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.
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We 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!
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.
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Throughout 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\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\n
We 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
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The 8 chapters in this book are all written by experts in their topics. This excellent book provides the practicing physician and other healthcare personnel, who take care of patients with coronary artery disease, new information valuable in care of patients with coronary artery disease.",isbn:"978-953-51-3710-8",printIsbn:"978-953-51-3709-2",pdfIsbn:"978-953-51-4026-9",doi:"10.5772/68027",price:119,priceEur:129,priceUsd:155,slug:"coronary-artery-bypass-graft-surgery",numberOfPages:186,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"1fc460064df1f705a67a5e583524f982",bookSignature:"Wilbert S. Aronow",publishedDate:"December 20th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/6068.jpg",numberOfDownloads:16049,numberOfWosCitations:7,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:6,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:17,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 28th 2017",dateEndSecondStepPublish:"March 21st 2017",dateEndThirdStepPublish:"September 22nd 2017",dateEndFourthStepPublish:"October 22nd 2017",dateEndFifthStepPublish:"December 22nd 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"164597",title:"Dr.",name:"Wilbert S.",middleName:null,surname:"Aronow",slug:"wilbert-s.-aronow",fullName:"Wilbert S. Aronow",profilePictureURL:"https://mts.intechopen.com/storage/users/164597/images/system/164597.jpg",biography:"Wilbert S. Aronow, MD, is a Professor of Medicine at New York Medical College and Director of Cardiology Research at Westchester Medical Center, Valhalla, NY, USA. He has edited 20 books and is the author or co-author of 1653 papers, 210 book chapters, 846 commentaries, 50 letters to the editor, and 1187 abstracts. He has also presented or co-presented 1565 talks at meetings. He has been a member of four national guidelines committees including being a co-author of the 2010 Society for Post-Acute and Long-Term Care Medicine (AMDA) guidelines for heart failure, co-chair and first author of the 2011 American College of Cardiology/American Heart Association (ACC/AHA) expert consensus document on hypertension in the elderly, a coauthor of the 2015 American College of Cardiology/American Heart Association/American Society of Hypertension (AHA/ACC/ASH) scientific statement on the treatment of hypertension in patients with coronary artery disease, and a co-author of the 2017 ACC/AHA guidelines for the management of patients with hypertension. He was also a co-author of a 2015 position paper from the International Lipid Expert Forum. Dr. Aronow was a consultant to the American College of Physicians Information and Educational Resource (PIER) on the module of aortic stenosis, a consultant to the American Board of Internal Medicine on hypertension, a member of the board of directors of the ASPC, a member of the ACCP Cardiovascular Medicine and Surgery Network Steering Committee, a committee member of other professional societies, and a consultant to many government agencies.",institutionString:"New York Medical College and Westchester Medical Center",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"New York Medical College",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1141",title:"Cardiothoracic Surgery",slug:"cardiothoracic-surgery"}],chapters:[{id:"56834",title:"Evaluation of Coronary Artery Bypass by CT Coronary Angiography",doi:"10.5772/intechopen.70439",slug:"evaluation-of-coronary-artery-bypass-by-ct-coronary-angiography",totalDownloads:2225,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Coronary computed tomography angiography (CCTA) is an accurate method for graft imaging and assessment than invasive coronary angiography (ICA). CTA has excellent sensitivity and specificity. The chapter describes the role of CTA in evaluation of coronary bypass graft. It covers the appropriate indications for performing CTA after bypass operation, patient preparation, as well as protocol and technique of CTA. The chapter describes the post-examination processing of the images and how to interpret CTA images for detection of graft patency or dysfunction as occlusion, partial thrombosis, poor blood flow, and stealing flow from native artery. According to the American College of Cardiology, the American College of Radiology, and the North American Society for Cardiovascular Imaging, graft patency assessment with CTA is an appropriate approach in symptomatic patients at risk for graft stenosis/occlusion. Cardiac CT can be used to assess the patency of coronary artery bypass graft (CABG) with high diagnostic accuracy compared with ICA and even with a better performance compared to the assessment of native coronaries.",signatures:"Ragab Hani Donkol, Zizi Saad Mahmoud and Mohammed Elrawy",downloadPdfUrl:"/chapter/pdf-download/56834",previewPdfUrl:"/chapter/pdf-preview/56834",authors:[{id:"73459",title:"Prof.",name:"Ragab",surname:"Donkol",slug:"ragab-donkol",fullName:"Ragab Donkol"},{id:"214773",title:"Dr.",name:"Zizi",surname:"Saad Mahmoud",slug:"zizi-saad-mahmoud",fullName:"Zizi Saad Mahmoud"},{id:"215357",title:"Dr.",name:"Mohammed",surname:"Elrawy",slug:"mohammed-elrawy",fullName:"Mohammed Elrawy"}],corrections:null},{id:"56664",title:"The Choice of Graft Conduits in Coronary Artery Bypass Grafting",doi:"10.5772/intechopen.70398",slug:"the-choice-of-graft-conduits-in-coronary-artery-bypass-grafting",totalDownloads:1701,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The use of the left internal mammary artery (IMA) has been shown to improve long-term survival and has been a gold standard in coronary artery bypass grafting (CABG). However, the choice of second or third graft conduit is still controversial. Multiple studies demonstrated the benefit of using multiple arterial grafts such as right IMA and radial artery in addition to left IMA in terms of long-term survival and graft patency. However, most of the centers still perform CABG with one IMA and vein grafts in a real world. The challenges for bilateral IMA utilization include longer operative time and concerns for higher rates of perioperative morbidity and mortality associated with increased sternal wound infection. Several studies reported that skeletonization technique can reduce the risk of sternal wound infection. Radial artery is another arterial conduit, which does not increase the risk of sternal wound infection and is easy to harvest. The superiority between radial artery and right IMA has been controversial. In the meantime, multiple trials have been made to improve the patency of vein grafts. The choice of graft conduits in CABG should be well considered preoperatively based on each patient’s