxhlet | Ethanol | 78 | 480 | 25.8 ± 0.9 (wt% extract) | [114] | |
Soxhlet | Methanol | 40 | 360 | 267.33 ± 3.12 mg/g dw | [115] | |
Soxhlet | Ethanol | 360 | 218 ± 4.24 mg/ dw | [115] | ||
Soxhlet | Petroleum ether | 360 | 30.47 ± 2.34 mg/g dw | [115] | ||
Soxhlet | Eth:W (70:30) | 360 | 257 ± 3.47 mg/g dw | [115] | ||
Soxhlet | Methanol | — | 2880 | 11.5 mg/g dw | [116] | |
ASE | Met:W (80:20) | 80 | 10 | 3.9 mg/g dw | [117] | |
ASE (3) | Eth:W (40:60) | 40 | 30 | 49.22 mg GAE/g dw | [118] | |
ASE (3) | Eth:W (40:60) | 80 | 30 | 41.46 mg GAE/g dw | [118] | |
ASE (3) | Ethanol | 40 | 30 | 110.89 mg GAE/g dw | [118] | |
ASE (3) | Ethanol | 80 | 30 | 101.61 mg GAE/g dw | [118] | |
ASE (1) | Eth:W (70:30) | 40 | 10 | 72.60 mg GAE/g dw | [118] | |
ASE (1) | Eth:W (70:30) | 80 | 10 | 79.43 mg GAE/g dw | [118] | |
ASE (5) | Eth:W (70:30) | 40 | 50 | 65.78 mg GAE/g dw | [118] | |
ASE (5) | Eth:W (70:30) | 80 | 50 | 84.53 mg GAE/g dw | [118] | |
ASE (1) | Eth:W (40:60) | 60 | 10 | 58.54 mg GAE/g dw | [118] | |
ASE (1) | Ethanol | 60 | 10 | 85.83 mg GAE/g dw | [118] | |
ASE (5) | Eth:W (40:60) | 60 | 50 | 60.21 mg GAE/g dw | [118] | |
ASE (5) | Ethanol | 60 | 50 | 80.31 mg GAE/g dw | [118] | |
ASE (3) | Eth:W (70:30) | 60 | 30 | 60.57 mg GAE/g dw | [118] | |
ASE (3) | Eth:W (70:30) | 60 | 30 | 63.70 mg GAE/g dw | [118] | |
ASE (3) | Eth:W (70:30) | 60 | 30 | 60.89 mg GAE/g dw | [118] | |
ASE | N-hexane | 200 | 13 | 839.2 ± 232.3 QE/100 mg dw | [119] | |
ASE (2) | Water | 100 | 20 | 4.83 ± 1.52 mg/GAE g dw | [120] | |
ASE (2) | Methanol | 100 | 20 | 15.3 ± 0.6 mg/GAE g dw | [120] | |
ASE (2) | Met:W (50:50) | 100 | 20 | 4.28 ± 0.24 mg/GAE g dw | [120] | |
ASE (2) | Met:AA (99.5:0.5) | 100 | 20 | 11.58 ± 0.5 mg/GAE g dw | [120] | |
ASE (2) | Acetone | 100 | 20 | 13.8 ± 0.6 mg/GAE g dw | [120] | |
ASE (2) | A:W (50:50) | 100 | 20 | 13.2 ± 0.3 mg/GAE g dw | [120] | |
ASE (2) | A:AA (99.5:0.5) | 100 | 20 | 13.5 ± 0.8 mg/GAE g dw | [120] | |
ASE (2) | Met:W:AA (50:49.5:0.5) | 100 | 20 | 15.1 ± 0.1 mg/GAE g dw | [120] | |
ASE (2) | A:W:AA (50:49.5:0.5) | 100 | 20 | 14 ± 1 mg/GAE g dw | [120] | |
Mac | Ethanol | 60 | 120 | 70.13 ± 4.43 mg QE/g dw | [121] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.32 ± 0.05 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.18 ± 0.01 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.1 ± 0.01 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.1 ± 0.01 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.94 ± 0.7 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.44 ± 0.07 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.045 ± 0.002 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.51 ± 0.04 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.08 ± 0.01 mg GAE/g fw | [122] | |
Mac (2) | A:W (70:30) Methanol | 4 | 1440 | 0.32 ± 0.02 mg GAE/g fw | [122] |
Summary of studies of extraction of flavonoids from different sources.
SBE: sequential batch extraction; HRE: heat reflux extraction; SAE: stirring-assisted extraction; QE: quercetin equivalent; RE: rutin equivalent; Mac: maceration; AA: acetic acid; A: acetone; MA: maceration with agitation; GAE: gallic acid equivalent; ASE: accelerated solvent extraction; dw: dry weight; and fw: fresh weight.
Non-conventional extraction techniques put their effort in concentrate the energy to extract the bioactive compounds in a more efficient and/or selective way than in conventional extractions. Nowadays, methods that employ microwaves, ultrasounds, high pressure, supercritical fluids or digestive enzymes can extract more compounds of interest at a lower cost. Moreover, these novel techniques decrease the extraction time, increase the compounds’ selectivity and reduce the amount of solvent per extraction. In addition to solvent reduction, some of these techniques allow the use of solvents less harmful to the environment and human health. Therefore, some of these techniques are green methods that can be used with green solvents. This fact has prompted companies to optimize these techniques for subsequent implementation on an industrial scale [101, 123].
The parameter most characteristic of ultrasound is the frequency. The frequency of ultrasound is between 20 kHz and 10 MHz, while the frequency of sound is between 16 Hz and 20 kHz. The ultrasound-assisted extraction (UAE) uses one of the two types of ultrasound, power ultrasound (low frequency and high intensity), to extract different compounds from a wide variety of sources [124]. The mechanism of action of UAE consists in the formation of cavitation bubbles in the medium or solvent used. The appearance of voids by the compression and rarefaction cycle, which subjects the liquid to points above its critical molecular distance, creates cavitation bubbles in the medium. The compression and rarefaction cycle produce the enlargement of the bubbles until the bubbles collapse. This collapsing liberates a considerable amount of energy and subject the medium to high temperatures (4726.85°C) and pressures (2000 atm) now of the collapse. This extreme condition produces microjets that can break solid surfaces like vegetable cells favoring intracellular compounds’ extraction. Moreover, microjets also benefit the solvent-substrate interaction by reducing the particle size [124, 125, 126].
