Chemical composition of original wheat and wheat distiller grain (% of dry matter).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\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:"7200",leadTitle:null,fullTitle:"Green Energy and Environment",title:"Green Energy and Environment",subtitle:null,reviewType:"peer-reviewed",abstract:"Energy is a vital element in sustaining our modern society but the future of energy is volatile, uncertain, complex, and ambiguous; especially when facing a continuous drive to ensure a sustained and equitable access as well as mounting pressures to reduce its emissions. Traditional approaches in developing energy technologies have always been in isolation with distinct and unique contexts. However, we cannot afford to work in silos any longer. Future energy systems and their relationship with the society and the environment will have to be conceived, designed, developed, commissioned, and operated alongside and within contemporary geo-political, ethical, and socio-economic contexts. This has posed an unprecedented volatility, uncertainty, complexity, and ambiguity (VUCA), where systemic and holistic approaches are often warranted. This book aims to focus on the VUCA of addressing the future of energy and environment by considering contemporary issues and insights from diverse contexts, viewed as a system, and anchored upon emerging and smart energy technologies.",isbn:"978-1-83880-572-2",printIsbn:"978-1-83880-571-5",pdfIsbn:"978-1-83880-573-9",doi:"10.5772/intechopen.74000",price:119,priceEur:129,priceUsd:155,slug:"green-energy-and-environment",numberOfPages:148,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"72ad3cb35d7eb84855d6cb05c6e73897",bookSignature:"Eng Hwa Yap and Andrew Huey Ping Tan",publishedDate:"July 15th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7200.jpg",numberOfDownloads:4244,numberOfWosCitations:3,numberOfCrossrefCitations:14,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:19,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:36,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 6th 2019",dateEndSecondStepPublish:"September 2nd 2019",dateEndThirdStepPublish:"November 1st 2019",dateEndFourthStepPublish:"January 20th 2020",dateEndFifthStepPublish:"March 20th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"185577",title:"Associate Prof.",name:"Eng Hwa",middleName:null,surname:"Yap",slug:"eng-hwa-yap",fullName:"Eng Hwa Yap",profilePictureURL:"https://mts.intechopen.com/storage/users/185577/images/system/185577.jpeg",biography:"In the Faculty of Transdisciplinary Innovation, Eng Hwa Yap is\nthe Acting Associate Dean: Teaching and Learning (Operations).\nHe also leads the Bachelor of Technology and Innovation (BTi)\nas the Course Director. His research at the university focuses\non curated multidisciplinary and mixed approaches of enquiry\nto understand and respond to complex problems surrounding\ntechnology, environmental sustainability, and future energy\nsystems. In his research, Eng Hwa uses methods centering on systems thinking to\ninvestigate emerging and contemporary issues in technologies and their interaction\nwith society, the environment, economics, and policy.",institutionString:"University of Technology Sydney",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Technology Sydney",institutionURL:null,country:{name:"Australia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"299780",title:"Dr.",name:"Andrew Huey Ping",middleName:null,surname:"Tan",slug:"andrew-huey-ping-tan",fullName:"Andrew Huey Ping Tan",profilePictureURL:"https://mts.intechopen.com/storage/users/299780/images/system/299780.jpeg",biography:"Andrew Huey Ping Tan has extensive engineering experience\nin both Motorola Solutions and Agilent Technologies, where he\nspecializes in ensuring high quality and timely manufacture of\nindustrial products for downstream customers. By implementing\nsystems thinking and knowledge, life-cycle assessments, and\ntechnical improvisations, he specializes in product line setup and\nprocess improvements for new product developments. Andrew\ncompleted his PhD at the University of Nottingham where he developed a systemic measurement for the Water-Energy-Food Security Nexus in Malaysia using a\ntransdisciplinary and systems approach. He also graduated with MEng (Hons) in\nMechanical Engineering with First Class Honors from the same university",institutionString:"KDU University College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"KDU University College",institutionURL:null,country:{name:"Malaysia"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"770",title:"Renewable Energy",slug:"engineering-energy-engineering-renewable-energy"}],chapters:[{id:"71738",title:"Sustainable Advanced Manufacturing of Printed Electronics: An Environmental Consideration",doi:"10.5772/intechopen.91979",slug:"sustainable-advanced-manufacturing-of-printed-electronics-an-environmental-consideration",totalDownloads:887,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Printing technologies have become a novel and disruptive innovation method of manufacturing electronic components to produce a diverse range of devices including photovoltaic cells, solar panels, energy harvesters, batteries, light sources, and sensors on really thin, lightweight, and flexible substrates. In traditional electronic manufacturing, a functional layer must be deposited, typically through a chemical vapor or physical vapor process for a copper layer for circuitry production. These subtractive techniques involve multiple production steps and use toxic etching chemicals to remove unwanted photoresist layers and metals. In printing, the same functional material can be selectively deposited only where it is needed on the substrate via plates or print heads. The process is additive and significantly reduces not only the number of manufacturing steps, but also the need for energy, time, consumables, as well as the waste. Thereby, printing has been in the focus for many applications as a green, efficient, energy-saving, environmentally friendly manufacturing method. This chapter presents a general vision on green energy resources and then details printed electronics that consolidates green energy and environment relative to traditional manufacturing system.",signatures:"Bilge Nazli Altay, Martin Bolduc and Sylvain G. Cloutier",downloadPdfUrl:"/chapter/pdf-download/71738",previewPdfUrl:"/chapter/pdf-preview/71738",authors:[{id:"310591",title:"Dr.",name:"Bilge Nazli",surname:"Altay",slug:"bilge-nazli-altay",fullName:"Bilge Nazli Altay"},{id:"315590",title:"Dr.",name:"Sylvain",surname:"Cloutier",slug:"sylvain-cloutier",fullName:"Sylvain Cloutier"},{id:"315591",title:"Dr.",name:"Martin",surname:"Bolduc",slug:"martin-bolduc",fullName:"Martin Bolduc"}],corrections:null},{id:"70392",title:"Techno-Economic Optimization and Benchmarking of a Solar-Only Powered Combined Cycle with High-Temperature TES Upstream the Gas Turbine",doi:"10.5772/intechopen.90410",slug:"techno-economic-optimization-and-benchmarking-of-a-solar-only-powered-combined-cycle-with-high-tempe",totalDownloads:622,totalCrossrefCites:4,totalDimensionsCites:7,hasAltmetrics:0,abstract:"This work presents a techno-economic parametric study of an innovative central receiver solar thermal power plant layout that applies the combined cycle (CC) as thermodynamic power cycle and a multi-tower solar field configuration together with open volumetric air receivers (OVARs). The topping gas turbine (GT) is powered by an air–air heat exchanger (two heat exchanger trains in the case of reheat). In order to provide dispatchability, a high-temperature thermocline TES system is placed upstream the gas turbine. The aim is threefold, (i) investigating whether the multi-tower concept has a techno-economic advantage with respect to conventional single-tower central receiver plants, (ii) indicating the techno-economic optimum power plant configuration, and (iii) benchmarking the techno-economic optimum of the CC plant against that of a conventional single-cycle Rankine steam plant with the same receiver and TES technology. It is concluded that the multi-tower configuration has a techno-economic advantage with respect to the conventional single-tower arrangement above a total nominal solar power level of about 150 MW. However, the benchmarking of the CC against a Rankine single-cycle power plant layout shows that the CC configuration has despite its higher solar-to-electric conversion efficiency a higher LCOE. The gain in electricity yield is not enough to outweigh the higher investment costs of the more complex CC plant layout.",signatures:"Fritz Zaversky, Iñigo Les, Marcelino Sánchez, Benoît Valentin, Jean-Florian Brau, Frédéric Siros, Jonathon McGuire and Flavien Berard",downloadPdfUrl:"/chapter/pdf-download/70392",previewPdfUrl:"/chapter/pdf-preview/70392",authors:[{id:"311080",title:"Dr.",name:"Fritz",surname:"Zaversky",slug:"fritz-zaversky",fullName:"Fritz Zaversky"},{id:"314549",title:"MSc.",name:"Iñigo",surname:"Les",slug:"inigo-les",fullName:"Iñigo Les"},{id:"314550",title:"Dr.",name:"Marcelino",surname:"Sánchez",slug:"marcelino-sanchez",fullName:"Marcelino Sánchez"},{id:"314552",title:"MSc.",name:"Benoît",surname:"Valentin",slug:"benoit-valentin",fullName:"Benoît Valentin"},{id:"314553",title:"MSc.",name:"Jean-Florian",surname:"Brau",slug:"jean-florian-brau",fullName:"Jean-Florian Brau"},{id:"314555",title:"MSc.",name:"Frédéric",surname:"Siros",slug:"frederic-siros",fullName:"Frédéric Siros"},{id:"314556",title:"MSc.",name:"Jonathon",surname:"McGuire",slug:"jonathon-mcguire",fullName:"Jonathon McGuire"},{id:"314557",title:"MSc.",name:"Flavien",surname:"Berard",slug:"flavien-berard",fullName:"Flavien Berard"}],corrections:null},{id:"70307",title:"The Emerging of Hydrovoltaic Materials as a Future Technology: A Case Study for China",doi:"10.5772/intechopen.90377",slug:"the-emerging-of-hydrovoltaic-materials-as-a-future-technology-a-case-study-for-china",totalDownloads:878,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Water contains tremendous energy in various forms, but very little of this energy has yet been harvested. Nanostructured materials can generate electricity by water-nanomaterial interaction, a phenomenon referred to as hydrovoltaic effect, which potentially extends the technical capability of water energy harvesting. In this chapter, starting by describing the fundamental principle of hydrovoltaic effect, including water-carbon interactions and fundamental mechanisms of harvesting water energy with nanostructured materials, experimental advances in generating electricity from water flows, waves, natural evaporation, and moisture are then reviewed. We further discuss potential applications of hydrovoltaic technologies, analyze main challenges in improving the energy conversion efficiency and scaling up the output power, and suggest prospects for developments of the emerging technology, especially in China.",signatures:"Jiale Xie, Liuliu Wang, Xiaoying Chen, Pingping Yang, Fengkai Wu and Yuelong Huang",downloadPdfUrl:"/chapter/pdf-download/70307",previewPdfUrl:"/chapter/pdf-preview/70307",authors:[{id:"311114",title:"Dr.",name:"Jiale",surname:"Xie",slug:"jiale-xie",fullName:"Jiale Xie"},{id:"313395",title:"BSc.",name:"Liuliu",surname:"Wang",slug:"liuliu-wang",fullName:"Liuliu Wang"},{id:"313397",title:"BSc.",name:"Xiaoying",surname:"Chen",slug:"xiaoying-chen",fullName:"Xiaoying Chen"},{id:"313398",title:"Dr.",name:"Pingping",surname:"Yang",slug:"pingping-yang",fullName:"Pingping Yang"},{id:"313399",title:"BSc.",name:"Fengkai",surname:"Wu",slug:"fengkai-wu",fullName:"Fengkai Wu"},{id:"313400",title:"Prof.",name:"Yuelong",surname:"Huang",slug:"yuelong-huang",fullName:"Yuelong Huang"}],corrections:null},{id:"71541",title:"A Circular Economy of Electrochemical Energy Storage Systems: Critical Review of SOH/RUL Estimation Methods for Second-Life Batteries",doi:"10.5772/intechopen.91257",slug:"a-circular-economy-of-electrochemical-energy-storage-systems-critical-review-of-soh-rul-estimation-m",totalDownloads:792,totalCrossrefCites:5,totalDimensionsCites:5,hasAltmetrics:1,abstract:"Humanity is facing a gloomy scenario due to global warming, which is increasing at unprecedented rates. Energy generation with renewable sources and electric mobility (EM) are considered two of the main strategies to cut down emissions of greenhouse gasses. These paradigm shifts will only be possible with efficient energy storage systems such as Li-ion batteries (LIBs). However, among other factors, some raw materials used on LIB production, such as cobalt and lithium, have geopolitical and environmental issues. Thus, in a context of a circular economy, the reuse of LIBs from EM for other applications (i.e., second-life batteries, SLBs) could be a way to overcome this problem, considering that they reach their end of life (EoL) when they get to a state of health (SOH) of 70–80% and still have energy storage capabilities that could last several years. The aim of this chapter is to make a review of the estimation methods employed in the diagnosis of LIB, such as SOH and remaining useful life (RUL). 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The growth of renewable energy sources (RES) may also have the potential to stimulate employment in the European Union (EU), through the creation of jobs in new green technologies. In this chapter, first, we introduce the information on renewable energy sources, their statistics, and legislation background in Slovakia. In more detail, we further introduce the information on forest and agricultural biomass as a renewable energy source. 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On average, wheat grain contains 65% starch, 15% protein, 14% fibre, 2.2% oil and 10% moisture [1]. With expansion of fuel ethanol production in North America and other places in the world during the last decade wheat grain has been used as second feedstock after corn for ethanol production due to its high starch content. Many different classes and types of wheat can be used for ethanol production. In general, soft wheats such as soft white and soft red classes are preferred to hard wheats because they contain higher starch content. Varieties with higher protein are less desirable, but may still be used when blended with one or more high starch varieties.