backgrounds.",signatures:"Takashi Murashita",downloadPdfUrl:"/chapter/pdf-download/56664",previewPdfUrl:"/chapter/pdf-preview/56664",authors:[{id:"192448",title:"Dr.",name:"Takashi",surname:"Murashita",slug:"takashi-murashita",fullName:"Takashi Murashita"}],corrections:null},{id:"58131",title:"Left Main Coronary Artery Disease: Current Treatment Options",doi:"10.5772/intechopen.71562",slug:"left-main-coronary-artery-disease-current-treatment-options",totalDownloads:2500,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Significant left main coronary artery disease is defined as a greater than 50% angiographic narrowing of the vessel. In general, there are three options for the treatment of LMCA disease which include optimal medical therapy, percutaneous revascularization, or surgical revascularization, either off-pump or on-pump. It is the highest-risk lesion subset of ischemic heart disease and until recent years, coronary artery bypass grafting was the major choice of treatment. Although there is a marked increase in use of percutaneous coronary intervention in left main disease, there are still some questions about its efficacy when compared with surgery. Although bypass surgery is the gold standard, current treatment guideline recommendations canalized the treatment of this potentially lethal disease into percutaneous interventions in selected patients who had low to intermediate anatomic complexity. Left main disease with low SYNTAX scores (≤22) can be treated either by bypass surgery or percutaneously, whereas SYNTAX score > 32 is an indication for only coronary artery bypass surgery. The heart team should always be in collaboration, give therapeutic options to patients and decide the best treatment strategy for the welfare of the patient.",signatures:"Omer Tanyeli",downloadPdfUrl:"/chapter/pdf-download/58131",previewPdfUrl:"/chapter/pdf-preview/58131",authors:[{id:"207372",title:"Dr.",name:"Omer",surname:"Tanyeli",slug:"omer-tanyeli",fullName:"Omer Tanyeli"}],corrections:null},{id:"56794",title:"Coronary Artery Bypass Grafting in Patients with Diabetes Mellitus: A Cardiologist’s View",doi:"10.5772/intechopen.70416",slug:"coronary-artery-bypass-grafting-in-patients-with-diabetes-mellitus-a-cardiologist-s-view",totalDownloads:1511,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The review presents current data on the prevalence of diabetes in the cohort of patients undergoing coronary artery bypass grafting. The relevance of active approach to the identification of diabetes and prediabetes in patients with coronary artery disease (CAD) before coronary revascularization is reviewed. Recent information about the negative impact of diabetes on the prognosis of myocardial revascularization is reported as well as the main mechanisms responsible to the development of adverse outcomes of interventions in these patients. Target perioperative values of glycemia recommended by the leading associations of the study of diabetes have been compared. Beneficial potential of other carbohydrate metabolism markers (glycated hemoglobin, fructosamine, 1,5-anhydroglucitol) in patients with diabetes mellitus (DM) in terms of their impact on cardiovascular prognosis, including coronary intervention. The results of studies comparing different management strategies for these patients are reviewed. The significance of carbohydrate metabolism compensation during myocardial revascularization is reported; thus, a too stringent glycemic control has no benefits neither for percutaneous nor for open coronary intervention. Recent trials suggest the groups of antidiabetic drugs and evidence of their impact on the cardiovascular system. The importance of comprehensive monitoring of major risk factors in diabetic patients with coronary intervention has been proved.",signatures:"Bezdenezhnykh Natalia Alexandrovna, Sumin Alexei Nikolaevich,\nBezdenezhnykh Andrey Viktorovich and Barbarash Olga\nLeonidovna",downloadPdfUrl:"/chapter/pdf-download/56794",previewPdfUrl:"/chapter/pdf-preview/56794",authors:[{id:"206416",title:"Dr.",name:"Natalia",surname:"Bezdenezhnykh",slug:"natalia-bezdenezhnykh",fullName:"Natalia Bezdenezhnykh"},{id:"207219",title:"Prof.",name:"Alexei",surname:"Sumin",slug:"alexei-sumin",fullName:"Alexei Sumin"},{id:"207222",title:"Prof.",name:"Olga",surname:"Barbarash",slug:"olga-barbarash",fullName:"Olga Barbarash"},{id:"207321",title:"Dr.",name:"Andrey",surname:"Bezdenezhnykh",slug:"andrey-bezdenezhnykh",fullName:"Andrey Bezdenezhnykh"}],corrections:null},{id:"58188",title:"Coronary Artery Bypass and Stroke: Incidence, Etiology, Pathogenesis, and Surgical Strategies to Prevent Neurological Complications",doi:"10.5772/intechopen.72389",slug:"coronary-artery-bypass-and-stroke-incidence-etiology-pathogenesis-and-surgical-strategies-to-prevent",totalDownloads:1509,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Current data suggest that cardiac bypass surgery is the single largest cause of iatrogenic stroke. Among the strategies to decrease or eliminate aortic manipulation, there is the use of off-pump coronary artery bypass grafting (CABG) through an aortic “no touch” technique, which reduces significantly the stroke rate. However, this off-pump aortic “no touch” technique is not always applicable, and, when saphenous vein and/or free arterial aortocoronary grafts are used, there is still risk of neurological injury due to tangential aortic clamp applied during the proximal anastomosis sewing. We aim to analyze the current incidence, etiology, and physiopathology of the neurological complications after coronary artery bypass surgery. We describe the methods and techniques that provide reduction in the occurrence of neurological complications. CABG with multiple clamp technique failed to find a better outcome in terms of neuropsychological deficit in the OPCABG group. By the way, patients undergoing CABG with single clamping seems to have better outcomes, suggesting that the cross-clamping technique used and minimal aortic manipulation could have had a role in reducing neurocognitive impairment. Moreover, surprisingly, CPB seemed to be a neuroprotective factor, and this aspect could be linked to the mild hypothermia used during on-pump surgery.",signatures:"Marco Gennari, Gianluca Polvani, Tommaso Generali, Sabrina\nManganiello, Gabriella Ricciardi and Marco Agrifoglio",downloadPdfUrl:"/chapter/pdf-download/58188",previewPdfUrl:"/chapter/pdf-preview/58188",authors:[{id:"57128",title:"Dr.",name:"Marco",surname:"Gennari",slug:"marco-gennari",fullName:"Marco Gennari"}],corrections:null},{id:"56902",title:"Arrhythmias Post Coronary Artery Bypass Surgery",doi:"10.5772/intechopen.70423",slug:"arrhythmias-post-coronary-artery-bypass-surgery",totalDownloads:2508,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Arrhythmias are common after cardiac surgery such as coronary artery bypass grafting surgery. Although most of these arrhythmias are transient and have a benign course, it may represent a significant source of morbidity and mortality. Postoperative arrhythmias (POAs) include atrial tachyarrhythmias, ventricular arrhythmias, and