This method has been used in the food and pharmaceutical industries for several purposes [125]. The yield of the flavonoid extraction depends on diverse parameters: frequency, solvent, solid-solvent ratio. Table 2 shows numerous studies about the optimization of flavonoid extraction from different raw materials. Although UAE is considered a green extraction technique for their reduction of energy and time consuming, the use of green solvents with UAE is currently a new trend. In the case of flavonoids and other phenolic compounds, deep eutectic solvents (DES) are becoming a viable alternative to traditional polluting solvents (Table 2) [127, 128, 129, 130, 131]. The use of UAE has numerous benefits compared with other conventional and novel techniques. UAE obtains higher yields and productivity with lower extraction times and solvent consumption than the conventional techniques. Moreover, it is more ecofriendly and a wider variety of solvents can be used. Furthermore, the extraction can be carried out at low temperatures reducing the risk of thermal degradation of flavonoids. Nevertheless, UAE has some drawbacks. Before the extraction, a filtration step is required, and the unstable compounds are not suitable for this method [132].
Type (cycles) | Substrate | Solvent | Temperature (°C) | Time (min) | Yield | References |
---|---|---|---|---|---|---|
UAE | Eth:W (65:35) | 40 | 29 | 23.60 ± 0.31 mg QE/g dw | [72] | |
UADESE | CC:1,2-Propanediol (33:67) | Rt | 90 | 4.9 mg/g fw | [35] | |
UADESE | CC:Glycerol (33:67) | Rt | 90 | 2.9 mg/g fw | [35] | |
UADESE | CC:EG (33:67) | Rt | 90 | 8.7 mg/g fw | [35] | |
UADESE | CC:Malic a. (50:50) | Rt | 90 | 11.1 mg/g fw | [35] | |
UADESE | CC:Malonic a. (50:50) | Rt | 90 | 8 mg/g fw | [35] | |
UADESE | CC:p-Ta (33:67) | Rt | 90 | 88.9 mg/g fw | [35] | |
UADESE | CC:La. (33:67) | Rt | 90 | 16.5 mg/g fw | [35] | |
UADESE | CC: Oxalic a. (33:67) | Rt | 90 | 11 mg/g fw | [35] | |
UADESE | CC:Resorcinol (25:75) | Rt | 90 | 6.5 mg/g fw | [35] | |
UADESE | CC:Xylitol (50:50) | Rt | 90 | 3.2 mg/g fw | [35] | |
UADESE | CC: Urea (33:67) | Rt | 90 | 5.5 mg/g fw | [35] | |
UADESE | Water | Rt | 90 | 3.6 mg/g fw | [35] | |
UADESE | Methanol | Rt | 90 | 3.2 mg/g fw | [35] | |
UADESE | Ethanol | Rt | 90 | 4.2 mg/g fw | [35] | |
UAE | Water | 40 | 30 | 19.595 ± 2.114 mg GAE/g dw | [73] | |
UAE | Eth:W (72:28) | 65 | 37 | 16.45 ± 0.2 mg/g dw | [74] | |
UAE | Eth:W (60:40) | 64 | 47 | 16.4 mg/g dw | [75] | |
UAE | Eth:W (41:59) | 79 | 30.5 | 36.2 mg/g dw | [76] | |
HPAE | Eth:Water (50:50) | 25 | 3 | 5.8 ± 0.1 mg QE/g dw | [77] | |
UAE | Eth:Water (50:50) | 25 | 20 | 5.9 ± 0.2 mg QE g dw | [77] | |
HHPE | Hexane:W (60:40) | 20 | 10 | 21.5 ± 0.1 mg QE g dw | [78] | |
HPAE | Methanol | 150 | 240 | 15.5 mg/g dw | [79] | |
HPAE | Eth:W (75:25) | 80 | 120 | 200 ± 8.63 mg/g dw | [80] | |
MAE | Eth:W (80:20) | 50 | 1 | 77.26 mg RE/g dw | [16] | |
MAE | Eth:W (80:20) | 80 | 4 | 37.18 mg QE/g dw | [81] | |
MAE | Ethanol | Rt | 4 | 135 ± 3 mg QE/g dw | [82] | |
MAE | Eth:E (60:20) | 65 | 25 | 97.19 mg/g dw | [83] | |
MAE | Eth:W (90:10) | 110 | 25 | 1.19 ± 0.04 mg dw | [84] | |
SFE (CO2) | Eth:W (90:10) | 52.5 | 113 | 29.011 mg/g dw | [85] | |
SFE (CO2) | Eth:W (95:05) | 65 | 270 | 18.92 mg QE g dw | [86] | |
SFE (CO2) | Eth:W (20:80) | 51 | 120 | 4.24 mg/d dw | [87] | |
SFE (CO2) | Ethanol | 50 | 90 | 16.95 ± 0.43 mg/g dw | [88] | |
SFE (CO2) | Eth:W (10:80) | Rt | 30 | 72.18 ± 1.13 mg/g dw | [89] | |
SFE (CO2) | Eth:W (96:4) | 50 | 70 | 58 mg RuE/g dw | [90] |
Parameters that affect novel extraction techniques of flavonoids from different sources.
UAE: ultrasound-assisted extraction; CC: choline chloride; EG: Ethylene glicol; a.: acid; p-Ta: p-toluenesulfonic acid; La.: levulinic acid; UADESE: ultrasound-assist deep eutectic solvent extraction; HPAE: high pressure assisted extraction; HHPE: high hydrostatic, pressure extraction; Rt: room temperature; SFC-CO2: supercritical CO2 fluid extraction; dw: dry weight; and fw: fresh weight.
Le Chatelier’s principle states that if a system in equilibrium is perturbed, it restores the balance changing other parameters [133]. Therefore, if a system (solvent – raw material) is subjected to an increase in pressure, it will suffer a decrease in volume that will result in a more efficient extraction [134]. The volume changes produce variations in the cellular membrane and other big molecules that can cause the cell membrane and organelles’ rupture, thus facilitating the transfer of bioactive compounds to the solvent [135]. The process of high pressure-assisted extraction (HPAE) has three stages. Firstly, the sample is mixed with the solvent in the pressure vessel at ambient pressure. The sample is subjected to a sudden pressure change up to 100–1000 MPa. At this point, the plant cell wall, the cell membrane, or any other barriers are subjected to a large differential pressure between the inside and outside of the barrier producing deformations and ruptures. The solvent penetrates the barriers through the ruptures and deformations, accessing the cell interior. Once the solvent is in the cell interior, the mass transfer of soluble compounds is favored. Moreover, the differential pressure could exceed the cell’s deformation limit (cell wall and/or membrane). This will collapse, resulting in the liberation of all the compounds which will flow to the outside and dissolved in the solvent. Finally, all pressure is quickly released to atmospheric pressure, which produces cell expansion deforming the cell wall and membrane again [136]. The parameters that are usually considered at the time of the extraction are: temperature, pressure, type of solvent and concentration, holding pressure time, the ratio of solvent to raw material and the number of cycles [137]. Table 2 shows how some of these parameters affect the extraction of flavonoids.