\nIncrease of fuel ethanol production has resulted in a significant increase in the use of distiller grains in the diets of livestock animals, especially in ruminant feeding. Distiller grains have historically been used as a protein source for dairy cattle. Whereas, increased supply and reduced cost make it also a source of energy to replace grain. The distiller grain has comparable energy value to its original grain, high quality protein and high fibre content but highly digestible which is suitable for ruminant feed but not suitable for monogastric animals or poultry because of high fibre content. Wheat distiller grain is the major by-product of ethanol production when wheat grain is used as a substrate for ethanol production. In the last decade, research has documented the variation in chemical composition of wheat distiller grain, and its feed value as protein, energy or fibre source for dairy and beef cattle as well as small ruminant animals. Studies have frequently focused on comparing the feed value of wheat distiller grain to corn distiller grain and characterizing the impact of inclusion of these by-products on nitrogen and phosphorus excretion in manure. To our knowledge, there is no review article that has addressed these research findings, even though several review articles on the use of corn distiller grain in animal production and one book chapter on use of wheat distiller grain in pigs and poultry have been published [2, 3]. The objective of this chapter is to describe some recently developed knowledge and application of wheat distiller grain in ruminant animal diets.
\nThere are two main distillery processes, dry-milling and wet-milling distillery. The dry-milling process is the main process for producing ethanol [4]. The dry-milling process includes primarily the follow steps: grinding or milling, liquefaction, saccharification, fermentation and distillation [5]. The grain is ground to produce bran-free flour, and then mixed with water and enzymes (amylases) to produce a mash (liquefaction). The saccharification is conducted by adding enzymes to the mash to transform starch into dextrose. After saccharification, yeast is added to start the fermentation process to produce a ’beer‘ and CO2. The beer is separated through a continuous distillation column to yield alcohol [5]. The remaining material is called whole stillage and consists of all the components of the original grain (except the starch), yeast and added water. The whole stillage is centrifuged to produce wet distiller grain (solid fraction) and thin stillage (liquid fraction). The wet distiller grain contains 30–35% dry matter, while thin stillage has only 5–7% solids. The thin stillage is concentrated through evaporation into condensed distiller solubles, which are mixed with wet distiller grain and dried to become dried distiller grains with solubles, which are the most produced co-products from bioethanol plants. In general, from each tonne of wheat grain, ethanol production results in approximately 365 l of ethanol, 290 kg of CO2 and 290 kg of distiller grain. With continuing changes of technologies in ethanol plants, it should be noted that wheat distiller grain are still evolving, thus the composition and feed value of distiller grain are changing.
\nDuring ethanol production process, starch is mostly converted into ethanol and it leaves all other components of grain to be condensed. Therefore, compared to the original wheat grain, starch contents of distiller grain is very low (4.3%), whereas the contents of non-fermentable components including crude protein, neutral detergent fibre, acid detergent fibre, ether extract and phosphorus are considerably higher (\nTable 1\n). The primary nutrient contents of wheat distiller grain are crude protein and neutral detergent fibre ranging from 30 to 45% or from 25 to 55%, respectively. The chemical composition of wheat distiller grain can vary considerably depending on numerous factors mainly including wheat source and technology used in ethanol plant (\nTable 2\n). Physical and chemical characteristics of grain vary with grain source (variety, growing conditions, etc.), which thus directly affect the composition of distiller grain. Furthermore, the variations in nutrient content of wheat distiller grain have not only been reported from plant to plant, but also from batch to batch [6]. The differences among ethanol plants could be substantial according to the method of grain preparation with or without previous de-hulling, the fermentation conditions, drying method, duration and temperature of drying, amount of solubles added back to wet distiller grain and grinding procedure used. All these can potentially contribute to the product variability. The quantity of solubles added to wet distiller grain pre-drying is easily controlled process but it also can potentially create the variability in wheat distiller grain [6]. Solubles are high in fat (up to 34% of dry matter) and low in neutral detergent fibre, therefore, the more solubles are added to wet distiller grain, the higher the fat and the lower the neutral detergent fibre content. The heat damage is another source of variability and it occurs during the drying process. Wheat distiller grains that have undergone high processing temperature will have a reduced protein degradability in ruminants. The heat damage can be easily checked with the colour of distiller grain which varies from light yellow to dark brown. Cozannet et al. [7] measured the luminance values of 10 European wheat distiller grains and it ranged from 43 (black products) to 63 (yellow products) using a Minolta colorimeter. These authors indicated that wheat distiller grain with luminance values <50 was overheated, which will have a high incidence of Maillard reactions.
\nItem | \nWheat | \nWheat distiller grain | \n
---|---|---|
Organic matter | \n97.9 | \n94.4 | \n
Starch | \n60.2 | \n4.3 | \n
Neutral detergent fibre | \n14.3 | \n31.6 | \n
Acid detergent fibre | \n4.2 | \n11.4 | \n
Crude protein | \n15.1 | \n38.8 | \n
Ether extract | \n2.3 | \n3.8 | \n
Calcium | \n0.05 | \n0.12 | \n
Phosphorus | \n0.39 | \n1.0 | \n
Chemical composition of original wheat and wheat distiller grain (% of dry matter).
Item | \nMean | \nSTD | \nMin | \nMax | \n
---|---|---|---|---|
Organic matter | \n94.6 | \n0.3 | \n93.9 | \n95.9 | \n
Neutral detergent fibre | \n30.4 | \n6.5 | \n22.7 | \n36.5 | \n
Acid detergent fibre | \n12.3 | \n1.6 | \n9.7 | \n13.7 | \n
Crude protein | \n37.9 | \n3.3 | \n30.6 | \n44.7 | \n
Starch | \n4.2 | \n1.2 | \n2.1 | \n6.4 | \n
Crude fat | \n4.0 | \n0.3 | \n3.7 | \n4.4 | \n
Mean values, standard error and range of nutrient content of DDGS.
The amino acid profile of protein is an important nutrition attribute to ruminant animals. We observed that protein of wheat distiller grain had amino acid profiles partly in agreement with that of the initial grain [8]. Li et al. [8] reported that the changes in amino acid profiles from the original grain to its distiller grain did not follow the same trend as changes in the crud protein; proportion of amino acid increased for some, and decreased, or remained unchanged for others. Han and Liu [9] suggested that the amino acid from yeast source during ethanol fermentation would have important influences on amino acid profiles of distiller grain. Yeasts used for starch fermentation represent an additional protein source equivalent to about 5% of the total distiller grain protein content [10]. Theoretically, yeast cannot hydrolyse protein from grain to free amino nitrogen due to the lack of extracellular proteolytic activity [9]. Li et al. [8] discussed that the differences in amino acid composition between the original grain and its distiller grain also depends on the amino acid composition of the yeast used in ethanol fermentation. In fact, it was reported that yeast protein could contribute up to 20% of the protein in distiller grain, and that amino acid profiles of yeast protein were different from those of grain protein [9]. In addition, the level of soluble fractions added into distiller grain is another source influencing the protein content and the amino acid profile. Cozannet et al. [7] reported that although amino acid profile is quite comparable in wheat and wheat distiller grain, lysine and arginine are lower for wheat distiller grain, and the lysine and arginine levels in the crude protein of wheat distiller grain are highly variable, even in light-coloured products: 1.7–3.0% and 3.7–4.6%, respectively.
\nThe considerable variability in chemical composition of wheat distiller grain is one of the main issues challenging in feed formulation for precisely feed livestock animals. Hence, in practice, a determination of nutrient contents of wheat distiller grain from each delivery is recommended if the nutrient profiles are not provided.
\nThe values of energy and protein are two key nutrient components for a feed ingredient fed to ruminant animal, which ultimately determine whether the nutrient requirement by animal is met. Wheat distiller grain is a good source of energy and protein for ruminants.
\nWheat DDGS is commonly used as energy source owing to its highly digestible fibre and moderate level of fat. The energy value of a feed depends primarily on its digestibility in the digestive tract of animal. The digestibility of wheat distiller grain in the rumen of beef cattle was 66.5 and 54.8% for dry matter and neutral detergent fibre, which was lower that of dry matter (82.4%) and fibre (67.9%) of original wheat [11]. The lower ruminal digestibility of distiller grain versus its original grain is due to lack starch in the distiller grain and grain starch is highly fermentable in the rumen. It appears that the digestibility of wheat distiller grain varies between studies [11, 12] which could be due to the variation in chemical composition of distiller grain, animal production level or physiology status, etc.; therefore, the energy value of distiller grain varies from study to study. Beliveau and McKinnon [13] did not find the difference in finishing performance of beef cattle fed diets containing increasing replacement of barley grain with wheat distiller grain up to 23% of the dietary dry matter. These authors concluded that wheat distiller grain had similar value of net energy for maintenance (NEm) and net energy for gain (NEg) to barley grain (i.e. 2.00–2.06 Mcal/kg NEm and 1.34–1.40 Mcal/kg NEg, respectively). However, in the study by Gibb et al. [14], increasing substitution of wheat distiller grain for barley grain from 0, 20, 40 to 60% in diets fed beef cattle linearly increased feed consumption but linearly reduced digestibility of dry matter from 76.4 to 68.9%, as a result, dietary energy content (NEg, MCal/kg) declined linearly from 1.15, 1.14, 1.09 to 1.07, and the NEg of wheat distiller grain decreased from 1.36, 1.27 to 1.21%. Although fibre from wheat distiller grain is considered to be highly digestible [6], the lowered digestibility of diets with increasing levels of distiller grain may have resulted from increased passage rate of feed from the rumen and leave the feeds stay shorter in the rumen, and thus not favourable for fibre digestion [15].