bradyarrhythmias. The incidence of POAs has not changed despite improvements in anesthetic and surgical techniques. The tachyarrhythmias in the postoperative period include atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia. The clinical significance of each arrhythmia depends on several factors that include cardiac function, patient’s comorbidities, arrhythmia duration, and ventricular response rate. Tachycardia with uncontrolled ventricular rates can cause diastolic and later on systolic dysfunction, reduce cardiac output, and result in hypotension or myocardial ischemia. In the other hand, bradyarrhythmias may have a remarkable influence on patients with systolic or diastolic ventricular dysfunction. Arrhythmia management starts preoperatively with optimizing the patient’s condition and controlling patient’s risk factors, intra-operatively with careful attention to hemodynamic changes during surgery and uses appropriate anesthesia, and postoperatively with correction of temporary and correctable predisposing factors, as well as specific therapy for the arrhythmia itself. The POAs treatment urgency and management options are determined by the clinical presentation of the arrhythmia.",signatures:"Bandar Al-Ghamdi",downloadPdfUrl:"/chapter/pdf-download/56902",previewPdfUrl:"/chapter/pdf-preview/56902",authors:[{id:"189192",title:"Prof.",name:"Bandar",surname:"Al-Ghamdi",slug:"bandar-al-ghamdi",fullName:"Bandar Al-Ghamdi"}],corrections:null},{id:"57760",title:"Physical Training Programs After Coronary Artery Bypass Grafting",doi:"10.5772/intechopen.71978",slug:"physical-training-programs-after-coronary-artery-bypass-grafting",totalDownloads:1972,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Exercise-based rehabilitation is considered an important adjunct therapy for secondary prevention in patients with coronary artery disease, mainly in populations with coronary artery bypass graft (CABG) and percutaneous coronary intervention. Thus, the increasing number of cardiac surgeries along the years is enlarging the participation of patients in cardiac rehabilitation programs. Encouraging exercise-based cardiac rehabilitation might decreases in-hospital stay, speeds returns to work and reduces costs in public health. Recently, two training modalities of exercise gained much attention in cardiac rehabilitation programs: continuous exercise and high-intensity interval aerobic training (HIIAT). The aim of this chapter is to review the effects of HIIAT in patients that undergone to CABG or other cardiac surgeries regarding clinical and physiological parameters such as death, cardiovascular outcomes, aerobic capacity, anaerobic capacity, quality of life and other parameters, beyond to evaluate the feasibility and safety of HIIAT in this patient’s group.",signatures:"Aikawa Priscila, Nakagawa Naomi Kondo, Mazzucco Guillermo,\nPaulitsch Renata Gomes and Paulitsch Felipe da Silva",downloadPdfUrl:"/chapter/pdf-download/57760",previewPdfUrl:"/chapter/pdf-preview/57760",authors:[{id:"67407",title:"Prof.",name:"Naomi Kondo",surname:"Nakagawa",slug:"naomi-kondo-nakagawa",fullName:"Naomi Kondo Nakagawa"},{id:"127508",title:"Dr.",name:"Priscila",surname:"Aikawa",slug:"priscila-aikawa",fullName:"Priscila Aikawa"},{id:"207394",title:"Dr.",name:"Felipe",surname:"Paulitsch",slug:"felipe-paulitsch",fullName:"Felipe Paulitsch"},{id:"220151",title:"BSc.",name:"Guillermo",surname:"Mazzucco",slug:"guillermo-mazzucco",fullName:"Guillermo Mazzucco"},{id:"220152",title:"MSc.",name:"Renata Gomes",surname:"Paulitsch",slug:"renata-gomes-paulitsch",fullName:"Renata Gomes Paulitsch"}],corrections:null},{id:"57784",title:"Medical and Surgical Management and Outcomes for Coronary Artery Disease",doi:"10.5772/intechopen.71979",slug:"medical-and-surgical-management-and-outcomes-for-coronary-artery-disease",totalDownloads:2123,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Coronary artery disease (CAD) is a major cause of death and disability in developed countries. Although coronary artery disease mortality rates worldwide have declined over the past decades, CAD remains responsible for about one third or more of all deaths in individuals over the age of 35 years. Various methods of treatment have been proposed including medical therapy, catheter-based interventions, and lastly, coronary artery bypass grafting. The purpose of this chapter is to outline those treatment regimens and examine the literature detailing their outcomes in hopes of guiding treatment.",signatures:"Allan Mattia and Frank Manetta",downloadPdfUrl:"/chapter/pdf-download/57784",previewPdfUrl:"/chapter/pdf-preview/57784",authors:[{id:"219621",title:"Dr.",name:"Frank",surname:"Manetta",slug:"frank-manetta",fullName:"Frank Manetta"},{id:"220462",title:"Dr.",name:"Allan",surname:"Mattia",slug:"allan-mattia",fullName:"Allan Mattia"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3542",title:"Artery Bypass",subtitle:null,isOpenForSubmission:!1,hash:"6b48ec67e1291ca98f3aded6a9af92ca",slug:"artery-bypass",bookSignature:"Wilbert S. 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1. Introduction
Life in the society is shaped by a set of principles, values, and concepts that determine approval or disapproval judgments in the interpersonal relationships and actions of the individuals. In this context, ethics seeks to reflect and understand the presuppositions of morality, aimed at achieving the best result for people and society [1].
However, this concept was expanded through scientific and technological advances, emerging bioethics in the 1970s, which means “ethics of life” in the literal sense. Bioethics proposes the dialog between the biological and human sciences. In 1971, the oncologist and university professor Van Rensselaer Potter published the book Bioethics: A Bridge to the Future, placing bioethics as necessary to ensure human survival in the accelerated civilization development. He reported that knowledge has been acquired at a speed far greater than the capacity and ability to know what to do with it [2].
Bioethics needs to be considered not only in the research and development area but also in interprofessional relationships in health, not limiting the analysis of such relationships only to deontological codes. In this sense, the North American principalist model is shown as a good ally in directing actions, reflections, and decisions of health professionals [1].
The beneficence, non-maleficence, autonomy, and justice principles can be applied prima facie in health decision-making. Beneficence suggests the need to do good, requiring professionals’ knowledge and skills to distinguish which procedures and practices are beneficial and which can harm. Non-maleficence is not exposing the patient to risk situations, minimizing damages, and seeking other alternatives. Autonomy represents the patient’s right to decide what is done to his body and health, based on his life purpose, principles, and creed. The principle of justice is the social duties and benefits, which are contemplated and guaranteed in the Federal Constitution of 1988 and in the Organic Law of Health (Law 8080/90) [3].