Regarding their advantages, the use of HPAE has demonstrated that the extraction could be performed at low temperatures without damaging heat-sensitive compounds or other compounds. Moreover, HPAE is considered an environment-friendly process, so it is a suitable alternative [138]. Other advantages are: the possible combination of more than one solvent to extract more than one type of compound, short periods of extraction, low use of energy or high cell penetration, resulting in higher mass transfer and extraction performance [137]. Nevertheless, in most cases, this technique uses some contaminant solvents, and after the extraction process, a filtration step is mandatory [139].
The microwave-assisted extraction (MAE) consists of applying electromagnetic waves to produce changes in the cell wall and membrane. Microwaves have a frequency between 300 MHz and 300 GHz and belong to the electromagnetic field [140]. The MAE process’s main advantage is the synergetic combination of heat and mass gradients flowing in the same direction [141]. The electromagnetic waves interact with the polar components inside the cells producing heat through ionic conduction and dipole rotation only in the compounds with an adequate dielectric constant [142]. Depending on the interaction between the compounds and the microwaves the compounds can be classified into three categories: opaque, transparent and absorbing materials. Microwaves heat only absorbing materials by the absorption of the energy of the electromagnetic waves. The mass transfer of flavonoids is produced because of the capacity to heat the cell’s intracellular volume, causing an increase of the intracellular pressure producing the collapse of the cell wall and membrane. Then, the compounds can flow out of the cell and the gradient of heat flows [143].
The yield of the flavonoid extraction will depend on the raw material and selected parameters, such as temperature and time of the extraction, composition of the solvent, solvent-to-feed ratio, microwave power, the water content of the matrix and the number of cycles for optimal extraction of flavonoids [141]. Table 2 shows the yields of some flavonoid extractions by MAE and how some parameters affect flavonoid recovery. In comparison with conventional extractions, MAE has demonstrated better time of the extraction, yield, selectivity and quality of the flavonoid extracted. Moreover, the amount of solvent required is lower than in other techniques [144]. Nevertheless, the solvent and target compounds must fulfill some characteristics, compounds must be polar, and solvent must be not too viscous and absorb microwave energy. However, thermally labile compounds cannot be extracted with this method and after the extraction, extract filtration is required [132].
A supercritical fluid (SF) is a homogeneous liquid in which the liquid and gas state’s demarcation surface disappears. This homogeneous state is caused by exceeding the critical point of temperature and pressure [145]. The diffusivity and density of a SF are between what is expected in a gas and a liquid. As the same as gases, SFs experience a change of density when temperature or pressure are altered, which can produce variations in the density affecting the solvating power [146]. Therefore, these phenomena can improve the solubility of the compounds in the SFs. Supercritical fluid extraction (SFE) is a complex process widely studied along the literature [145, 146, 147, 148]. Nowadays, CO2 is the most SF used for SFE. CO2 has some very advantageous characteristics for SFE, low critical temperature (32°C) and pressure (704 MPa). Moreover, CO2 in low concentrations is non-explosive, non-toxic, non-inflammable and is easy to purchase at a low price with a high degree of purity. Besides, CO2 has more than double the diffusivity of other fluids with lower surface tension and viscosity. Nevertheless, CO2 is more suitable for nonpolar compounds than for polar compounds [149, 150].
The main limiting parameters are temperature, pressure and time of extraction [151]. Table 2 shows how these parameters affect the yield of flavonoid SFE. Moreover, other factors like flow rate, modifiers and fractionation can affect the yield of the extraction [146]. The main advantages of SFE are rapidity, low amount of solvent, high selectivity and yield. On the other hand, SFE is a complex process with many parameters to optimize. High investment is needed, and specific alterations such as adding modifiers when extracting polar compounds are necessary [132].
The enzyme assisted extraction (EAE) consists of the disruption of the plant cell wall and membrane by the enzymatic digestion of the polysaccharides that conform these two barriers. The plant cell wall comprises a complex structural mixture of polysaccharides, such as hemicellulose, cellulose and pectin, together with other molecules such as structural proteins and lignin [152]. Pectin is composed of a chine of α-D-galacturonate and L-rhamnose units linked by glycosidic bonds in α-1,4 or 1,2 that create the structure called pectic elbows [153]. For the hydrolysis of pectin, several types of pectinases (protopectinases, esterases, depolymerases) are used in the juice industry but also in the extraction of polyphenols [154, 155]. Cellulose is a polymer consisting of glucose β-1,4, which linked to other molecules, gives protection and stability to the cell wall [156]. Cellulases catalyze the breakdown of cellulose. Although its mechanism of action is not fully established, the most accepted theory affirms that three different types of proteins work synergistically during cellulose catalysis. Endonucleases act first, followed by the cellobiohydrolases and, finally, exoglucanases, resulting in free glucose molecules [157]. Hemicellulose is a heterogeneous mixture of carbohydrates homologous to cellulose, such as xyloglucans and mannans. Hemicellulases are a big group of enzymes with several enzymatic activities to break down all hemicellulose forms [158]. Lignins refer to aromatic polymers resulting from the oxidative combinatorial coupling of 4-hydroxyphenylpropanoids [159]. Nowadays, enzymes kits for digestion of the cell wall are prepared to carry out the functions previously mentioned and thus liberate flavonoids in the cell interior and improve the solvent’s mass transfer [160]. Besides, EAE could be used alone or combined with other techniques (MAE, UAE, SFE or HPAE) [161].
Parameters like temperature and pH are essential when working with enzymes. Moreover, selected enzymes, mode of action and time are other parameters to consider [161]. Table 3 shows several studies of the extraction of flavonoids from different sources and the yield variation depending on some parameters that affect extraction efficiency. In terms of environmental pollution, this method is one of the most environmentally friendly. Besides, EAE could be performed at low temperature, valid for many different raw materials, and different enzymes can be selected depending on the targets of the extraction [160, 162, 163, 164, 165].