\nThe protein of wheat distiller grain has lower ruminal degradability (49%) than that of wheat grain (79%), and similar to that of corn distiller grain (47%), but it has more desirable amino acid profile as it contains more arginine, lysine, threonine and valine [8]. Li et al. [8] found that the decrease in ruminal degradability of distiller grain protein versus its original grain resulted from the reduced degradation rate. The distiller grain usually has higher rumen undegradable protein compared to the protein from the original grain [12], and consequently, distiller grain has been historically fed to cattle as a rumen undegradable protein source. Highly degradable feed protein is often not favourably received by the ruminant nutritionist since the highly degradable protein is rapidly broken down by the microbial population in the rumen and the released ammonia nitrogen is absorbed through the rumen wall, converted to urea in the liver and excreted in the urine. This metabolic pathway has not only an energy cost but also it presents an environmental issue. The urinary urea nitrogen is rapidly hydrolysed to ammonia upon excretion and can contribute to nitrous oxide emissions. In contrast, ruminal undegradable protein resists fermentation in the rumen and a proportion of the amino acids arising from this protein can be directly absorbed in the small intestine. The rumen undegradable protein of wheat distiller grain could vary substantially and range from 38.3 to 71.7% [6, 8]. The variation in rumen undegradable protein content is primarily caused by differences in heat treatment during the drying of distiller grain. Additionally, the inherent characteristics of the protein fractions within the original grain source [6], and the milling process such as conventional versus fractionation [8] also cause this variation. The effective protein degradability of wheat distiller grain (54%) was found to be similar to that of triticale distiller grain (51%) and higher than that of barley distiller grain (49%) but normally higher than corn distiller grain (47.1%) [8, 16]. Therefore, wheat distiller grain can be used as a good source of degradable and undegradable protein in the rumen [17].
\nThe lower rumen degradability of distiller grain protein versus its original grain appears due to protein molecular changes. Yu et al. [18] reported that the grain had higher ratio of protein amide I to II in the protein structure than its distiller grain produced from bioethanol processing (grain vs. distiller grain; 4.58 vs. 2.84). Protein vibration of amide I and II depends on the protein secondary structure of the backbone and is therefore most commonly used for secondary-structure analysis [19]. It was also reported a positive correlation of protein amide I to amide II ratio with the soluble fraction (
Ruminal undegradable protein of wheat distiller grain has a good intestinal digestibility and is one of the best sources of metabolizable protein. However, differences may exist between distiller grain from wheat and corn. Li et al. [8] reported that protein quality (i.e. amino acid profile) of the rumen undegradable protein in wheat distiller grain and corn distiller grain was slightly lower compared with that in the original grains. Nuez-Ortin et al. [12] reported that a wheat and corn blend distiller grain was a better source of truly digested and absorbed protein in the small intestine than wheat distiller grain and corn distiller grain alone. The rumen undegradable protein fraction in corn distiller grain may provide similar amounts of intestinally absorbable total amino acid, but greater absorbable essential amino acid, than the undegradable protein in wheat distiller grain.
\nDistiller grain from corn grain fermentation is historically fed to dairy cattle mainly as rumen by-pass protein, and rarely used as feed ingredient in beef production because of limited amount of production and higher price compared to other available feed sources. The inclusion of distiller grain in beef cattle diets, especially feeding wheat-based distiller grain in Canada has become a common practice only last decade because of increased availability of distiller grain and reduced price along with increased grain cost. Typical beef production in North America includes three different operations: cows and calf production, growing cattle and finishing cattle.
\nCow-calf operations are widespread throughout beef-producing countries, and the goal of a cow-calf operation is to produce young beef cattle, which are usually sold. Typically lower-quality forages high in fibre and low in protein are the basis for the beef cows and replacement heifers operations. Cow-calf operations generally raise their stock primarily on pasture and other forms of roughage rather than grain feeds. The cattle require protein, energy and phosphorus supplementation at this feeding system. Because most forage protein is degraded in the rumen, the wheat distiller grain can be an acceptable supplement in an extending grazing system for beef cows. The nutritive profile of wheat distiller grain makes it attractive in forage-based production setting distiller grain as an excellent source of total digestible nutrient containing digestible fibre and relatively high fat. Distiller grain is also high in crude protein with high rumen by-pass protein. Distiller grain is also a good source of phosphorus (0.6%), a nutrient commonly deficient in forage-based diets. The study using distiller grain in cows and calf operation is lacking. Van De Kerckhove et al. [20] reported that wheat distiller grain was an alternative to barley grain as an energy and protein supplement in a chaff and hay grazing system supplemented with rolled barley, wheat distiller grain fed at levels to meet the requirements of total digestible nutrients by cows. Beef cows require maintenance levels of energy and protein, which increase as the animals get close to calving time. The energy from wheat distiller grain is largely in the form of digestible fibre and fat. Therefore, distiller grain fits well as energy supplement in forage-based diet.
\nThe growing step operation is the process of growing cattle at moderate rates of gain with the goal to develop frame and muscle, and to minimize fat deposition. The daily gains target from 0.9 to 1.2 kg, depending on the type of cattle being fed. Cattle are typically fed either in a feedlot or on-farm by providing a forage-based diet supplemented with protein and energy source. It is evident that growing cattle fed under dry lots or on pasture have the potential to use wheat distiller grain as a supplemental source of energy and protein. Beliveau and Mckinnon [13] conducted a growing study using beef steers fed diets with increasing rates of replacement of barley grain with wheat distiller grain from 0, 8, 16, 24 to 32% (dietary dry matter) and observed a linear improvement of feed consumption and growth performance. Similarly, in another study from the same team, McKinnon and Walker [21] observed a linear improvement of average daily gain and feed efficiency with increasing replacement of wheat distiller grain for barley grain. However, other studies [14, 22] did not find evident beneficial effects of including wheat distiller grain in place of barley grain in growing cattle diets. The discrepancy between studies could be due to dietary factors such as levels and quality of forage used in diets, proportion of distiller grain included and its quality.
\nGrowing beef cattle require protein in the form of amino acids to maximize growth rate. One of the most effective and practical methods of improving feed efficiency, growth performance and reducing nitrogen excretion in beef cattle operations is to optimize protein formulation in the diet of growing cattle. Previous works show the necessity of protein supplements to maintain optimum growth rate in growing cattle diets, when these diets are based on barley or corn grain. Wheat distiller grain has not only the similar content of energy for cattle growth because of highly digestible fibre and relative high fat, but also has high protein content either in total or in the form of rumen by-pass. We previously conducted a growing study using beef steers to compare protein source with canola meal, wheat distiller grain, corn distiller grain or fractionated corn distiller grain, and found an improvement of averaged daily gain and feed efficiency over the control group (no protein supplement) [23]. However, steers fed corn distiller grain performed slightly better than that of steers fed wheat distiller grain, likely because of higher fat in corn than wheat distiller grain. McKinnon and Walker [21] reported that growing steers fed wheat distiller grain at 25 or 50% of dietary dry matter gained faster and were more efficient than steers fed a barley grain diet. In contrast, no benefit was reported when wheat distiller grain was fed at level of 17% [24] or at levels up to 40% [14] in growing diets. It appeared that when the level of wheat distiller grain is too high, dietary protein level can be exceeded to the protein requirement by animal. For example, in the study by Gibb et al. [14], including 40% of wheat distiller grain resulted in a dietary crude protein concentration up to 26%, which considerably exceeded the protein requirement of 12–14% for growing cattle. Although protein can be utilised for energy, the transamination, deamination and excretion of excess nitrogen is physiologically costly to the animals and results in an overall loss of net energy.
\nFollowing growing period, beef cattle then go into the finishing phase. Rations for finishing beef cattle are high energy rations designed to put gain on as rapidly and efficiently as possible, to lay down adequate marbling, and to maximize carcass yield within a limited time frame. Thus, the finishing diets usually consist of high grain such as barley, corn or wheat at ranging 85–95%, and 5–15% of roughage. The role of roughage in finishing diets primarily serves as fibre source to stimulate chewing activity and to maintain rumen health. Number of studies were attempted to determine the optimum inclusion rate of wheat distiller grain as energy source in finishing diets. In barley grain-based finishing diets, no protein supplement is necessary since the protein requirement is met (12%). Feed consumption was either linearly increased [14, 25], linearly decreased [26] or did not differ [13] with increasing the inclusion rate of wheat distiller grain from 10, 20, 40 to 60%; however, growth performance and feed efficiency were overall not affected with increasing the replacement of grain with wheat distiller grain. These results indicated that wheat distiller grain can be successfully incorporated to substitute a portion of grain within finishing diets with minimal or no adverse impact on cattle growth performance.
\nThe low starch content, but high fibre content of wheat distiller grain is suggested that feeding wheat distiller grain may help reduce the ruminal acidosis and maintain rumen health. It is speculated that a possible reduction in ruminal acidosis by feeding wheat distiller grain may reduce the requirement for roughage in finishing cattle diets [27]. By entirely replacing roughage with wheat distiller grain, we observed that steers maintained a similar ruminal pH status, but reduced feed intake and improved digestibility compared to a diet containing minimum roughage (i.e. 5%) [11]. Apparently, cattle were able to prevent a further decline in ruminal pH status by adjusting feed intake; thus, cattle fed a roughage-free diet consumed less feed to keep a similar ruminal pH status as cattle fed a standard finishing diet. Our results suggested that wheat distiller grain is less effective than barley silage for maintaining ruminal pH even though the rapidly fermented starch content of diets containing wheat distiller grain is less compared with conventional finishing diets. Based on the previous metabolism study, a growth study was conducted using finishing steers fed diets that were replaced partly for barley grain and entirely for roughage with wheat distiller grain so that up to 35% of distiller grain was incorporated in total. The results showed that final live weight, daily gain and feed efficiency were not affected by increasing levels of wheat distiller grain. Therefore, although substitution of wheat distiller grain for roughage in finishing diets may increase the incidence of ruminal acidosis, this outcome does not appear to adversely impact the performance of the cattle. Such a practice could provide an alternative to roughage source to feedlot producers when the roughage is in shortage or provide a potential saving from reducing acres to roughage production.