In different healthcare settings, terminality is a topic full of ethical dilemmas that require decision-making by the professional who is always trying to overcome death and interfere in different ways in this process. As death is still a “taboo” in our society, when it occurs in health services, it becomes more evident as a medical failure than the simple understanding of the natural course of life, leading to bioethical discussions and problems [3].
Facing the current conjuncture of advances in technological development for the extension of life, death previously seen naturally and as part of the process of human finitude is now tried to be avoided. At present the usefulness of life support therapies is questioned, such as: When to interrupt or maintain life without hurting the principles of bioethics? [4].
The problems revealed with end-of-life care express the importance of intensifying the debate about the imminence of death and human terminality, analyzing the progress of the social behaviors and the ethical precepts of health professionals in palliative care [5].
In this context, the theme of the advance directives (ADs) has been discussed in Brazil, which consists of deciding what care to receive in the period before death, ensuring to the patient more dignity and quality in this process. Refusing unnecessary interventions, pain and suffering relief, and home care around the family rather than hospital isolation are debatable issues that express the patient’s autonomy.
Therefore, legal issues of effectiveness of the social rights and the affirmation if they contemplate the fundamental rights of the constitutional legal order expressed by the Democratic State of Law will be addressed, with due guarantees and legal safeguards of the existential minimum or the possible reserve, accessibility to justice as a common good.
Thus, this chapter addresses the bioethical and legal issues involving ADs and nursing in the Brazilian context, proposing a deepened reflection and criticism on the topic and subsidies for decision-making involving the nursing professional.
2. Advance directives and nursing
Brazil is following the world trend with a significant increase in the population over 65 years old, from 4.1% in 1991 to 7.4% in 2010. In 2020, it is assumed that Brazil will be sixth worldwide, considering the older adult population [6].
In this context, the increase in life expectancy and in the supportive technologies has led to a substantial increase of terminally ill patients. During the terminality of life, the individual is faced with unusual events and arduous decisions regarding health care, including communication of bad news, palliative care, advance directives (living will), order of not resuscitating, and dysthanasia [7].
Little is prepared for death. Even the health professionals are prepared to seek only life above all, putting death as something to be defeated [8]. In the situations where the medical behaviors are exhausted, the palliative care appears to offer better assistance to the patient and to minimize the suffering [9].
Biologically, death is a consequence of the vital functions, cardiac and respiratory end, and over the years, even feared, it has been postponed through the use of various technologies. Cardiopulmonary resuscitation (CPR) in some cases keeps the heart pumped only for a short period turning into an invasive and traumatic experience and sometimes depriving the patient of their choice of death that can lead to a loss of dignity and prolongation of suffering [10, 11]. Thus, the question is: What benefits are added to the state of human existence in which the person does not establish more relationships with other people, as in the case of the state of coma? Why increase the days of life, concomitantly, to the affliction of the patient and their relatives? [3].
Under some conditions, the decision to maintain life at any cost must be taken by the patient, because although death is relatively close, he is still alive and conscious, and his wishes must be respected as far as possible [12]. The act of deciding what care to receive in the period before his death guarantees more dignity during the process of dying [13] since the bioethical principle of autonomy can interfere, question, and choose procedures or treatments [3].
In the meantime, it is worth noting that the principle of autonomy foresees that decision-makers are rational agents with appropriate cognitive conditions for the understanding of their own interests and without any external controlling influences. Thus, the obligation to respect the autonomy of the patient can exceed the duty of beneficence of doctors and health professionals, if rationality and knowledge of the patient’s situation can be confirmed [14].
Also a greater vulnerability of the patients with chronic neurological-incapacitating conditions should be considered, such as Parkinsonism or muscular dystrophy. In these cases, it is important to create a formal communication process, from the diagnosis of a serious illness. For neurology patients, the period between the diagnosis and the loss of communication capacity is frequently limited, and the opportunity of effective communication in this period should not be missed [14].
Under the view of humanization, the technical-scientific advance restricts the patient, since health care is directed to attend only biological and physiological aspects. Thus, ADs enable patients to express the subjectivities of their desires and, with dignity, to direct what they expect for their days to the end of life.
These advances have enabled some patients to survive in persistent or minimally conscious vegetative states for decades. In these cases, due to emotional issues, the caregivers opt for care continuity. However, such decisions have impacts on the patient’s quality of life and ethical responsibility for the distributive justice of health systems. Doctors are encouraged to make decisions in individual cases since conflicts may be unavoidable. In cases of some conflict, doctors may ask help to nurses as they are professionals who are with patients most of the time, being potential experts of their wishes [14].
Given such conditions, advanced care planning (ACP) strategies have been discussed in India, ensuring that adults at any age or stage of health understand and share their personal values, life goals, and preferences regarding future medical care. In this context, the main responsibilities of neurologists in medical practice in end-of-life care appear in two situations: catastrophic brain injury (CBI) and life-limiting neurological illness (LLNI). Patients with CBI are hospitalized in an altered mental status, and life-sustaining treatments (LST) are often performed immediately after. Also the difficulties of decision-making for not presenting legislation on the declaration of death by neurological criteria were pointed out, recommending that the medical team makes decisions, in conflicting cases, in consensus with the relatives and other members of the health team [14].
In Brazil, as being a very recent topic, there is little research that explains the ADs and the understandings of health professionals and society on the theme [15].
Currently, the consideration for the patient autonomy is being discussed, as well as the power to express opinions, make decisions, and proceed according to their personal principles and rules [16]. This right is shown in Article 15 of the Civil Code and Articles 22, 23, and 24 of the Code of Medical Ethics (CEM).
In the world context, ADs appeared in the United States in the 1960s and were initially presented by the American Society for Euthanasia in 1967 through the document entitled “Living Will (TV),” in which the individual could register their wishes to cease the medical conceptions of continuity of life [17].
It is suggested that advance care planning initially includes information about the types of life-sustaining treatments available and decisions about the types of treatment that patients would or would not want if they were diagnosed with a life-limiting illness. Afterward, it is necessary to encourage the sharing of personal values by patients and their families, and only then the ADs should be written, expressing what kind of treatment they would like or not if they could not speak for themselves [18].