Substrate | Enzymes | Solvent | Temperature (°C) | Time (min) | Compound | Yield | References |
---|---|---|---|---|---|---|---|
Cellulase and pectinase | Eth:W (50:50) | 60 | 1800 | Flavonoids | 28.3 mg/g dw | [91] | |
Grape skins | Lallzyme EX-V (commercial) cellulase and hemicellulose, polygalacturonase, pectin lyase, pectin methylesterase | Water | 45 | 179 | Flavonoid glycoside and flavan-3-oil | 4 mg/g dw | [92] |
Grape skins | Lallzyme HC (commercial) cellulase, polygalacturonase, pectin lyase, pectin methylesterase | Water | 31 | 162 | Flavonoid glycoside and flavan-3-oil | 3.7 mg/g dw | [92] |
Grape skins | Endozym Rouge (commercial) cellulase and hemicellulose, polygalacturonase, pectin lyase, pectin methylesterase | Water | 39 | 85 | Flavonoid glycoside and flavan-3-oil | 3.7 mg/g dw | [92] |
Grape skins | Endozym Contact Pelliculaire (commercial) cellulase and hemicellulose, polygalacturonase, pectin lyase, pectin methylesterase | Water | 36 | 128 | Flavonoid glycoside and flavan-3-oil | 3.7 mg/g dw | [92] |
Cellulase, beta-glucosidase, pectinase | Water | 32.5 | 1080 | Luteolin and apigenin | 0.4 mg/g dw | [93] | |
Cellulase, pectinase | Water | 32 | 1080 | Flavonoids | 4.96 ± 0.29 mg/g dw | [94] | |
Cellulose ® MX, Kleerase ® AFP | Water | 50 | 180 | Phenolics | 1.62 mg GAE/g fw | [95] |
Parameters that affect enzyme assisted extraction (EAE) of flavonoids.
SBE: sequential batch extraction; HRE: heat reflux extraction; SAE: stirring-assisted extraction; QE: quercetin equivalent; RE: rutin equivalent; dw: dry weight; and fw: fresh weight.
Bioavailability refers to the concentration of a molecule or related like-molecules that become absorbed and available for exerting their biological activity in the site of drug action of the target tissue, organ or system [166]. The term bioavailability is strongly related to the concept of bioaccessibility and to bioactivity. Bioaccessibility refers to the number of compounds that, after digestion, becomes available and absorbable through the intestinal epithelium. This definition is linked to bioactivity, which involves the physiological effects that biomolecules trigger in the organism and includes their transport through systemic circulation to the target receptor and their interaction with other biomolecules [167].
The bioavailability of polyphenolic compounds has been described to be poor since they hardly reach bioaccessibility rates higher than 30–50% [167]. Among the parameters involved in this low bioavailability, there are several physicochemical properties of flavonoids which include their chemical structure, polymerization degree, solubility, variability of attached saccharides or potential interactions they established with other compounds, or flavonoids stability, both during storage and along the digestion process [168]. Different approaches have been developed to enhance the accessibility to the final number of flavonoids or to blur their metabolism through digestion and improve and extend their chemical stability. These intend to maximize the bioavailability of flavonoids. To increase the available concentration of flavonoids in food, different treatments have been applied to food matrixes. The main purpose is to alter the matrix’s structural organization in which biomolecules are embedded so they can get easily released. Both heating and freezing approaches have been tested and demonstrated to positively affect the bioaccessibility of polyphenols [167]. Nevertheless, other techniques requiring more technological development have demonstrated a better performance to improve flavonoids bioaccessibility (Figure 7). In fact, the pharmaceutical industry has established alternative approaches to improve the oral bioavailability of flavonoids with clinical applications. Some of the most utilized strategies are the use of absorption enhancers (nonionic surfactants, myo-inositol hexaphosphate, chitosan or pectin), the induction of structural transformations which include the introduction of functional groups with higher polarity (sulfuric acids, amino acids, carbamoyls, glycosides, etc.), or the complexation with a carrier (such as cyclodextrins, phospholipids or polymeric carriers) [169].
Strategies to enhance flavonoids bioavailability. Nanosuspension, nanoencapsulation or nanoemulsions have been proved as successful approaches to improve flavonoids solubility and enhance their bioavailability, bioaccesibility and, bioactivity.
Among these approaches, nanosuspension, in which pure drug particles are combined with stabilizers, has been demonstrated as a promising strategy to enhance the bioavailability of flavonoids. This system facilitates the delivery of flavonoids using particles in the nanometers range, which allows reaching a higher concentration quickly by increasing solubility and dissolution rates. For instance, in a recently published work in which different nanosuspension formulae were applied, the solubility of myricetin was increased from 43 to nearly 75 times. This increment was accompanied by an improved bioavailability in the relative range of 161–357% [169]. Another flavonol, quercetin, was also submitted to nanosuspension. This strategy improved its saturation solubility about eleven times which also provided a much better bioaccessibility. The bioaccesibility increased slowly, reaching its maximum peak between 2 and 3 h, while the pure molecule reached this maximum at 1.5–2 h. The amount of quercetin released from the nanosuspension was higher than the pure, duplicating its bioaccessibility even at the last measured times [170]. The bioactivity of the orally administrated flavanone, naringenin, was also tested using rats. It was shown that the nanosuspension of naringenin was nearly 4 times higher when compared against the control [171].