\nCarcass traits and beef quality can be significantly impacted by changing diet formulation and quality of feed ingredients. However, several studies showed that the beef quality from cattle fed wheat distiller grain is comparable with that produced using the diets without wheat distiller grain incorporation. Yang et al. [23] reported that feeding wheat distiller grain to replace a portion of barley grain and barley silage in finishing beef cattle rations had overall no impacts on carcass traits. Actually, substituting wheat distiller grain for barley silage in diets fed to growing beef cattle improved meat fatty acid profiles by increasing content of total polyunsaturated fatty acids, linoleic fatty acids and alpha-linolenic acid in beef [28]. These results suggest that replacement of barley silage with wheat distiller grain cause favourable changes in the fatty acid profile of meat such as omega-3 fatty acids in beef. Similarly, Walter et al. [25] included 40% wheat distiller grain in finishing diets and observed no adverse impact on carcass quality or sub-primal boneless boxed beef yields. Animals fed wheat distiller grain included at 20 or 40% produced backfat, yield, ribeye area and marbling scores consistent with barley-finished cattle with no change in meat quality (chemical composition, cooking time, cooking loss, tenderness, drip loss, colour) or differences in sensory tests (taste, smell, sight) [29]. The addition of 20 or 40% of wheat distiller grain to the diet improves the meat fatty acid profiles by decreasing the fatty acid isomers 10
The co-products from brewing or wet milling corn processing that are similar to the distiller grain from ethanol plant, has been historically fed to dairy cattle as protein supplement, especially as ruminal undegradable protein source. However, with expansion of ethanol production and consequently increasing distiller grain availability, feeding wheat distiller grain to dairy cattle has been spread recently not only as protein source but also as energy or fibre sources [31]. In fact, high-producing dairy cows are often at risk of subacute rumen acidosis, a common digestive disorder usually caused by feeding a diet containing highly fermentable carbohydrates with insufficient effective fibre to maintain rumen health [32]. Because the distiller grain contain low starch which is highly fermentable in the rumen, and high digestible fibre as well as relative high fat, it was suggested that feeding distiller grain in dairy cow diets could be potentially reduce the incidence of rumen acidosis while maintain milk production. Numbers of studies have been conducted to assess wheat distiller grain as a fibre and energy source to partly replace grain, or roughage or both. Penner et al. [33] evaluated wheat distiller grain to include 10% of wheat distiller grain in the ration showed that feeding wheat distiller grain as a forage substitute increased milk yield by 7% and milk protein content by 9%, whereas milk fat content decreased from 3.36 to 3.04% even though milk fat yield was not affected. Zhang et al. [34] reported that feeding wheat distiller grain in partial replacement of barley grain had no negative effect on dairy cow production. Feeding wheat distiller grain as a partial replacement of barley silage can improve dairy cow production, but, it may decrease chewing time, ruminal pH and milk fat concentration [35]. Overall, substitution of wheat distiller grain for part of concentrate or roughage in dairy cow diets improves milk production as a result of increase of feed consumption without negatively impacting milk fat. In contrast, feeding wheat distiller grain to partly replace roughage may reduce milk fat content due to reduction of chewing activity and rumen pH. Thus, dairy producers and nutritionists formulate dairy rations to ensure cow chewing time is sufficient to maintain rumen pH which is linked to maintaining milk fat concentrations [34].
\nAbundant distiller grain from ethanol production can be used as alternatives to feed grains and other premium ingredients in sheep feeding to reduce feeding costs for sheep farmers. However, most of the studies with feeding wheat distiller grain are with cattle or pigs. With our best knowledge, only one study was conducted using growing lambs fed diets containing wheat distiller grain. O’Hara et al. [36] reported that wheat distiller grain could replace a mixture of barley grain and rapeseed meal at 20% dietary dry matter without negatively affecting feed intake, daily gain and carcass traits of growing lambs. Replacing part of barley grain with 20% of wheat distiller grain in finishing lambs also maintained a healthy rumen function, growth performance and carcass characteristics [36]. McKeown et al. [37] also found that triticale-based distiller grain could replace up to 60% barley grain without adversely affecting on growth performance or carcass traits of lambs. Inclusion of wheat distiller grain in growing or finishing lamb diets is likely a viable feeding management since wheat distiller grain can entirely replace protein supplement to meet protein requirement of growing lambs, and simultaneously used as energy and fibre source because of its high contents of protein, energy and fibre.
\nAmmonia emitted from animal feeding operations is a major air and water pollutant contributing to eutrophication, soil acidity, aerosol formation, and impaired visibility. Although ammonia is not a greenhouse gas, it may indirectly contribute to agricultural emissions of nitrous oxide, a potent greenhouse gas with a global warming potential of approximately 300 times that of CO2. During last decade, dramatic increase of high-protein by-products feeding in livestock animals as a result of increased production of corn and wheat distiller grain. Consequently, inclusion of the distiller grain in cattle diets as protein and energy source has been becoming a common practice in cattle production because of high nutritional value. With the increased use of high protein distiller grain in cattle diets, the potential for increased manure nitrogen is a concern. For instance, finishing diets that contain 30% wheat distiller grain have more than 20% (dry matter basis) crude protein, compared to the animal’s requirement of about 12%. As a result, the excess nitrogen is excreted in manure (feces, urine and bedding) leading to greater NH3 and N2O emissions. In feedlot cattle, only a small percentage of the protein consumed by feedlot cattle is retained in animal tissue and as a result 80–90% is excreted in urine and feces, mostly in urine since digestibility of feed protein is relatively high for most types of feeds. Li et al. [38] reported that increased nitrogen intake due to increased distiller grain feeding quantitatively increased nitrogen retention, excretion in feces and urine, whereas, proportionally, nitrogen excretion in urine increased (primarily in the form of urea) and nitrogen excretion in feces decreased. The study clearly identified that urinary nitrogen is the principal source of NH3-N volatilized from cattle manure during the initial 10 days of storage, accounting for an average of 90% of the emitted NH3-N. Thus, from an environmental point, it is important to match dietary protein supplies as closely as possible to rumen microbial and animal needs. However, when the distiller grain is included at high proportion as energy source in cattle diets, high nitrogen excretion is not avoidable, a factor that needs to be considered for manure management.
\nWheat distiller grain also contains high concentrations of phosphorus and sulphur [11]. The resulting manure from cattle fed wheat distiller grain, with high phosphorus content, can be beneficial for crop production, but it may also have a negative environmental impact due to increased phosphorus accumulation in crop lands surrounding feedlots [39]. Environmental concerns regarding phosphorus excretion are primarily associated with pollution of surface water. Dietary phosphorus intake was positively associated with the amount of phosphorus excreted in livestock manure [40]. Concentration of sulphur in wheat distiller grain was reported to range from 3.9 to 11.4 g/kg in dry matter [6, 11]. The high sulphur in distiller grain is mostly from chemicals added during the ethanol fermentation to control pH and for cleanup. Excreted sulphur can contribute to H2S emissions from livestock manure [41]. Li et al. [38] reported that increasing substitution of wheat distiller grain for barley grain and barley silage in diets fed to finishing cattle increased urinary phosphorus excretion. Thus, potential environmental implications of liquid runoff from the feedlot surface and potential phosphorus contamination of surface water need to be considered. In addition, the increased intake and urinary excretion of sulphur as a result of increased inclusion of distiller grain in feedlot diets [38] may increase ammonia and H2S emissions from the feedlot, in particular when combined with increased nitrogen excretion. Therefore, cattle producers that replace grains or forages with distiller grain need to take appropriate steps to develop nutrient management programs in order to minimize nutrient loss to the environment and to maximize use of both nitrogen and phosphorus.
\nIncrease of biofuel ethanol production has resulted in an increase of the production of wheat-based distiller grain, and thus increases in the use of distiller grains in the diets of livestock animals. The chemical composition of wheat distiller grain can vary considerably from plant to plant or between batches within plant depending on the type of wheat fermented and technology of fermentation used in ethanol plants. Direct nutrient analysis of each lot of wheat distiller grain is recommended if such information is not provided to ensure accurate ration formulation for precisely feeding ruminant animals. Wheat distiller grain contains higher protein, fibre, fat and minerals but very lower starch than the original grain. Protein quality in wheat distiller grain is high with moderate rumen degradability, and its fibre is highly digestible in the rumen. Therefore, wheat distiller grain can be used as good protein and energy source in ruminant diets. Wheat distiller grain is commonly fed in beef and dairy cattle feeding as either a protein or energy source or both. It is recommended that wheat distiller grain not be included in dairy rations at levels above 20%, whereas they can be fed to 40% of the diet of growing and finishing cattle. Wheat distiller grain can also be used as fibre source to partly replace roughage in cattle diets, whereas its effectiveness of stimulating chewing activity and maintaining rumen pH status is limited. Thus, feeding wheat distiller grain in place of roughage may increase the risk of rumen acidosis especially if it is used to replace all of the forage in beef cattle diets. With the mandatory inclusion of renewable fuels in gasoline, distiller grain is certain to continue to be an important feed source for ruminants. Development of rapid analysis procedures such as near-infrared spectroscopy may allow this ingredient to be formulated into diets with greater accuracy. The wheat distiller grain is high in nitrogen and phosphorus, and high inclusion in cattle diets, especially when it is used as energy source in cattle diets may exceed the protein requirement, thus increase the manure nitrogen excretion, a factor that needs to be considered for manure management.
\nCisplatin is a chemotherapy medicine which can cause hearing loss, tinnitus and vertigo. The most common and well documented toxicity affecting the ear is hearing loss and will be the main focus of this chapter [1, 2].
Cisplatin was first successfully used in the late 1970s as chemotherapy, in addition to surgery, for the treatment of men with testicular cancer and published in a landmark study in 1980 [3]. At that time Dr. Jon Pritchard at the Great Ormond Street Hospital for Children (GOSH) in London was researching new treatments for childhood cancer and had a particular patient with widespread ovarian cancer who would previously have been moved to palliative care. However, seeing the effect of cisplatin on testicular cancer in young men, he thought it might work on ovarian cancer in young women and got urgent permission to treat his patient with this new medication. The child’s tumour had a spectacular response and shrank enough for the surgeon, at the time Professor Spitz, to successfully remove the tumour without having to perform a hysterectomy. She was cured and when she had children of her own, Jon became Godfather to her first child. The History of cisplatin and its introduction to medicine was captured by The Wellcome Trust in 2006 [4].
However, the challenge of introducing this powerful new chemotherapy to treat children with cancer was its toxicity, it was extremely emetogenic provoking severe nausea and vomiting, and was toxic to the kidneys (renal toxicity), ears (ototoxicity) and peripheral nervous system (neurotoxicity). Research into the side effects of this medicine on children at GOSH began in 1985 when Dimitrios Kouliouskas started studying the renal toxicity [5, 6].
In 1987, both in Brussels and London, a combination treatment of cisPLAtin and DOxorubicin was showing promise in the treatment of children with large liver tumours (hepatoblastoma). These tumours need expert surgery to remove the whole tumour intact; this combination was able to shrink hepatoblastomas to make surgery safer and in some cases make it possible to remove previously unresectable tumours. It was Jon Pritchard who coined the phrase “PLADO” for this combination treatment when passing a Play-Doh store on the way back to the airport in Brussels. Later that same year at the annual meeting of the International Society of Paediatric Oncology (SIOP) in Jerusalem Jon, along with Dr. Jacques Plaschkes (Paediatric Surgeon, Berne), Dr. Giorgio Perilongo (Padua) and others formed the International Society of Paediatric Oncology Epithelial Liver group SIOPEL to improve the treatment of children with liver cancer.