If the patient does not have the cognitive conditions to decide, it is suggested that the substitute decision-maker meets the following criteria: being able to make a decision, being available and willing to do so, and being legally established as representatives of the patient. In the absence of a legally established representative for decision-making, the next of kin may be considered a substitute [18].
In Brazil, from the juridical point of view, in the current Constitutional Order, principles are considered as guidelines, and unlike the norm that regulates an end, the principle regulates a means, and it is the foundation of any legal system. In the case of ADs, the principles seek to eliminate gaps, offering coherence and harmony to the legal order. Although widely discussed worldwide for years, the ADs were inserted in the national healthcare scenario only in 2012, through Resolution CFM 1995/2012 which guides the medical practice in end-of-life conditions, ensuring patient’s self-sufficiency and the preservation of human integrity [19].
According to the CFM, the ADs are characterized as a grouping of wills, clearly expressed by the patients about their treatments and care they want to receive when they are unable to manifest their wishes [19]. This resolution considers the probability of the patient to name a representative so his demands can be met when he can no longer pronounce them [19]. The instruction to interrupt treatments that unnecessarily prolong the life of the patient with a severe or incurable illness allowed to the doctor was already provided for in Resolution CFM 1805 of 2006 [20].
When talking about ADs, it is essential to understand that this is the junction of the Durable Mandate (DM) and TV in a single document [17].
The DM is the patient’s indication of one or more attorneys-in-fact to be consulted by the medical team in case of his definitive or momentary impossibility when it is necessary to make a decision on the treatment or not treatment [16]. The TV is a document in which the patient details the treatments and procedures he intend to do or not to do when he is incapacitated to manifest his will, being useful only in cases of terminality [16].
The TV is a legal instrument that enables to certify the domination of the individual in the decisions about his health, having the “good death” as his final purpose [19].
Brazilian doctors still do not have legal support in relation to the ADs. However, they must obey CFM Resolution 1995/2012 [16]. The doctor should transcribe in medical records the ADs that are formally declared by the patient. If the person in the hospital is not known and if there is no appointed attorney-in-fact, available relatives, or concordance between them, the doctor should refer to the Bioethics Committee of the institution. If there is no committee, the hospital’s Ethics Committee or Regional and Federal Council of Medicine needs to document their opinion on ethical confrontations, when considering this measure as indispensable and appropriate [19].
Currently, the Bill 149 of 2018 is in process in the Brazilian Federal Senate, which regulates the advance directives on health treatments. The Article 2, paragraph I of this Bill defines ADs as a “manifestation documented by public deed, without financial content, of the will of the reporting person to receive or not certain medical care or treatment, to be respected when the person can not express his will, freely and autonomously” [21].
Also in Article 3, the Bill proposes that “every greater and capable person has the right to declare in advance, his or her will to receive or not certain medical treatments in the future when being in clinical condition” [20]. Article 5 of this same Bill reports that “advance directives must be met by health professionals and public or private health services, as well as by relatives, legal guardians, and the declarant’s representative” [21].
The respect for the independence of the actions related to the ADs is an important benefit for their application, especially in the disease termination, not only for doctors but also for the nurse [22].
ADs are seen by nursing professionals as synonymous with attending to the principle of autonomy of the patient and their relatives, with undeniable character and with inevitable growth [23]. It is an instrument capable of facilitating decision-making on ethical issues related to the end of life [24].
Nursing is recognized as the professional category that plays a primary role in the exercise of the right to self-determination, helping and facilitating patient decision-making, as it is present throughout the death process [25]. When establishing effective and early communication with the hospitalized patient, the nursing team creates a bond of trust between patient and professional that allows the conscious and autonomous exercise of the right to self-determination, ensuring that the patient’s wishes and choices are taken into account in situations involving decision-making in terminality [26].
The Code of Ethics of Nursing Professionals [26], in its Article 42, Sole paragraph, describes that the nursing professional must “Respect the person’s advance directives regarding the decisions about care and treatment that he or she wishes or not to receive at the moment when he/she is unable to freely and autonomously express his/her wishes.”
However, the lack of knowledge of regulations aimed at nursing professionals and the fear of ethical-legal implications interfere with the use of ADs. Faced with this reality and to avoid conflicts, nurses prefer to attend the wishes of family members, even if these wishes are not in accordance with the wishes expressed by the patient [27, 8].
For nursing professionals to feel effectively supported and safe in the use of ADs, it is necessary to include this subject in the curricula of the Nursing Undergraduate Courses, and the dissemination of scientific knowledge should be in agreement with the benefits brought to the patients with their wills met.
Currently, the National Curricular Guidelines of the Nursing Undergraduate Program indicate that nurses’ training should cover issues related to the prevention, promotion, healing, and rehabilitation of the health of individuals and the community. Thus, higher education institutions guided by these guidelines offer technical-scientific training that favors therapeutic obstinacy, aiming only at maintaining life at any cost [28].
It is believed that curricular changes, which deepen the ethical debate around issues related to the dying process, are necessary in the training of the nurse since the proximity of the nursing team with the hospitalized patient provides emotional exhaustion, and these professionals feel they are helpless before death. It is necessary that the process of dying be debated within educational institutions, so future nursing professionals understand and respect terminality as a phase present in human existence [23].
Rethinking treatment related to terminal patient care within higher education institutions favors the reduction of difficulties in dealing with the death process and therapeutic obstinacy and providing more humanized care [29].
Thus, it is important that the future nurse be encouraged to know the ADs during the professional training process, to understand its applicability in their clinical practice and to stimulate its use by patients, terminal or not, informing the possibility of construction and the importance of the ADs and presenting the necessary explanations for the elaboration of a document of this nature [28].
3. Conclusion
In Brazil, there is still no legislation that deals with ADs, which makes this topic little debated and diffused among health professionals, more specifically among the professionals of the nursing team.
Guaranteeing the individuals the right to carry out their wills in terminality through the ADs is still not enough since collective work is indispensable and necessary to respect their autonomy and reflections on the cultural actions of professionals’ health and family members that determine the paradigm of sustaining life at any cost.
The main challenge found during the dying process is to ensure that in practice, the patient’s wishes are met. It is noticeable that the implications and obstacles resulting from the ceaseless transformations of the right to health as a whole are far from over, especially the relationships inherent to the principle of human dignity, individual freedom, and the practices of health professionals.