A common methodology applied in both food and pharmacological industries for increasing flavonoids bioavailability and bioaccesibility, which ultimately enhances their potential bioactivity, relies on their encapsulation [169, 172]. Different techniques, with diverse complexity degrees, permit the encapsulation of a considerable variability of core ingredients using different shell materials for obtaining capsules with various physical properties. Some of the most used encapsulation methods include spray or freeze-drying, spray chilling and cooling, coacervation, fluidized bed coating, liposome entrapment, rotational suspension separation, extrusion and inclusion complexation, (micro)emulsions, etc. [173]. The main aim of the encapsulation process is to prevent biological and physicochemical degradation of bioactive ingredients. Encapsulation permits to extend the chemical stability of the target molecules and thus their bioactivities. Besides, encapsulation may also allow the controlled release of the compounds delivered using concentrations. Scientific literature provides several examples of flavonoids that have been encapsulated. Among the benefits of encapsulation, bioaccesibility and bioavailability are two parameters that can be improved using this approach. Besides, encapsulation permits to embed flavonoids in the most appropriate matrices to reinforce their stability [172]. The flavonoid subclass of anthocyanins has been extensively used to evaluate the performance of different encapsulation techniques and materials. For instance, anthocyanins from grape peels have been submitted to encapsulation by emulsification/internal gelation using both spray and freeze-drying techniques. The former provided smaller microcapsules (0.6 μm) with higher encapsulation efficiency and better microcapsule and anthocyanins stability, which extended their release in simulated gastrointestinal digestion and improved their bioaccessibility [174]. Two major anthocyanins were identified in extracts from
Another technique tested for enhancing the bioavailability of flavonoids is based on their emulsion. This emulsion can be created by utilizing emulsifying agents or mixtures of oil-(co)surfactants-water, which permit the self-emulsion with a simple process, agitation. In fact, different alternatives of this approach have been proved successful for different kinds of flavonoids. Anthocyanins from blueberry fruits were micro-emulsified and their bioavailability and bioactivity were evaluated against the control (without vehicle). Non-purified and purified anthocyanins, especially malvidin-3-
Therefore, very different techniques have been proved to improve the poor solubility of flavonoids and to enhance their bioavailability, bioaccesibility and, hence, their bioactivity. Among these techniques, the most successful ones are based on the application of nanosuspensions, encapsulations or emulsions of the flavonoids.
Currently, consumers are increasingly aware of their healthier food choices, associating them with their health and well-being. In this way, there is a global demand on the part of the food industry to develop innovative natural products and health promoters that contain bioactive components [186].
Different bioactive ingredients, namely flavonoids, have been studied to adapt organoleptic, sensory and conservation properties. They have also been explored as functional ingredients with bioactive properties, such as antioxidant, anti-inflammatory and immunomodulatory referred to earlier in this manuscript [187, 188, 189]. Thus, bioactive compounds are considered valuable options to be explored in the design of innovative food formulations with health benefits.
Different flavonoids have been studied, and their bioactive properties have been proven by several authors, which has arisen the high interest of the food industry in their application in functional foods. Foods and beverages such as dairy products, bakery and confectionery products, meat products, juices and energy drinks, snacks, pasta, gums and sweets are some of the products explored the most in the addition of bioactive compounds [190].
In a recent study, the stability of anthocyanins from grape residues was evaluated when applied as a food coloring in carbonated water and proved that the degradation of the incorporated anthocyanins followed the kinetic behavior during storage, when exposed to light or dark [191]. The anthocyanin malvidin-3-glycoside showed the greatest stability when added to the water. Additionally, it was found that the light had adverse effects on the color of the carbonated water. Bakery and pastry products, recognized for providing consumers of all ages with pleasure and fun, have been explored exponentially in an attempt to find functional natural ingredients and/or colors with potential for application in a highly competitive area [192]. A recent study intended to explore the bioaccesibility and bioavailability of phenolic compounds (namely flavonoids) obtained from green tea in wheat bread. The results showed an increase in the nutraceutical potential and the protection of lipids against oxidation. Also,
Dairy products have been extensively tested and explored due to the industry’s high interest to supplement functional ingredients [195]. Aqueous extracts of
Some fruits have also been explored as natural ingredients. In a recent study, extracts from
However, incorporating these compounds in this type of food product has represented a challenge about the quality of the final product and the stability of bioactive compounds. The high-water content and low pH value of yogurt as well as the low solubility of polyphenols have represented a great challenge for the use of herbal extracts, especially hydrophobic extracts [200]. The use of bioactive compounds as natural ingredients in food products has been characterized in several studies as limited due to their stability and bioavailability. Storage conditions, thermal and non-thermal processes and extraction treatments are some of the parameters identified as responsible for affecting these compounds’ effectiveness [201, 202]. Some bioactive compounds are susceptible to environmental factors, namely pH, temperature, oxygen, enzymes, light, metal ions, sulfur dioxide and ascorbic acid [203]. The molecular interactions between bioactive compounds with other food ingredients can also affect some properties of these compounds, such as bioavailability, bioactivity and organoleptic properties [204]. After oral consumption, the chemical structure and bioactivities of the components are altered in intestinal metabolism. Thus, it is necessary to ensure that the bioactive compounds in the gastrointestinal tract are stable and allow controlled release at target points [205].
This type of limitations has been a concern for the food industry since it can hamper its industrial application. For example, quercetin is a flavonol recognized for its anti-diabetic properties; however, its low solubility and aqueous permeability limit its application. Anthocyanins, which are very attractive due to their ability to provide color and potential health benefits, have also represented a major industrial challenge in controlling their deterioration and increasing their bioavailability in food systems [206, 207].
For this reason, different microencapsulation and delivery systems have been explored to guarantee the production of functional foods with acceptable organoleptic characteristics and the controlled release of flavonoids, thus preventing interactions with other food components, and overcoming problems encountered during food processing and gastrointestinal transit [208, 209]. Some examples will be mentioned as follows. A blueberry-derived mixture of anthocyanins was encapsulated into chitosan nanoparticles, and its stability in a drink was evaluated. The results suggested that the chitosan nanoparticles delayed the anthocyanin degradation in the simulated gastrointestinal fluid and increased the anthocyanin storage stability in the drink [201]. In other work, an encapsulated polyphenolic extract (rich in anthocyanins) from Artemide black rice obtained through the atomization process with maltodextrins and gum arabic (50:50, w/w) was incorporated into biscuits. The results showed that the encapsulated ingredient emerged as the most stable during storage and cooking and with the most significant antioxidant capacity than the control biscuit [210].
Also,
The exploitation of natural ingredients with antioxidant and antimicrobial properties in combination with natural polymers has also been ceased by the scientific community in the development of edible films that allow to reduce the dependence on synthetic polymers and offer viable solutions for industrial application [214]. Polyamide, polyethylene terephthalate, ethylene vinyl alcohol, polyvinylidene chloride, polypropylene and polyethylene are some of the most widely used polymer materials in the food industry for food preservation. However, some authors report that polymers in direct contact with food allow the migration of the additives and other components to food, causing some adverse effects for consumers [215]. In this sense, studies on plastics and plasticizers and non-toxic bio-based food coatings to replace their synthetic counterparts have been increasing [216]. These coatings make it possible to coordinate natural polymers with bioactive ingredients from plant extracts with preservative and antimicrobial properties that improve the organoleptic and functional properties of food [217].