With increased use of cisplatin an alarming incidence of hearing loss was observed and at GOSH, Consultant Audiologist Sue Bellman noted a striking pattern seen on hearing tests (audiograms). Audiograms are a measure of the intensity of sound in decibels (dB) required for a person to hear a particular frequency measured in Hertz (Hz). The patterns seen in children with cisplatin-related hearing loss were very consistent and led to the development of an ototoxicity grading scale (the Brock Grading Scale) which could be used to evaluate the hearing loss acquired by one child and compare it to that of other children treated with cisplatin [7]. In this way different treatment regimens of cisplatin could be compared for ototoxicity. The grading scale showed that some children were more susceptible to cisplatin ototoxicity compared to others when given the same cumulative dose. This idiosyncratic and varied severity suggests possible biological or genetic susceptibility to hearing loss and has led to years of study of the genetic predisposition of patients towards cisplatin ototoxicity.
Cisplatin remains one of the most effective chemotherapy drugs for childhood cancer and is a key component in the treatment of solid tumours, specifically, malignant germ cell tumours, liver tumours, neuroblastoma, osteosarcoma and retinoblastoma, but also brain tumours, particularly medulloblastoma and ependymoma. However, the occurrence of irreversible hearing loss that occurs in approximately 50% of cisplatin-treated children, is a serious clinical challenge [8, 9, 10].
The impact of the hearing loss, tinnitus and potentially vertigo caused by cisplatin has serious consequences for the child, their family and the society in which they live [11]. Very young children with even mild forms of hearing loss have difficulty developing the skills of language leading to communication problems and reduced school performance [1]. Acquired hearing loss in adolescents with previously normal hearing, causes serious social and emotional difficulties [12].
In children with brain tumours, cisplatin-related ototoxicity is made more debilitating by damage to the hearing from surgery and radiotherapy, and ototoxicity may compound the learning difficulties caused by radiation to the whole brain.
Other platinum based medications have been developed, (carboplatin and oxaliplatin), with the aim of reducing toxicity but they do not have the efficacy in many cancers to replace cisplatin except in certain circumstances. Carboplatin, which is now widely used in childhood cancer, is less ototoxic (its main toxicity is to bone marrow), but it cannot be substituted for cisplatin without careful clinical trial evidence that it is as effective. When used in combination with cisplatin, the combined ototoxicity is greater than the sum of the two individual drugs [13]. When carboplatin is used at high dose, such as for bone marrow ablation prior to autologous bone marrow transplantation, it is ototoxic.
As it is unlikely cisplatin will be replaced by other agents to treat childhood cancer any time soon, monitoring its impact on a child’s development and education, increasing awareness of its effects and support for families, and finding ways to prevent ototoxicity are the key medical needs for the foreseeable future. The results of recent oto-protection clinical trials testing agents to mitigate cisplatin hearing loss have recently been assessed and a clinical guideline published [14, 15].
Hearing and balance are the two senses that are perceived by means of the inner ear that consists of the cochlea (the organ of hearing) and the vestibular system (the organ of balance), see Figure 1.
The ear.
Hearing is the perception of sound and the vestibular system detects motion of the head and body. Together with vision and propriosepsis, which is the internal sense of positioning within the body, these senses are elementary for orientation and sense of safety in the world. For the developing child, normal hearing is essential to learn to detect, discriminate and identify sounds, culminating in the ability to use and understand spoken language, enjoy music and identify potential harm. A normal function of the vestibular system is essential for learning to move freely and efficiently. The importance of hearing for the development of speech and spoken language is well recognised and in several countries national newborn hearing screening programs have been implemented to detect congenital hearing loss as early as possible, and enable timely intervention. Hearing loss has many impacts on daily auditory functioning, communication, psychosocial wellbeing, and general health, so high quality hearing care for children is best delivered by multidisciplinary teams consisting of medical specialists, audiologists, speech language therapists and (developmental) psychologists. Acquired hearing loss may have multiple causes, but one of the common causes in childhood follows treatment for childhood cancer with cisplatin.
For a sound to be perceived, it has to travel through the external ear, the middle ear, the cochlea and the auditory nervous system to the auditory cortex in the brain. Sound waves are collected by the pinna and channelled by the external auditory canal to the tympanic membrane, causing it to vibrate. The middle ear is an air-filled cavity containing the ossicles (malleus, incus and stapes). The footplate of the malleus rests on the eardrum (tympanic membrane). When the membrane vibrates in response to sound it causes movement of the malleus. This movement is, in turn, transmitted via the incus and the stapes to the fluid filled cochlea.
The normal cochlea is a coiled structure with two and a half turns. It is divided lengthways into three fluid-filled compartments by two membranes (the basilar and Reissner’s membrane). These create three fluid filled spaces, the scala tympani is the lower compartment, the cochlear duct (scala media) the middle one and the scala vestibuli the upper compartment, as shown in Figure 2. The inner ear hearing apparatus (the organ of Corti) consists of two types of sensory hair cells, the inner hair cells and the outer hair cells, resting on the basilar membrane, also shown in Figure 2.
Cross section of the cochlear scalae in the basal turn.
When the middle ear stapes footplate moves, pressure waves in the cochlear fluid produce movement of the basilar membrane and the inner and outer hair cells in the organ of Corti. Excitation on the surface of the inner hair cells creates a neurotransmitter impulse which is transmitted along the cochlear nerve (VIIIth cranial nerve) to the brain stem and auditory region of the brain. Damage to both the inner and outer hair cells from cisplatin, causes loss of this signal transmission, with the highest sound frequencies lost first.
Childhood cancer is divided into haematological cancer and solid tumours. Haematological cancers occur in the bone marrow and lymph glands (leukaemia and lymphoma) and solid tumours occur in organs such as the liver, kidneys and nerves; solid tissues such as bone and muscle; and the brain (brain and spinal tumours). Cisplatin is currently used alone or in combination with other chemotherapy to treat solid tumours and brain tumours, and only rarely for leukaemia or lymphoma.
When given to children intravenously cisplatin causes acute nausea and vomiting, and may cause renal impairment (nephrotoxicity), neurotoxicity and ototoxicity. When given to adult patients, the dose limiting toxicity is neurological (peripheral neuropathy, tinnitus and vertigo) whereas in children its major long-term effect is ototoxicity with permanent irreversible hearing loss. The severity of ototoxicity varies with age being more severe in younger children, the dose of cisplatin administered at each treatment and cumulative dose of cisplatin given during the course of treatment. However, susceptibility to these effects and their severity vary from individual to individual. Some children will develop very little toxicity despite large cumulative doses and others will develop relatively severe toxicity with only one or a few doses. The significant heterogeneity in the occurrence of ototoxicity among similarly treated patients, suggests that genetic susceptibility contributes to the occurrence of cisplatin-related hearing loss in individual children [16, 17, 18, 19] (section 2.5.3).
Cisplatin is a simple chemical compound made up of an atom of the platinum metal bound with two atoms of chlorine on one side (cis) and two molecules of ammonia on the other side. When in solution in the blood surrounded by a high concentration of chloride ions cisplatin remains in its neutral form. However, when cisplatin enters a normal cell or a cancer cell which has lower concentrations of chloride ions, cisplatin undergoes spontaneous hydrolysis with water. In this activated state it can enter the nucleus of a cell and become irreversibly bound into the double strands of nuclear DNA forming a cisplatin-DNA adduct (Figure 3).
Cisplatin structure and mechanism of action [
Both normal and cancer cells have complex molecular mechanisms that have evolved to repair the damage to DNA caused by toxins such as cisplatin and other chemotherapy agents. If a cell can activate its molecular repair mechanism and successfully repair the damaged DNA, it will survive and continue to thrive, but if the damage is irreparable, both normal and cancer cells can switch on a molecular process called programmed cell death (apoptosis) and the affected cell will die. Cells can also resist the effect of cisplatin by producing free radicle oxygen molecules within the cell cytoplasm that neutralise the cisplatin molecule. The use of cisplatin in the treatment of children with cancer relies on the fact that solid tumour cancer cells are less able to repair DNA damage than normal cells, and are less resistant to cisplatin, making them more susceptible to apoptosis than the child’s normal tissues. However, within the cells of some normal tissues such as within the hearing apparatus, the kidney and peripheral nerves are directly damaged by the effects of cisplatin.
Cisplatin is administered intravenously. It is infused via a central venous catheter over various times but usually between 1 and 6 hours, and given with a large amount of hydration fluid with a high chloride concentration to reduce its toxicity. The hydration is usually administered over 24 hours so the child must stay in hospital during its administration. If the child is not hospitalised throughout this time, adequate hydration needs to be managed by other means.
In the early years, cisplatin was administered for an hour following a period of hydration of about 6 hours, with another 24 hours hydration afterwards.
Times of administration of cisplatin began to lengthen in the late 1980’s when it was found that lengthening the infusion time reduced the severity of the nausea and vomiting the child experienced. Cisplatin infusion times in Europe reached up to 96 hours continuous infusion. However, with the introduction of new classes of antiemetic drugs in the 1990’s, specifically the HT3 inhibitors (ondansetron and others) the cisplatin infusion times were able to be reduced [20].
In some settings and for some cancers, the dose of cisplatin was split over 5 days reducing the need for 24-hour hydration and hospitalisation. So, in place of a standard dose, and very emetogenic dose of 100 mg/m2 on one day, 20 mg/m2 would be given on day 1 through 5.
Cisplatin is highly emetogenic. The nausea and vomiting which ensues appears to be universal. Fortunately, the introduction of the HT3 inhibitors in the 1990s and additional classes of antiemetics more recently, the severity of emesis can be greatly modified in most children [20]. However, effective antiemesis requires a cocktail of antiemetics to be given at least 30 minutes prior to administering cisplatin and that the best antiemetic control is achieved from the very first cisplatin dose. Inadequate antiemetic treatment at the start of cisplatin therapy can lead to the development of anticipatory vomiting which is a particular problem in adolescents. This is when a patient starts to vomit when the idea of receiving chemotherapy is triggered for example on sight of the hospital or if they meet a ward staff member in a shop. Once anticipatory vomiting has become established it is very difficult to control.
Cisplatin is almost entirely excreted through the kidney. When in its ionised form, cisplatin is very toxic to kidneys, so to ensure cisplatin is excreted in non-ionised form it needs a high concentration of chloride ions in the posthydration fluid. Nephrotoxicity in young children is partially reversible although this may be due to further maturation of the kidney in very young children rather than actual improvement [5, 6].
The hearing loss caused by cisplatin is permanent and bilateral and it may worsen with time. It is worse in very young children, the ear at this age appears to be more susceptible to damage compared to that in older children and adults. Cisplatin causes high frequency hearing loss which may happen following the first cycle of treatment and once acquired it tends to worsen with increasing cumulative doses of cisplatin and eventually may spread towards the lower frequencies important for speech [7].