There is a need to disseminate among nursing professionals the importance of encouraging the free and informed autonomy of patients and of the Federal Nursing Council regulation that supports professionals who respect the ADs of the individuals under their care. The knowledge of the Code of Ethics of Nursing Professionals and the inclusion of ADs in the curricula of Nursing Undergraduate Courses are essential for Brazil to make a positive contribution to this issue.
In view of the current Brazilian health scene, the ADs are characterized as a new subject, and its applicability involves cultural change, family and health professionals’ agreement, and an early approach in both undergraduate and care education.
Conflict of interest
We declare there is no conflict of interest in this research.
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In Brazil, life expectancy and supportive technologies have increased, leading to growth of the number of terminally ill patients. However, there is still no legislation regulating ADs causing legal uncertainty in health professionals. Nursing professionals have the support of the Federal Nursing Council to respect the ADs, but, because it is an issue little explored, nursing professionals do not feel safe in the use of ADs, and changes in the curricula of the undergraduate courses in nursing are extremely needed, ensuring that patients have their wishes met during the dying process. Thus, this chapter deals with bioethical and legal issues involving ADs and nursing in the Brazilian context, proposing to deepen reflection and criticism on the issue and subsidies for decision-making.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/66920",risUrl:"/chapter/ris/66920",book:{id:"7798",slug:"neuroethics-in-principle-and-praxis-conceptual-foundations"},signatures:"Jacqueline Resende Boaventura, Juliana Dias Reis Pessalacia, Luciana Ferreira Da Silva, Ana Paula Da Silva, Larissa Da Silva Barcelos, Carlos Eduardo Pereira Furlani and Adriano Menis Ferreira",authors:[{id:"224763",title:"Dr.",name:"Juliana",middleName:null,surname:"Dias Reis Pessalacia",fullName:"Juliana Dias Reis Pessalacia",slug:"juliana-dias-reis-pessalacia",email:"juliana@pessalacia.com.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"290311",title:"Prof.",name:"Adriano",middleName:null,surname:"Menis Ferreira",fullName:"Adriano Menis Ferreira",slug:"adriano-menis-ferreira",email:"amr@ig.com.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Universidade Federal de Mato Grosso",institutionURL:null,country:{name:"Brazil"}}},{id:"290312",title:"BSc.",name:"Ana Paula",middleName:null,surname:"Da Silva",fullName:"Ana Paula Da Silva",slug:"ana-paula-da-silva",email:"anapaulasenf@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Federal University of Mato Grosso do Sul",institutionURL:null,country:{name:"Brazil"}}},{id:"290313",title:"BSc.",name:"Jacqueline",middleName:null,surname:"Resende Boaventura",fullName:"Jacqueline Resende Boaventura",slug:"jacqueline-resende-boaventura",email:"jacqueboaventura@yahoo.com.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Federal University of Mato Grosso do Sul",institutionURL:null,country:{name:"Brazil"}}},{id:"290315",title:"BSc.",name:"Luciana",middleName:null,surname:"Ferreira Da Silva",fullName:"Luciana Ferreira Da Silva",slug:"luciana-ferreira-da-silva",email:"psic201@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Federal University of Mato Grosso do Sul",institutionURL:null,country:{name:"Brazil"}}},{id:"293517",title:"BSc.",name:"Larissa",middleName:null,surname:"Da Silva Barcelos",fullName:"Larissa Da Silva Barcelos",slug:"larissa-da-silva-barcelos",email:"barceloslari@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Federal University of Mato Grosso do Sul",institutionURL:null,country:{name:"Brazil"}}},{id:"293518",title:"BSc.",name:"Carlos Eduardo",middleName:null,surname:"Pereira Furlani",fullName:"Carlos Eduardo Pereira Furlani",slug:"carlos-eduardo-pereira-furlani",email:"carlos.furlani@ufms.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Federal University of Mato Grosso do Sul",institutionURL:null,country:{name:"Brazil"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Advance directives and nursing",level:"1"},{id:"sec_3",title:"3. Conclusion",level:"1"},{id:"sec_7",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Koerich MS, Machado RR, Costa E. Ética e bioética: Para dar início à reflexão. Texto & Contexto – Enfermagem. 2005;14(1):106-110. DOI: 10.1590/S0104-07072005000100014'},{id:"B2",body:'Zoboli ELCP. Bioética e atenção básica: Um estudo de ética descritiva com enfermeiros e médicos do Programa de Saúde da Família [thesis]. São Paulo: Faculdade de Saúde Pública, Universidade de São Paulo; 2003'},{id:"B3",body:'Xavier M, Miziara C, Miziara I. Terminalidade da vida: Questões éticas e religiosas sobre a ortotanásia. Saúde, Ética & Justiça. 2014;19(1):26-34. DOI: 10.11606/issn.2317-2770.v19i1p26-34'},{id:"B4",body:'Marengo M, Flávio D, Silva R. Terminalidade de vida: Bioética e humanização em saúde. Medicina (Ribeirao Preto. Online). 2009;42(3):350-357. 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DOI: 10.15210/JONAH.V5I1.5497'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Jacqueline Resende Boaventura",address:null,affiliation:'
Federal University of Mato Grosso do Sul, Três Lagoas, Mato Grosso do Sul, Brazil
'},{corresp:"yes",contributorFullName:"Juliana Dias Reis Pessalacia",address:"juliana@pessalacia.com.br",affiliation:'
Federal University of Mato Grosso do Sul, Três Lagoas, Mato Grosso do Sul, Brazil
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Federal University of Mato Grosso do Sul, Três Lagoas, Mato Grosso do Sul, Brazil
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Federal University of Mato Grosso do Sul, Três Lagoas, Mato Grosso do Sul, Brazil
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Federal University of Mato Grosso do Sul, Três Lagoas, Mato Grosso do Sul, Brazil
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1. Introduction
Cyanoprokaryotes are Gram-negative photosynthetic algae considered to have arisen approximately 3.5 billion years ago [1]. In nature, they are found as single cell species or as colonies rapidly growing in fresh water, all types of aquatic ecosystems, and terrestrial habitats. Cyanobacteria are photosynthetic organisms, and as such, they are considered primary first-level consumers in the food chains in water ecosystems. Blue-green algae play an important role in carbon and nitrogen balance in the biosphere [2]. They produce a high number of bioactive molecules, and certain species produce cyanotoxins that contribute as defense mechanisms against different ambient stress factors [3]. The growth of cyanobacteria at high blooming densities increases in expansion and frequency following anthropogenic activities and climatic change, globalization, and increasing commodity exchanges [4]. This, in turn, raises morbidity and death rates of wild and domestic animals [5, 6] and brings some risk to human health.