Although many bioactive compounds are currently tested in different food matrices to improve their organoleptic properties, to fortify and functionalize these same products, it is considered that the protection of such functional ingredients in the food matrix during processing, storage and passage the gastrointestinal tract has been little explored. Several flavonoids have been extensively studied and have shown to be highly promising bioactive compounds, capable of improving the physical-chemical, sensory and health properties of food products. However, studies on the effectiveness and interactions of these bioactive compounds for the development of new innovative products are still scarce and there are some gaps between digestion, metabolism and bioactive substance delivery approaches across biological barriers that must be explored. This type of studies’ transition to a commercial scale is an essential future step in innovation to provide more practical information that can be transposed to industry. Thus, and to meet consumers preferences and requirements, there is a great need for new and more complete
The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for financial support through national funds FCT/MCTES to CIMO (UIDB/00690/2020); and L. Baros thanks the national funding by FCT, P.I., through the institutional scientific employment program-contract for her contract. The research leading to these results was supported by MICINN supporting the Ramón&Cajal grant for M.A. Prieto (RYC-2017-22891), by Xunta de Galicia and University of Vigo supporting the post-doctoral grant for M. Fraga-Corral (ED481B-2019/096), by EcoChestnut Project (Erasmus+ KA202) that supports the work of Bernabé Núñez-Estévez and M. Carpena; by IberoAmerican Program on Science and Technology (CYTED – AQUACIBUS, P317RT0003) and by the Bio Based Industries Joint Undertaking (JU) un-der grant agreement No 888003 UP4HEALTH Project (H2020-BBI-JTI-2019), the JU receives support from the European Union’s Horizon 2020 research and innovation pro-gram and the Bio Based Industries Consortium.
The authors declare no conflict of interest.
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It has played a vital role in human evolution and is an imperative constituent of a well-balanced diet. It is a good source of proteins, zinc, iron, selenium, and phosphorus followed by vitamin A and B-complex vitamins. Average value of meat protein is about 23% that varies from higher to lower value according to the type of meat source. Meat fat and its fatty acid profile is point to worry, with respect to its consumption, but its moderate usage is always advised by doctors and nutritionists, in order to lead a healthy life. Fat content of animal carcasses ranges between 8 and 20%. Quality traits of meat along with its nutritional composition become dependent upon animal breed type, feeding source (grains, pasture and grass), genetics of animal and post mortem techniques. This chapter will mainly focus on the variant aspects of nutritional constituents of meat including proteins and essential amino acids, fats and fatty acid profile, carbohydrates, vitamins and minerals along with their health benefits to human health.",book:{id:"6669",slug:"meat-science-and-nutrition",title:"Meat Science and Nutrition",fullTitle:"Meat Science and Nutrition"},signatures:"Rabia Shabir Ahmad, Ali Imran and Muhammad Bilal Hussain",authors:[{id:"235082",title:"Dr.",name:"Ali",middleName:null,surname:"Imran",slug:"ali-imran",fullName:"Ali Imran"},{id:"239057",title:"Dr.",name:"Rabia Shabir",middleName:null,surname:"Ahmad",slug:"rabia-shabir-ahmad",fullName:"Rabia Shabir Ahmad"},{id:"243634",title:"Mr.",name:"Muhammad Bilal",middleName:null,surname:"Hussain",slug:"muhammad-bilal-hussain",fullName:"Muhammad Bilal Hussain"}]},{id:"19983",doi:"10.5772/20101",title:"Dietary Effect of Soybean (Glycine max) Products on Gut Histology and Microbiota of Fish",slug:"dietary-effect-of-soybean-glycine-max-products-on-gut-histology-and-microbiota-of-fish",totalDownloads:4471,totalCrossrefCites:6,totalDimensionsCites:47,abstract:null,book:{id:"497",slug:"soybean-and-nutrition",title:"Soybean and Nutrition",fullTitle:"Soybean and Nutrition"},signatures:"Daniel L. Merrifield, Rolf Erik Olsen, Reidar Myklebust and Einar Ringø",authors:[{id:"37424",title:"Prof.",name:"Einar",middleName:null,surname:"Ringø",slug:"einar-ringo",fullName:"Einar Ringø"},{id:"37436",title:"Dr.",name:"Daniel",middleName:null,surname:"Merrifield",slug:"daniel-merrifield",fullName:"Daniel Merrifield"},{id:"91338",title:"Dr.",name:"Rolf Erik",middleName:null,surname:"Olsen",slug:"rolf-erik-olsen",fullName:"Rolf Erik Olsen"},{id:"91341",title:"Prof.",name:"Reidar",middleName:null,surname:"Myklebust",slug:"reidar-myklebust",fullName:"Reidar Myklebust"}]},{id:"60270",doi:"10.5772/intechopen.75961",title:"Antioxidants from Natural Sources",slug:"antioxidants-from-natural-sources",totalDownloads:4436,totalCrossrefCites:24,totalDimensionsCites:40,abstract:"Antioxidants are the defense system of the body against the damage of reactive oxygen species, which is normally produced during the various physiological processes in the body. There are various sources of these antioxidants like endogenous antioxidant present in the body and exogenous food source. In recent decades, alternate of synthetic food antioxidants by natural ones has fostered interest on vegetable sources and the screening of inexpensive raw materials particularly from the agriculture for identifying new antioxidants. Polyphenols are the significant plant compounds with antioxidant activity, though not the only ones. Some but not only restricted to biological properties such as anticarcinogenicity, antimutagenicity, antiallergenicity, and antiaging activity have been reported for natural and synthetic antioxidants. Among the sources of natural antioxidants, the most important are those coming from routinely consuming vegetables and fruits; however, antioxidant from other plant and agriculture waste should not be ignored.",book:{id:"6678",slug:"antioxidants-in-foods-and-its-applications",title:"Antioxidants in Foods and Its Applications",fullTitle:"Antioxidants in Foods and Its Applications"},signatures:"Haseeb Anwar, Ghulam Hussain and Imtiaz Mustafa",authors:[{id:"240684",title:"Dr.",name:"Haseeb",middleName:null,surname:"Anwar",slug:"haseeb-anwar",fullName:"Haseeb Anwar"},{id:"244522",title:"Dr.",name:"Ghulam",middleName:null,surname:"Hussain",slug:"ghulam-hussain",fullName:"Ghulam Hussain"},{id:"244523",title:"Ms.",name:"Jaweria",middleName:null,surname:"Nisar",slug:"jaweria-nisar",fullName:"Jaweria Nisar"},{id:"244524",title:"Mr.",name:"Imtiaz",middleName:null,surname:"Mustafa",slug:"imtiaz-mustafa",fullName:"Imtiaz