Cisplatin enters the inner ear or cochlea through a number of molecular transport pathways as shown in Figure 4 [21]. The cochlea (and vestibulum) are surrounded by several distinct barriers separating the inner ear vasculature and the inner ear fluid compartments that are filled with perilymph, endolymph or intrastrial fluid. Their anatomical sites are not yet clearly identified, but Neiberg et al. [22] summarise them as follows: “tightly coupled vascular endothelial cells form the blood-perilymph or blood-labyrinth barrier (BLB)”. The same authors consider the separation between blood, endolymph and intrastrial fluid as being more complex: “tightly coupled strial endothelial cells form the barrier between blood and intrastrial fluid”. This latter is separated from endolymph by epithelial marginal cells in conjunction with endothelial basal cells from the intrastrial compartment. These are also referred to as the blood-strial barrier or intrastrial fluid-blood barrier. The more general use of the term BLB covers all of these barriers.
Model of the cochlea and cisplatin (Pt) trafficking routes. Potential pathways for systemic Pt to cross the blood-labyrinth barrier and enter hair cells include (1) a transstrial trafficking route from strial capillaries to marginal cells, followed by clearance into endolymph; (2,3) traversing the blood lymph barrier into perilymph and subsequently into endolymph via transcytosis across the epithelial perilymph/endolymph barrier. (4) once in endolymph, Pt enters haircells across their apical membranes. (5) Pt in the scala tympani could also pass through the basilar membrane into extra cellular fluids within the organ of Corti and enter haircells across their basolateral membranes. S stria vascularis; F spirocytes in spiral ligament [
The BLB plays an important role in cochlear homeostasis to maintain its functional integrity. As a highly specialised capillary network it selectively allows the passage of nutrients and ions in and out of the cochlea, and functions as a shield to protect the inner ear from toxic agents. However, cisplatin seems to affect the stria vascularis and might cause breakdown of the BLB [23]. The permeability of the BLB is also influenced by inflammation, diuretics, noise and a number of other factors [22]. Several organs including the liver, spleen and kidneys are able to rapidly clear cisplatin and its derivatives. Due to its unique structure, however, this ability is considered to be low for the cochlea [24]. Thus, the BLB may serve as a port of entry for cisplatin, from which it is hard to escape. Cisplatin may be retained in the cochlea for several months to years after treatment [24]. Another drawback of the BLB that is mentioned in [22] is the difficulty it poses to deliver otoprotective agents to the cochlea, as systemic delivery is highly inefficient, while local delivery is inherently invasive with limited permeability of the round window membrane.
Cisplatin causes irreversible damage to the hair cells of the cochlear apparatus located in the inner ear. Once within the perilymph cisplatin may remain permanently trapped in the inner ear and may continue to cause delayed hearing loss [24]. The molecular mechanism of cisplatin related ototoxicity and destruction of the hair cells is currently unknown. It is thought to involve the production and activation of Reactive Oxygen Species, (ROS), within the cell cytoplasm which the cell attempts to neutralise by a specific molecular mechanism. However, the capacity of the hair cells to neutralise ROS may become exhausted with time or exceeded by the cisplatin dose, leading to hair cell death. Hair cells in the cochlea are fixed in number and do not regrow, so once destroyed hearing begins to be lost. This would explain why higher doses of cisplatin given per day cause more toxicity. Figure 5 shows how the hydrated complex is neutralised by the cell [25].
Cisplatin’s interaction with the cochlear antioxidant defence system. Cisplatin is converted to a cis-diammine(aqua)chloroplatinum(II) (a monohydrate cisplatin complex) upon entering the cell cytoplasm. These reactive platinum species can react with molecular oxygen (O2) to generate superoxide (O2−−) which is detoxified by superoxide dismutase (SOD) to hydrogen peroxide (H2O2) and oxygen. Hydrogen peroxide is further detoxified by catalase to water (H2O) and oxygen. Cisplatin reactive intermediates readily bind to and oxidise the antioxidant reduced glutathione (GSH) to oxidised glutathione (GSSH). Glutathione peroxidase (GSH.Px) consumes GSH to produce glutathione disulfide (GSSG) in the process of converting H2O2 to H2O. Glutathione reductase (GR) reduces GSSR to GSH by using the reduced form of nicotinamide adenine dinucleotide phosphate (NADP+) NADPH, as cofactor [
Over the years, several studies have focused on genetic susceptibility to cisplatin-induced hearing loss using candidate single nucleotide polymorphism (SNP) approaches and more recently genome wide association studies (GWAS). Results to date are conflicting, as studies were often underpowered and did not included multiple testing or replication efforts. Differences in patient populations (e.g., ancestry), sample size, methods of audiometric testing and end point definitions with regards to audiological testing or classification attributable factors that may explain these discrepancies in results and have shown, that certain cohort and treatment factors (e.g. cranial irradiation, type of platinum agent, total cumulative doses and use of co-medication) may be even more important than genetic susceptibility. In addition, comparison of genetic studies to date have been hampered by heterogeneity in phenotype definitions Table 1 [26, 27, 28].
Candidate gene studies | |||
---|---|---|---|
SNP | Described variants | Reference | Statistically significant |
ACYP2 | rs1872328 | 1#,2, 16# | Yes see also below in GWAS studies |
TPMT | rs12201199 rs1142345 rs1800460 | 1#,3,4,6,12,15# 1#,3,4,6,12,15# 1#,3,4,6,12,15# | CR CR CR |
COMT | rs9332377 rs4646316 | 1,3,4, 6,12 1,3,4,6,12 | CR CR |
SOD2 | rs1880 | 13#,15# | CR |
ABCC3 | rs1051640 | 6, 15# | CR |
LRP2 | rs22288171 rs2075252 | 7#,15# 7#,8, 12, 15# | CR CR |
GSTM1 | null | 7#,12 | No |
GSTM3 | *B | 10 | Yes but no replication |
GJB2 | rs80338939 | 9 | Yes but no replication |
GSTP1 | rs1695 | 5,12,15# | CR |
SLC22A2 | rRs316019 | 15# | Yes but no replication |
ACYP2 | rs1872328 | 13# 1# 2 15# | Yes GWAS n = 238 replication in historical subjects n = 68 paediatric brain tumours Yes CGA n = 156 brain tumours Yes CGA n = 149 various CNS and solid tumours No CGA in 900 various ped cancers |
WFS1 | rs62283056 | 14# 15# | Yes GWAS n = 511 replication in 18.620 subjects testicular cancers No CGA in 900 ped cancer patients |
Relevant SNP studies on cisplatin related hearing loss in childhood cancer by candidate gene studies*.
SNPS that were tested once, but not found to be associated with ototoxicity were not included. CR = conflicting result CDA = candidate gene approach. #: studies that adjusted for multiple testing.
(1)Thiesen, Pharmacogenetics and genomics, 2017; (2)Vos,Ppharmacogenetics and genomics, 2016; (3)Hagleitner, PloSone, 2014; (4)Yang, Clinical Pharmacology and Therapeutics, 2013; (5)Rednam, 2013; (6)Pusegoda, Clinical Pharmacology and Therapeutics 2013; (7)Choeypasert,2013;, (8)Riedeman, 2008; (9)Knoll, Laryngoscope, 2006; (10)Peters, AntiCancer drugs, 2000; (11)Brown,Cancer Med, 2015; (12)Ross, Nat Gen, 2009; (13) Xu, Nat Gen, 2015; (14) Wheeler, Clin Cancer Research, 2017; (15)Langer, EJC, 2020).
Currently, efforts are being made to identify and meta-analyse relevant genetic variants, to enable the selection of children with a high risk of platinum related hearing loss to facilitate clinical decision making and where possible to intervene to prevent ototoxic damage. Alongside intensifying hearing screening any other intervention would require careful clinical risk assessment aided by thoughtful discussions with parents, carers and older children themselves. This could then lead to agreeing on an alternative cancer treatment plan for the child [29].
Functional hearing is represented by ‘air conduction’ thresholds measured using headphones, and ‘bone conduction’ thresholds measured using a vibrator placed on the mastoid bone. The air conduction thresholds indicate the status of the external ear, middle ear, cochlea and central auditory nervous system. The bone conduction thresholds indicate the status of only the cochlea and central auditory nervous system.
A check-up of external - and middle ear status is required to exclude any conditions causing obstruction for the sound to reach the cochlea. When sound is obstructed from reaching the cochlea, this is called a conductive hearing loss. Causes for conductive hearing loss include accumulation of cerumen, infections or tympanic membrane perforation [30]. Otoscopy allows for visual inspection of the auditory canal, the tympanic membrane and part of the middle ear. Tympanometry may be used to indicate the presence of middle ear pathology, by measuring the mechanoacoustic properties of the middle ear system [31]. A probe is placed in the ear canal for a few seconds, which delivers a tone and changes the air pressure. The way in which the pressure changes affect the sound level developed in the ear canal can provide useful information about the status of the middle ear.
Several behavioural tests are available to estimate hearing thresholds in children. The reliability of these tests depends on the child’s age, neurological status, development and motivation.
The usual way to assess hearing function in older children and adults is to measure the air and bone conduction thresholds, i.e. the quietest sounds which can be detected, as most hearing problems are associated with raised (poorer) thresholds. Audiometry is the process of measuring hearing thresholds at a range of frequencies (pitches). Thresholds may be measured in various ways and are usually displayed on an audiogram, which shows the thresholds at each audiometric frequency. Different types of hearing loss and their classifications can be found in a previous IntechOpen book [32]. Figure 6 shows a typical Pure Tone Audiogram of normal hearing on the left and moderate cisplatin induced high frequency sensorineural hearing loss on the right.
An audiogram showing normal hearing on the left, and an audiogram depicting a typically symmetrical high frequency hearing loss on the right. The red line represents the results for the right ear, and the blue line the results for the left ear. The x-axis portrays the frequency of sound in hertz, and the y-axis the hearing level in decibel with acoustic reference zero for calibration given in ISO-381-1 for frequencies up to 8 kHz and in ISO-381-5 for the extended high frequencies (Meijer A.J.M. Childhood cancer related hearing loss and tinnitus. Utrecht University; 2021).
The horizontal axis shows the test frequencies. Octave intervals are tested from 125 or 250 to 8000 Hz (8 kHz). The vertical axis is the level of sound in decibels - termed dB HL (Hearing Level) where the quietest levels are at the top. Thus, the “normal range” is anything down to 20 dB HL (vertical axis) and thresholds higher than 20 dB HL (lower on the audiogram) represent a clinically significant hearing loss. Where there is no conductive hearing loss the air - and bone conduction thresholds are more or less the same, but when there is a hearing loss the air conduction thresholds are depressed further.
Figure 7 shows the levels and conductive frequencies of a variety of environmental sounds and components of speech (the so-called “speech banana”) in an audiogram format. Overlaying any audiogram onto this can indicate which sounds are audible and those which would be inaudible, which can illustrate the functional implications of various configurations of hearing loss.
The speech banana.
For the results of audiometry to be reliable, the child has to understand the instructions and has to be motivated to comply. For children younger than 5 years of age, audiometry is generally too challenging. Therefore, several other behavioural tests are available to estimate hearing thresholds in children. The reliability of these tests depends on the child’s age, neurological status, development and motivation.
Visual reinforcement audiometry is applied to estimate hearing thresholds in young children (6 months to 3 years of age). A visual reinforcer, such as an animated toy or picture is used to generate and maintain a head turn response to the sound stimulus presented through a speaker or ear phones.