More than 90 microcystin isoforms, that are cyclic peptide cyanotoxins, have been described. The microcystin-leucine arginine (MC-LR) is known as the most toxic and the most abundant variant of microcystins [7]. Several authors have reported that MC-LR has been considered as the most widely spread microcystin in Portuguese waters [8]. However, Rodrigues et al. report similar results for microcystin MC-RR (a MC variant with the amino acid arginine in positions 2 and 4) [9]. MC-RR is the major toxin variant found in the rivers, lakes, and reservoirs in China [10] reaching concentrations of up to 93.5% in the cells of cyanoprokaryotes [11], thus associated with the contamination produced by intensive use of water sources and fast economic development [12]. In Bulgaria, a country rich in water reservoirs and natural water bodies, many cases of cyanoprokaryote blooms have been reported. Surveys conducted for a period of 15 years (2000–2015) in 120 Bulgarian water basins have recorded cyanobacteria blooms in 14 water bodies and have identified 16 cyanotoxins (microcystins LR, LA, RR, YR, nodularins, and saxitoxins) [13].
Cyanotoxins have various chemical structures; thus, their toxic effects are due to different mechanisms. Cyanotoxins are classified into three major groups according to their chemical structure: alkaloids (cylindrospermopsin, saxitoxin, lyngbyatoxin-a, and aplysiatoxin,), cyclic peptides (microcystins, MCs, and nodularins—NODs), and lipopolysaccharides [14]. Poisoning of humans with cyanotoxins is possible through various pathways, mainly by the consumption of contaminated food (vegetables, fish, seafood, and livestock), as well by bathing and recreational activities with contaminated water [15]. Different studies have reported high accumulation of cylindrospermopsin (CYN) in fish (up to 2.7 ng/g) [16], in mussels (up to 2.52 mg/g) [17], and in lettuce (up to 8.029 μg/kg) [18].
Along with the reports about the toxicity of cyanobacteria metabolites, there are studies describing their anticancer properties, hence, viewing them from a new perspective as novel potential sources for anticancer drug development [19]. However, to identify possible drug targets, the science about the mechanisms of the toxicity needs to be extracted out of the numerous scientific reports and review studies on cyanobacteria blooms, case studies and investigations on the effects of cyanotoxins described by different authors.
This review addresses the target mechanisms behind the effects of widely distributed groups of cyanotoxins with an impact on human health, the cyclic peptides microcystins and nodularins, and the alkaloid cylindrospermopsin.
Data collection was performed through keyword research, namely cyanotoxins, microcystins, nodularins, cylindrospermopsin, cyanotoxins/microcystins/nodularins/cylindrospermopsin molecular mechanisms/carcinogenicity/anticancer potential/clinical toxicology/poisoning incidence/clinical toxicology. ScienceDirect and PubMed databases were screened for the above-mentioned key words. More than 100 papers were examined and bibliography includes references dating back to 1878.
2. Water blooms, human and animal health
A great number of studies about cyanotoxins discuss their toxicity from different points of view. Clinical intoxication cases and epidemiological studies on reported cases of exposure to cyanobacteria and their toxins are described [20]. There are reports on acute poisonings of animals and humans due to exposure to cyanotoxins [21, 22]. Chronic intake of contaminated water; aerosolization, including respirable bioaerosols; consumption of contaminated seaborne food [23]; or even intake of dietary supplements containing blue-green algae are investigated and reported [24].
Observational studies on the correlation between clinical symptoms and contact with blooming water have been recorded throughout the centuries. The earliest report on such poisoning dates back 1000 years ago in China when green-colored river water consumption caused mortality in General Zhu Ge-Ling’s troops, according to data reviewed on the website of National Toxicology Program, Department of Health and Human Services of USA [25]. Later in 1878, cyanotoxin poisoning was suspected in Australia [26]. In several US states, gastroenteritis has been suspected to be related to water blooms [27]. In China, primary liver cancer has been attributed to cyanotoxin-contaminated drinking water [28]. In a profound recent review, Svircev et al. [20] identified 42 publications that describe 33 cases of cyanotoxin poisoning in 11 countries—Australia, Brazil, Canada, China, Namibia, Portugal, Serbia, Sri Lanka, Sweden, the UK, and the USA for the period between 1960 and 2016. Although there is no definitive general conclusion in the epidemiological literature, it identifies a possible link between microcystins and cancer and other human health issues [20]. Wood [21] presents an informative table summarizing reports about acute animal and human poisonings attributed to exposure to cyanotoxins since 1800; there is an estimate of the number of affected animals and individuals in incidents of mortality and morbidity from 1900 onwards. The author identified 115 human incidents of cyanotoxin intoxications reported until the year 2010, mostly seen in the United States and Canada, followed by Europe [21]. Taking into account the great variety of cyanobacteria and their overall environmental distribution in fresh and brackish waters and the fact that more than 90 different types of cyanotoxins are produced by the blue-green algae, the various routes of cyanotoxin poisoning, as well as the variety of clinical manifestations encountered, we may expect that the above numbers are quite underestimated. In Varna region, Bulgaria, no evidences to related cases of acute poisoning to cyanotoxins have been documented according to local database [118]. Furthermore, it is not always easy to derive information about countries classified by Woods as “the rest of world,” especially when information dated back centuries ago. Sometimes, data are published in the gray literature and in the local language; data available are not supported by adequate scientific information. Often clinical evidences of inflammatory response or allergic reactions are misleading for being common symptoms for other types of intoxications as well; such clinical cases remain in the group of idiopathic intoxications and are not reported as cases of cyanoprokaryota poisonings. Cyanobacteria content in the total mass of phytoplankton in different waters and sampling periods may vary up to 100%. Usually, in algae blooms, one species predominates and it releases various cytotoxins to the water. Some toxins have been detected even after the end of algae blooms, when cyanoprokaryota species are already in negligible concentrations [13].