Mustafa"}]},{id:"19751",doi:"10.5772/18808",title:"From Soybean Phytosterols to Steroid Hormones",slug:"from-soybean-phytosterols-to-steroid-hormones",totalDownloads:11618,totalCrossrefCites:19,totalDimensionsCites:38,abstract:null,book:{id:"496",slug:"soybean-and-health",title:"Soybean and Health",fullTitle:"Soybean and Health"},signatures:"Feng-Qing Wang, Kang Yao and Dong-Zhi Wei",authors:[{id:"32646",title:"Dr.",name:"Feng-Qing",middleName:null,surname:"Wang",slug:"feng-qing-wang",fullName:"Feng-Qing Wang"},{id:"32662",title:"MSc.",name:"Kang",middleName:null,surname:"Yao",slug:"kang-yao",fullName:"Kang Yao"},{id:"32663",title:"Prof.",name:"Dong-Zhi",middleName:null,surname:"Wei",slug:"dong-zhi-wei",fullName:"Dong-Zhi Wei"}]}],mostDownloadedChaptersLast30Days:[{id:"64570",title:"Banana Pseudo-Stem Fiber: Preparation, Characteristics, and Applications",slug:"banana-pseudo-stem-fiber-preparation-characteristics-and-applications",totalDownloads:9429,totalCrossrefCites:15,totalDimensionsCites:18,abstract:"Banana is one of the most well-known and useful plants in the world. Almost all the parts of this plant, that are, fruit, leaves, flower bud, trunk, and pseudo-stem, can be utilized. This chapter deals with the fiber extracted from the pseudo-stem of the banana plant. It discusses the production of banana pseudo-stem fiber, which includes plantation and harvesting; extraction of banana pseudo-stem fiber; retting; and degumming of the fiber. It also deals with the characteristics of the banana pseudo-stem fiber, such as morphological, physical and mechanical, durability, degradability, thermal, chemical, and antibacterial properties. Several potential applications of this fiber are also mentioned, such as the use of this fiber to fabricate rope, place mats, paper cardboard, string thread, tea bags, high-quality textile materials, absorbent, polymer/fiber composites, etc.",book:{id:"7544",slug:"banana-nutrition-function-and-processing-kinetics",title:"Banana Nutrition",fullTitle:"Banana Nutrition - Function and Processing Kinetics"},signatures:"Asmanto Subagyo and Achmad Chafidz",authors:[{id:"257742",title:"M.Sc.",name:"Achmad",middleName:null,surname:"Chafidz",slug:"achmad-chafidz",fullName:"Achmad Chafidz"},{id:"268400",title:"Mr.",name:"Asmanto",middleName:null,surname:"Subagyo",slug:"asmanto-subagyo",fullName:"Asmanto Subagyo"}]},{id:"61245",title:"Nutritional Composition of Meat",slug:"nutritional-composition-of-meat",totalDownloads:4483,totalCrossrefCites:32,totalDimensionsCites:58,abstract:"Meat ranks among one of the most significant, nutritious and favored food item available to masses, which aids in fulfilling most of their body requirements. It has played a vital role in human evolution and is an imperative constituent of a well-balanced diet. It is a good source of proteins, zinc, iron, selenium, and phosphorus followed by vitamin A and B-complex vitamins. Average value of meat protein is about 23% that varies from higher to lower value according to the type of meat source. Meat fat and its fatty acid profile is point to worry, with respect to its consumption, but its moderate usage is always advised by doctors and nutritionists, in order to lead a healthy life. Fat content of animal carcasses ranges between 8 and 20%. Quality traits of meat along with its nutritional composition become dependent upon animal breed type, feeding source (grains, pasture and grass), genetics of animal and post mortem techniques. This chapter will mainly focus on the variant aspects of nutritional constituents of meat including proteins and essential amino acids, fats and fatty acid profile, carbohydrates, vitamins and minerals along with their health benefits to human health.",book:{id:"6669",slug:"meat-science-and-nutrition",title:"Meat Science and Nutrition",fullTitle:"Meat Science and Nutrition"},signatures:"Rabia Shabir Ahmad, Ali Imran and Muhammad Bilal Hussain",authors:[{id:"235082",title:"Dr.",name:"Ali",middleName:null,surname:"Imran",slug:"ali-imran",fullName:"Ali Imran"},{id:"239057",title:"Dr.",name:"Rabia Shabir",middleName:null,surname:"Ahmad",slug:"rabia-shabir-ahmad",fullName:"Rabia Shabir Ahmad"},{id:"243634",title:"Mr.",name:"Muhammad Bilal",middleName:null,surname:"Hussain",slug:"muhammad-bilal-hussain",fullName:"Muhammad Bilal Hussain"}]},{id:"67214",title:"Microbial Contamination in Milk Quality and Health Risk of the Consumers of Raw Milk and Dairy Products",slug:"microbial-contamination-in-milk-quality-and-health-risk-of-the-consumers-of-raw-milk-and-dairy-produ",totalDownloads:3581,totalCrossrefCites:11,totalDimensionsCites:22,abstract:"The dairy products industry is going toward safe milk and its products in the food market. Milk quality and food safety concern in the consumers’ health and nutrition in public health surveillance prevent food-borne diseases, food poisoning, and zoonosis risk by raw milk and fresh dairy products. The aim of this work is focused on milk microbial contamination and its impacts on milk production and dairy industry with their implications in milk product quality, food-borne diseases from raw milk, and unpasteurized milk by food-borne pathogen microbial contamination and milk and dairy product spoilage. The microbial milk contamination source comes from herd hygiene and health status, mastitis prevalence, production environment, and milking parlor and milk conserving practices in dairy farm. Moreover, these facts are implicated in milk quality and milk spoilage and unsafe dairy products. The milk production system and the dairy plant operations keep track in pasteurized milk and fresh dairy products reviewing the traceability in field situational diagnosis report.",book:{id:"7943",slug:"nutrition-in-health-and-disease-our-challenges-now-and-forthcoming-time",title:"Nutrition in Health and Disease",fullTitle:"Nutrition in Health and Disease - Our Challenges Now and Forthcoming Time"},signatures:"Valente Velázquez-Ordoñez, Benjamín Valladares-Carranza, Esvieta Tenorio-Borroto, Martín Talavera-Rojas, Jorge Antonio Varela-Guerrero, Jorge Acosta-Dibarrat, Florencia Puigvert, Lucia Grille, Álvaro González Revello and Lucia Pareja",authors:[{id:"15423",title:"Qco.",name:"Lucia",middleName:null,surname:"Pareja",slug:"lucia-pareja",fullName:"Lucia Pareja"},{id:"199849",title:"Dr.",name:"Velazquez",middleName:"Ordoñez",surname:"Valente",slug:"velazquez-valente",fullName:"Velazquez Valente"},{id:"280178",title:"Dr.",name:"Esvieta",middleName:null,surname:"Tenorio-Borroto",slug:"esvieta-tenorio-borroto",fullName:"Esvieta Tenorio-Borroto"},{id:"280179",title:"Dr.",name:"Benjamín",middleName:null,surname:"Valladares-Carranza",slug:"benjamin-valladares-carranza",fullName:"Benjamín