To measure hearing thresholds in children aged 3 to 5 years, conditioned play audiometry may be applied. The child is conditioned to respond to a sound by performing an action (putting blocks in a box or stacking rings on a stick) [30].
Conventional audiometry has been considered the gold standard for obtaining hearing thresholds between 0.125 to 8 kHz in children of 5 years and older. The child presses a button in response to the sound stimulus. Additionally, the extended high frequencies (EHF) up to 16 kHz may be tested for identification of early ototoxic damage. EHF testing is less widely applied as special calibration of the equipment is required (A.J.M. Meier et al. in press).
For infants up to 6 months of age, behavioural tests are too inaccurate for hearing threshold estimation. To asses hearing of children of this age, objective tests are available and widely used in programs for new born hearing screening. These tests can also be used to confirm the outcome of behavioural testing in older children, and may be applied in children/adolescents who are not able to cooperate.
A simple and fast way to objectively assess hearing is a test of otoacoustic emissions (OAE), in which a soft probe is placed into the ear canal and the OAE or “cochlear echo” is recorded in response to moderate level clicks or a combination of pure tones delivered via the same probe. OAEs reflect the function of outer hair cells and are only produced in ears with normal hearing or a mild loss of 20–30 dB HL. Presence of an OAE response confirms normal or near-normal hearing. Absence of a response indicates the possibility of a hearing loss and the need for follow-up testing, though it is often due to temporary factors such as excessive head movement or middle ear fluid.
The main follow-up test in this age group is auditory brainstem response (ABR) testing. Disposable electrodes are attached to the baby’s head and rapid clicks or tone pips are delivered to the ear by an insert probe. The electrodes detect field potentials generated by the lower auditory pathways (cochlea and brainstem), producing a characteristic waveform response. The intensity of the stimuli is reduced until the waves are no longer visible, providing a close approximation to behavioural hearing thresholds. When the equipment is well calibrated and click stimuli are used, hearing thresholds around 3 kHz can be estimated, type of hearing loss can be determined (conductive or sensorineural) and integrity of the VIIIth cranial nerve and lower brainstem can be assessed. ABR is preferably measured during sleep, but in some situations sedation must be applied ([30], A.J.M. Meier et al. in press).
As cisplatin-induced ototoxicity in children may have a negative impact on speech-language development and quality of life, early detection of hearing loss by audiological assessments is important. Monitoring during and after cancer therapy facilitates audiological management including counselling of patients and family, and support of hearing function if necessary (hearing aids, assistive listening devices, speech and language therapy) [33]. During therapy, monitoring may also provide the opportunity to modify cisplatin dose, depending highly on the availability of an evidence-based alternative, and whether or not cisplatin is the backbone of treatment. For example, dose adjustment may not be applicable in patients with liver tumours, for whom cisplatin is the key component of survival [34].
A baseline assessment before start of cisplatin treatment, where possible, is important to identify pre-existing hearing loss, and is accompanied by questions on medical history including previous ear and hearing problems, family history, a check for dysmorphic features and presence of tinnitus. The timing of monitoring and the testing schedule during cancer therapy highly depends on the protocol and patient-specific circumstances. Serial assessments can be considered for patients who receive cisplatin, including a check of middle ear and inner ear function, and presence of tinnitus. A post-treatment assessment is used to identify hearing loss or to record progressive changes in hearing status, often performed within three months after cessation of treatment (A.J.M. Meier et al. in press). It may be necessary to continue monitoring up to several years after treatment to detect a delayed onset of hearing loss. Surveillance is advised annually for young survivors, every other year for older children, and every five years for adolescents and young adult survivors [35].
When cisplatin was first used in young children at GOSH there were no appropriate grading scales with which to compare ototoxicity measurements taken from children receiving the same or different treatments including cisplatin. There were the common toxicity criteria of adverse events (CTCAE) and the American Speech-Language Hearing Association (ASHA) criteria, but both compared hearing measured after treatment to baseline hearing. These approaches can be used in older children where baseline hearing can be established. In very young sick children it is difficult to get a reliable baseline and the tests used at a very young age are not the same as the tests used later on. Sue Bellman, the audiologist at the time at GOSH studied the particular pattern of hearing loss which the children were developing. She designed a scale which was published by Brock in 1991 and became known as the Brock grading [7]. Brock grading was later thought not to be sensitive enough and was developed further and a new scale published by Kay Chang in 2010 [36]. There followed a consensus meeting at the annual general meeting of SIOP in Boston and the SIOP scale was introduced and published in 2012 [21]. Grading can be done from the audiogram locally but when comparison of grading is required for the purposes of studying the toxicity of one treatment regimen with another in a clinical trial then central review of audiograms is necessary to assure consistency and quality. This is particularly the case in international clinical trials where the audiogram needs to be uploaded to the trial database for review.
The developmental and psychological impacts of deafness on children are diverse and substantial. In addition to the primary influence of hearing loss on the acquisition of language and literacy skills, children with any degree of hearing loss are at increased risk of experiencing social, emotional and behavioural difficulties as well as potential influences on quality of life, identity and self-esteem. All these consequences are well documented for children with congenital hearing loss, with research typically focusing on children with severe or profound deafness, and recently, those who have received cochlear implants. Research findings reveal a highly complex picture, with a large number of factors interacting to result in the difficulties presented by any individual child, including for example their language and communication skills, the cause of their deafness, their educational provision, and parental socio-economic status. The picture is somewhat less clear for children who have a mild or moderate hearing loss (often referred to as minimal hearing loss, and the largest group of children affected by ototoxicity), or those who acquired a loss during childhood due to illness directly (for example meningitis), or as in the case of ototoxicity, due to the treatment of illness. However, there is increasingly empirical evidence that is relevant in relation to the developmental and psychological impacts of ototoxicity-induced hearing loss.
The most significant impact of hearing loss is during infancy and early childhood, when language skills are developing at their fastest but delays may go unrecognised or untreated until the child enters school [37]. Thus age of exposure to ototoxic drugs is of particular importance, since even if the hearing loss is confined to the high frequencies, it can have subtle but significant impacts on speech perception and therefore speech production and intelligibility [38, 39]. Audibility and recognition of high-frequency speech sounds (s, f, th, sh, h, k, and t) and perception of fricative phonemes (e. g./s/) supports phonological and morphological development in young children with normal hearing and children with hearing loss [39]. Delays in language development acquired at this time may be hard to reverse, even with appropriate amplification and speech therapy [40].
A review of the literature on minimal hearing loss (comprising 69 articles, 6 of which included children with high-frequency hearing loss) concluded that although some individuals appeared to have no observable speech-language or academic difficulties, others experience considerable problems [37]. Those children that perform in the normal, average range on tests of language skills and academic attainments may in fact be under-performing in relation to their cognitive potential (IQ). In addition, children who appear not to have been negatively affected in terms of language and academic development, may still present with significant psychosocial problems. As a group, children with any degree of hearing loss, as well as those specifically with minimal hearing loss, exhibit higher rates of behaviour problems such as noncompliance, aggression, hyperactivity, impulsivity, and inattention than their hearing peers. They also have more emotional problems such as lower energy levels, higher stress and poorer self-esteem.
The psychosocial impact of hearing loss is also seen in terms of the effect on quality of life. A systematic review of 41 articles [41], showed that children with hearing loss generally report a lower quality of life than their normally-hearing peers. Their meta-analysis on four studies employing the Paediatric Quality of Life Inventory (PedsQL), revealed statistically and clinically significant differences in PedsQL scores between children with normal hearing and those with hearing loss, in the Social and School domains. Recently, a study reported detrimental effects of hearing loss on quality of life in children and adolescents who suffered hearing loss following ototoxic treatment compared with those whose hearing was unaffected [11]. All the areas assessed were impacted, including the ability to communicate with family and peers, level of independence, interactions with peers and emotional well-being. Long-term follow-up of childhood cancer survivors indicates significant hearing loss as predictive of poorer outcomes for school, employment and independent living [42].
As a result of these developmental and psychosocial consequences of ototoxicity-induced hearing loss it is essential that children are not only closely monitored in terms of their hearing thresholds, but also the wider language, learning, social, emotional and behavioural impacts. A range of interventions may be needed, including speech and language therapy, classroom and teaching accommodations and strategies to maximise access to speech and peer interactions, as well as therapeutic interventions to address emotional and behavioural problems.
The Global Initiative for Childhood Cancer (GICC) which was launched in 2018 by the WHO in partnership the International Society of Paediatric Oncology has the goal of improving the Global survival of children with cancer to 60% by 2030. As child cancer services develop and more gain children access cancer care, it will be necessary to develop policy and services to address the long term effects of chance treatment [43]. Cisplatin, is included in the WHO Essential Medicines List for Children (2017), but severe acquired hearing loss in child cancer survivors may have very significant impact on learning and future education opportunities of survivors and increase the health burden in families [44, 45]. Studies from low-and middle-income countries report the prevalence of hearing loss in community screened children as about 10%, while it is 23% for children with co-morbidities, such as HIV, tuberculosis, chronic suppurative otitis media and impacted cerumen% [46, 47]. Adding cisplatin as childhood cancer treatment may therefore increase the prevalence of hearing loss, which increases the need for early identification in the context of limited resources. Community health care workers have been successfully trained to assist and implement screening for hearing loss in communities, which should be used to assist in continuous assessment of hearing in children, surviving childhood cancer after cisplatin treatment and return to their communities [45]. These identified children should be referred back to the major urban treatment centres for further more sophisticated hearing assessment and management. However, it should be noted that in Sub-Saharan Africa, and in the most populous parts of South East Asia there is a general lack of audiologists and limited access to testing and hearing support, which may hamper rehabilitation. These resource-constricted countries should therefore establish partnerships with developed countries and non-governmental organisations to assist them in the management of childhood cancer survivors with hearing loss due to cisplatin [48].
A parent with a child going through treatment is always trying to find the balance between a desperate longing for their child to be cancer free whilst enduring the least possible short and long-term side effects. At the start of treatment, when doctors explain the risks of potential hearing loss when using cisplatin, it can be hard to fully appreciate and understand the long-term impact for your child. At this stage of treatment many different outcomes are as yet unknown. This is especially true if the child receiving treatment is very young and unable to communicate verbally. The impact of having to wear hearing aids and other assistive listening devices is unknown and therefore almost impossible to comprehend. Whilst going through treatment the support given by doctors and nurses is invaluable. Once treatment ends access to that level of specialised support ends too. Parents are delighted to have a child free from cancer but all too often they are left to deal with the consequences of long-term side effects on their own. This can mean that young children learning to speak, read and write are not given adequate learning support since parents do not always know how best to help them or even what kinds of basic learning support to ask for. At a young age the child will not know in what circumstances they find it difficult to hear and parents need to be aware of every situation in order to be able to help the child develop coping strategies. This is especially true in nursery and primary school settings where a child could quickly feel overwhelmed. It would be easy for that child to be incorrectly labelled as reclusive, of low ability or naughty in class. As the child gets older, they will be able to deal with situations more easily themselves but will easily get tired and quickly zone out. Parents might need to advocate for their child and make the school aware of their needs. Interventions could include sitting at the front of exam halls, increasing teacher awareness in situations like sports pitches, playgrounds, swimming pools and in noisy classrooms. It is easy for a child with hearing loss to retreat from interactions or to become frustrated and then behave poorly. Parents need assistance and information to know how best to help and support their child. Children need to be encouraged to ask for help rather than be singled out or stigmatised.
As soon as it was known that cisplatin caused irreversible hearing loss researchers began to look for drugs to protect against this side effect. Different medications have an impact at different points in the metabolism of the cell Figure 8 [49].
General mechanistic pathways of cisplatin-induced cytotoxicity in auditory cells and the mechanistic pathways by which the otoprotective clinical candidates combat cisplatin toxicity [
The most promising pre-clinical studies have come from Edward Neuwelt’s team in Portland Oregon [50, 51, 52]. They have been working on Sodium Thiosulfate (STS) and N-Acetyl Cysteine (NAC). As can be seen in Figure 8 these 2 drugs can act at different points both inside and outside the cell.
In 2019 a clinical guideline paper was written by a multidisciplinary team led by Lillian Sung and David Freyer [15]. The conclusion of this paper was that to date the most promising otoprotectant is STS, see Table 2 taken from this paper. STS is close to being licenced both in North America and Europe. The evidence for the use of STS in children comes from two phase III trials [53, 54] which both showed that the incidence of hearing loss can be reduced by 50% in children receiving STS as a 15 minute infusion given 6 hours after the cisplatin infusion ends.
Studies (n) | Patients (n) | Effect size * | 95% CI | I2 (%) | Value | |
---|---|---|---|---|---|---|
Any ototoxicity | 5 | 465 | RR 0.96 | 0.71 to 1.29 | 49% | 0.78 |
Severe ototoxicity | 4 | 223 | RR 0.85 | 0.34 to 2.12 | 0% | 0.72 |
Severe ototoxicity | 2 | 255 | RR 0.73 | 0.08 to 6.44 | 56% | 0.77 |
Any ototoxicity | 2 | 205 | RR 0.51 | 0.37 to 0.71 | 0% | <0.0001 |
Threshold at 4 kHz | 2 | 62 | MD-2.7 | −14.9 to 9.5 | 0% | 0.66 |
Threshold of 8 kHz | 2 | 62 | MD-1.6 | −14.8 to 11.6 | 0% | 0.81 |
Threshold at 4 kHz | 2 | 92 | MD-0.7 | −5.8 to 4.5 | 0% | 0.80 |
Threshold at 8 kHz | 2 | 92 | MD-8.7 | −18.1 to 0.7 | 34% | 0.07 |
Any ototoxicity | 2 | 78 | RR 1.60 | 0.62–4.13 | 0% | 0.33 |
Data synthesis of trials for cisplatin-induced ototoxicity prevention.
RR = risk ratio MD = mean difference *RR less than 1 and MD less than 0 favour intervention.
In adults, peripheral sensitive neurotoxicity which ranges from paresthesias to ataxic gait is the dose limiting toxicity of cisplatin [55]. This means that when patients develop severe neurotoxicity the dose of cisplatin needs to be adapted or stopped. In young children neurotoxicity is rarely observed.
Cisplatin hearing loss is considered to worsen with time. It is not clear whether this is due to ongoing toxicity from platinum retained in the cochlea or the addition of further assaults on the ear or both. Hearing educational programs for the young are few and far between [56]. It is clear that children who have received cisplatin as part of their therapy for cancer need to be supported but also educated as they go through follow up to conserve their hearing. It is possible that at the end of treatment ototoxicity damage is not yet apparent to the young person as it may only affect the higher frequencies out of their speech range. With time however as hearing worsens as a result of the toxicity, possibly in interaction with noise induced hearing loss [57], it may reach the speech frequencies and become apparent. Hearing conservation strategies should be introduced to the parents and child at an early stage and should encourage exclusion/reduction of factors which can lead to damage to residual hearing. Not all of these factors can be excluded however it is only fair that parents and patients are made aware of the additional risk to hearing that they bring. These include: loud sounds and noises; other ototoxic medication e.g., aminoglycosides; unhealthy diets; intracranial pressure changes for example as can occur with certain sports such as scuba diving; barotrauma; head injury and exposure to radiation and proton beam therapy. Where possible children and adolescents should be discouraged from listening to loud music through headphones over long periods of time, encouraged to wear protective ear plugs if exposed to loud noise, wear protective head gear when cycling; use a head rest/child safety car seat adjusted to height.
To raise awareness of policy makers to address the problems of preventable hearing loss worldwide, the WHO World Health Assembly adopted a resolution in 2017 (WHA70.13) to provide guidance for member states for the integration of ear and hearing care into national health plans. In response The World Report on Hearing has been developed (https://www.who.int/activities/highlighting-priorities-for-ear-and-hearing-care), proposing a set of interventions for prevention, screening, rehabilitation and communication.
A better understanding of the predisposing genetic factors and how to influence them as well as the introduction of licenced otoprotectants will hopefully reduce the incidence of acquired ototoxicity. In the meantime children who have already developed hearing loss or other ototoxicity need expert support, audiological intervention as well as encouragement, acceptance, patience and tolerance to support them fully socially integrating.
Cisplatin ototoxicity is a serious medical problem in children with cancer whos’ cure depends on the use of this drug. Progress has been made on understanding the mechanisms causing the toxicity and some of the predisposing factors. Expert counselling and management of the hearing loss, tinnitus and or vertigo is very important for all children. Understanding and adaptation at home, school and in the work place can facilitate better integration and outcomes for people suffering from acquired toxicity. Otoprotective drugs are being researched to reduce the severity of hearing loss and some will hopefully soon be licenced for use. However further research is needed in all areas to improve the quality of life for children who acquire this challenging side effect of treatment.
We would like to acknowledge Edward Neuwelt and his dedicated team of collaborators for all of the pre-clinical work on both STS. Also to David Freyer, Kristy Knight and Kay Chang for their dedication to the monitoring of late effects and particularly hearing loss in children receiving cisplatin and their efforts to research and prevent it.
Penelope Brock has been a consultant with Fennec Pharmaceuticals since 2017. All other authors have no conflict of interest.
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Fungi constitute a valuable source of pigments because they are capable of producing high yields of the substance in the cheap culture medium, making the bioprocess economically viable on the industrial scale. Some fungal species produce a dark-brown pigment, known as melanin, by oxidative polymerization of phenolic compounds, such as glutaminyl-3,4-dihydroxybenzene (GDHB) or catechol or 1,8-dihydroxynaphthalene (DHN) or 3,4-dihydroxyphenylalanine (DOPA). This pigment has been reported to act as “fungal armor” due to its ability to protect fungi from adverse conditions, neutralizing oxidants generated in response to stress. Apart from the scavenging activity, melanin exhibits other biological activities, including thermoregulatory, radio- and photoprotective, antimicrobial, antiviral, cytotoxic, anti-inflammatory, and immunomodulatory. 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Fungi constitute a valuable source of pigments because they are capable of producing high yields of the substance in the cheap culture medium, making the bioprocess economically viable on the industrial scale. Some fungal species produce a dark-brown pigment, known as melanin, by oxidative polymerization of phenolic compounds, such as glutaminyl-3,4-dihydroxybenzene (GDHB) or catechol or 1,8-dihydroxynaphthalene (DHN) or 3,4-dihydroxyphenylalanine (DOPA). This pigment has been reported to act as “fungal armor” due to its ability to protect fungi from adverse conditions, neutralizing oxidants generated in response to stress. Apart from the scavenging activity, melanin exhibits other biological activities, including thermoregulatory, radio- and photoprotective, antimicrobial, antiviral, cytotoxic, anti-inflammatory, and immunomodulatory. Studies have shown that the media composition and cultivation conditions affect the pigment production in fungi and the manipulation of these parameters can result in an increase in pigment yield for large-scale pigment production. This chapter presents a comprehensive discussion of the research on fungal melanin, including the recently discovered biological activities and the potential use of this pigment for various biotechnological applications in the fields of biomedicine, dermocosmetics, materials science, and nanotechnology.",book:{id:"5519",slug:"melanin",title:"Melanin",fullTitle:"Melanin"},signatures:"Sandra R. Pombeiro-Sponchiado, Gabriela S. Sousa, Jazmina C. R.\nAndrade, Helen F. Lisboa and Rita C. R. 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It gives an extended example of evaluation of animal behavior and brain properties using an original model of prenatal hypoxia in rats by various physiological, behavioral, immunohistochemical, molecular biological, and biochemical techniques at different stages of postnatal development, which provide a better understanding of the pathological processes in the human brain during the development of neurodegeneration.",book:{id:"5691",slug:"evolutionary-physiology-and-biochemistry-advances-and-perspectives",title:"Evolutionary Physiology and Biochemistry",fullTitle:"Evolutionary Physiology and Biochemistry - Advances and Perspectives"},signatures:"Igor А. Zhuravin, Nadezhda M. Dubrovskaya, Natalia L. Tumanova,\n\nDmitrii S. Vasilev and Natalia N. Nalivaeva",authors:[{id:"241024",title:"Dr.",name:"Igor А.",middleName:null,surname:"Zhuravin",slug:"igor-a.-zhuravin",fullName:"Igor А. 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Bera",authors:[{id:"77013",title:"Prof.",name:"Rajendra",middleName:null,surname:"Bera",slug:"rajendra-bera",fullName:"Rajendra Bera"}]},{id:"53118",title:"Oral Mucosal Melanosis",slug:"oral-mucosal-melanosis",totalDownloads:2784,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In the mouth, melanin is produced by melanocytes residing in the basal cell layer of the oral epithelium. Melanin influences the colour of the oral mucosa and provides protection against reactive oxygen species and bacterial-derived enzymes and toxins and acts as a physical barrier to both microorganisms invading the oral epithelium and to other microenvironmental stressors. The functional activity of epithelial melanocytes is regulated by biological agents in the microenvironment, including proopiomelanocortin-derived peptides, and by reciprocal interactions between melanocytes on the one hand and neighbouring keratinocytes and signals from the underlying lamina propria on the other hand. Oral mucosal melanin hyperpigmentation is common and may be physiological or pathological, and in either case the pattern of distribution and the intensity of the melanosis are variable. Physiological melanin hyperpigmentation is the result of increased melanin biosynthesis by melanocytes in the basal cell layer of the oral epithelium, but pathological melanin pigmentation may be the result of increased number of normal melanocytes or atypical melanocytes, of increased melanogenic activity of normal or atypical melanocytes, or of both. Oral mucosal melanin hyperpigmentation may be secondary to disease, medications, or smoking, and physiological oral melanin hyperpigmentation may be clinically and histopathologically similar so that the differentiation between pathological and physiological oral melanosis can at times be difficult.",book:{id:"5519",slug:"melanin",title:"Melanin",fullTitle:"Melanin"},signatures:"Liviu Feller, Razia A.G. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. The series on human physiology deals with the various mechanisms of interaction between the various organs, nerves, and cells in the human body.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11408,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}},series:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261"},editorialBoard:[{id:"213786",title:"Dr.",name:"Henrique P.",middleName:null,surname:"Neiva",slug:"henrique-p.-neiva",fullName:"Henrique P. 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