Valladares-Carranza"},{id:"280184",title:"Dr.",name:"Jorge",middleName:null,surname:"Acosta-Dibarrat",slug:"jorge-acosta-dibarrat",fullName:"Jorge Acosta-Dibarrat"},{id:"285302",title:"Dr.",name:"Martín",middleName:null,surname:"Talavera Rojas",slug:"martin-talavera-rojas",fullName:"Martín Talavera Rojas"},{id:"285303",title:"Dr.",name:"Lucia",middleName:null,surname:"Grille",slug:"lucia-grille",fullName:"Lucia Grille"},{id:"291633",title:"Dr.",name:"Alvaro",middleName:null,surname:"González Revello",slug:"alvaro-gonzalez-revello",fullName:"Alvaro González Revello"},{id:"301478",title:"Ph.D. Student",name:"Jorge Antonio",middleName:null,surname:"Varela-Guerrero",slug:"jorge-antonio-varela-guerrero",fullName:"Jorge Antonio Varela-Guerrero"},{id:"301479",title:"Ph.D. Student",name:"Florencia",middleName:null,surname:"Puigvert",slug:"florencia-puigvert",fullName:"Florencia Puigvert"}]},{id:"60461",title:"Biological Activities of the Doum Palm (Hyphaene thebaica L.) Extract and Its Bioactive Components",slug:"biological-activities-of-the-doum-palm-hyphaene-thebaica-l-extract-and-its-bioactive-components",totalDownloads:4246,totalCrossrefCites:7,totalDimensionsCites:13,abstract:"The doum palm (Hyphaene thebaica) is a type palm tree which has a wood texture and has edible oval fruits and the origin native to upper Egypt. The trunk of this small palm is dichotomous. It is one of the most important useful plants in the world. All parts of doum palm have a useful role such as fiber and leaflets which used to weave baskets and doum nuts which have antioxidants and secondary metabolites such as tannins, phenols, saponin, steroids, glycosides, flavonoid, terpenes and terpinoids. Also, roots, stems and leaves are used in medicine, ropes and baskets. Studies on anti-inflammatory, antioxidant, antimicrobial, anticancer and pharmacological potential of Hyphaene thebaica extracts and its major phytoconstituents like the phenolic, essential oil and flavonoid compounds are extensively discussed in this review.",book:{id:"6678",slug:"antioxidants-in-foods-and-its-applications",title:"Antioxidants in Foods and Its Applications",fullTitle:"Antioxidants in Foods and Its Applications"},signatures:"Hossam S. El-Beltagi, Heba I. Mohamed, Hany N. Yousef and Eman\nM. Fawzi",authors:[{id:"138817",title:"Dr.",name:"Heba",middleName:null,surname:"Mohamed",slug:"heba-mohamed",fullName:"Heba Mohamed"},{id:"240003",title:"Prof.",name:"Hossam",middleName:"Saad",surname:"El-Beltagi",slug:"hossam-el-beltagi",fullName:"Hossam El-Beltagi"},{id:"251695",title:"Prof.",name:"Eman",middleName:null,surname:"Fawzi",slug:"eman-fawzi",fullName:"Eman Fawzi"},{id:"251950",title:"Dr.",name:"Hany",middleName:null,surname:"Yousef",slug:"hany-yousef",fullName:"Hany Yousef"}]},{id:"71665",title:"Global Prevalence of Malnutrition: Evidence from Literature",slug:"global-prevalence-of-malnutrition-evidence-from-literature",totalDownloads:2054,totalCrossrefCites:7,totalDimensionsCites:13,abstract:"Malnutrition is a widespread problem, affecting the global population at some life stage. This public health epidemic targets everyone, but the most vulnerable groups are poverty-stricken people, young children, adolescents, older people, those who are with illness and have a compromised immune system, as well as lactating and pregnant women. Malnutrition includes both undernutrition (wasting, stunting, underweight, and mineral- and vitamin-related malnutrition) and overnutrition (overweight, obesity, and diet-related noncommunicable diseases). In combating malnutrition, healthcare costs increase, productivity is reduced, and economic growth is staggered, thus perpetuating the cycle of ill health and poverty. The best-targeted age for addressing malnutrition is the first 1000 days of life as this window period is ideal for intervention implementation and tracking for the improvement of child growth and development. There is an unprecedented opportunity to address the various forms of malnutrition, especially the 2016–2025 Decade of Action on Nutrition set by the United Nation. This aims to achieve the relevant targets of the Sustainable Development Goals that aim to end hunger and improve nutrition, as well as promote well-being and ensure healthy lives.",book:{id:"8030",slug:"malnutrition",title:"Malnutrition",fullTitle:"Malnutrition"},signatures:"Natisha Dukhi",authors:[{id:"311182",title:"Dr.",name:"Natisha",middleName:null,surname:"Dukhi",slug:"natisha-dukhi",fullName:"Natisha Dukhi"}]}],onlineFirstChaptersFilter:{topicId:"323",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:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:317,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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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. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of 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:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{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:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{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:"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:"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:"Igor Victorovich Lakhno 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.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in 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 been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), 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 a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). 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: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",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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Topics will include asset liability management, financial consequences of the financial crisis and covid-19, financial accounting, mergers and acquisitions, management accounting, SMEs, financial markets, corporate finance and governance, managerial technology and innovation, resource management and sustainable development, social entrepreneurship, corporate responsibility, ethics and accountability, microeconomics, labour economics, macroeconomics, public economics, financial economics, econometrics, direct marketing, creative marketing, internet marketing, market planning and forecasting, brand management, market segmentation and targeting and other topics under business and management. This book series will focus on various aspects of business and management whose in-depth understanding is critical for business and company management to function effectively during this uncertain time of financial crisis, Covid-19 pandemic, and military activity in Europe.
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