Few reports describe correlation between defined clinical symptoms and/or laboratory findings and a reported contact and/or consumption of contaminated water. The most severe human intoxication with cyanotoxins occurred in Brazil in 1996, where 100 of 131 dialysis patients developed acute hepatic failure due to cyanotoxin contamination of the dialysis water applied. The death of 52 of them has been confirmed to be due to the presence on cyanotoxins in treatment water provided from a local water treatment plant [29, 30]. Another incidence, again in Brazil, associates 2000 cases of gastroenteritis and 88 deaths with blooms [31]. Microcystis aeruginosa–contaminated water caused pneumonia in two patients in Staffordshire, England [32]. In Australia, 140 children and 10 adults have experienced liver and kidney problems. Cylindrospermopsin is reportedly the etiological agent [33]. Giannuzzi et al. [34] report a case from Argentina in 2007. Microcystin-LR is detected in water samples, where the patient has been immersed before experiencing acute clinical symptoms. In addition, laboratory examination identified increase of markers for liver injury (ALT, AST, and GGT).
3. Cyclic peptides—toxicity and biotransformations
The cyclic pentapeptide nodularins and cyclic heptapeptide microcystins are the most widespread cyanotoxins in water blooms. MCs are produced by different cyanobacterial species (Microcystis, Oscillatoria, Aphanocapsa, Cyanobium, Arthrospira, Limnothrix, Phormidium, Hapalosiphon, Anabaenopsis, Nostoc, and Synechocystis). It is known that nodularins are produced only by cyanobacteria from the genus Nodularia (Nodularia spumigena) [35]. Various investigations reveal approx. 100 known variants of MCs up-to-date with the most toxic and widely distributed MC being MC-LR [36]. The maximum concentration of MC-LR is up to 1 μg/L in drinking water. This is the conditional guideline value adopted by the World Health Organization (WHO). The value is based on tolerated daily intake (TDI) 0.04 μg/kg body weight [37].
Most of the microcystins have hydrophilic structure; thus, their cell uptake should be facilitated by transporting systems, such as the organic anion transporting polypeptides (OATPs). Many OATPs are expressed in a tissue-specific way, whereas others are expressed ubiquitously [38]. A selective uptake of MCs by the cells, depending on the organ type and on the expression of different OATPs, is established in intestines, liver, muscle, and brain cells of three different catfish species [39]; the highest contents are found in liver, gonads, stomach, heart, and kidneys in Wistar rats [40]. The fact that MC accumulation is primarily in the liver is explained by the amount of OATPs present in this organ, which is why MCs are considered as hepatotoxins. More specifically, the MC-LR has been determined as a substrate for OATP1A2, OATP1B1, and OATP1B3. MCs are established to require active transport for human cell uptake, and the high expression of these OATP1B1 and OATP1B3 transporters in the liver accounts for their selective liver toxicity [41, 42]. Researches reveal that OATP1B1 and OATP1B3 expression is detected in cell lines originating from liver, colon, and pancreatic tumors [43], as well as in hepatocellular carcinoma [44]. These results account for microcystin toxicity to be examined mainly in hepatocytes in vivo and in cultured hepatic cells in vitro.
The liver of the fish species O. bonariensis, collected from a shallow lake in Argentina, contained 10 times higher MC-RR levels than the muscles, reports a study [45]. Another study, on mice, elucidates that 9% of the MC-LR toxin fraction is filtrated in the kidneys and eliminated through urine, thus making kidneys a possible object for MC-LR toxicity as well [46]. Pflugmacher et al. [47] determine that the first stage in the detoxification of MCs is the formation of a glutathione conjugate of MC (MC-LR-GSH) in hepatocytes, identified earlier in mice and in rat livers [48]. MC-LR-GSH is then further metabolized to a cysteine conjugate (MC-LR-Cys) for excretion via urine [49], via feces as well, as free MCs or their metabolites [50].
Chronic exposure to sublethal doses of MCs could lead to induction of oxidative stress, necrotic cell death, and liver neoplasia in animals [51] and a possible reason for that could be the depletion of GSH cell stores. A study demonstrates the bioaccumulation of microcystin-LR (MC-LR) in mammals [52]. A pig experimental model has been used because of its liver, kidney, and gastrointestinal tract function similarities to humans, as well as similarities to humans’ metabolic rates [53]. Although MC-LR is not found in the serum of treated animals, free MC-LR is detected in the large intestine and kidneys, in liver as well, where the MC-LR-glutathione conjugate is in high quantity, approximately 1.1% of the applied MC-LR dose. The chemical structures of unabsorbed MCs are not modified, or few changes occur. MCs are transported to the intestine and further are excreted by feces. The other route is absorption and subsequent conjugation in the liver and rapid excretion of this compound in the bile [54]. MC-LR and its derivatives (MC-LR-GSH and MC-LR-Cys) may also enter the enterohepatic circulation and, being reabsorbed into the blood stream, may reach the brain, heart, lungs, and even testicles [55].
Animal studies mark the possible MC-LR accumulation in human hepatic tissue exposed chronically to high doses of cyanotoxins as well. Present-day study analyses daily exposure to MCs and their effects on human health; authors identify the presence of MCs in anglers’ serum, most likely resulting from exposure to ingested MC from consumed fish [56]. Serum enzymes aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and alkaline phosphatase, which are biomarkers of hepatic function, are elevated, pointing to liver damage in the fishermen. The smaller ring structure of NODs is taken up by the liver cells more easily than MC-LR, thus probably resulting in stronger hepatocellular effects [57]. Another research provides evidence that MC-LR can be transported across the blood-brain barrier in humans [41].
3.1 Cyclic peptides—molecular toxicity mechanism in relation to carcinogenicity
Different mechanisms of cytotoxicity are observed among MC variants and nodularins in a range of in vitro cell culture studies on cell viability and the ability to cause apoptosis or necrosis in varying concentrations applied to different cell types. Fastner et al. [58] explicates that primary rat hepatocytes are less susceptible to MC-RR (EC50 1500–4300 nM) compared to MC-LR (EC50 60–200 nM). Independently of the cell culture type (primary or transfected hepatocytes), MC-RR is always less cytotoxic than MC-LR [59]. Gacsi et al. [60] have studied the effects of MC-LR on cultured Chinese hamster ovary cells (CHO-K1) in order to detect cell viability and to determine if nonviable cells go through necrosis or apoptosis. The study demonstrates that low dose of MC-LR (<10 μM) after 24 h exposure does not induce apoptosis in the cell line. The application of higher MC-LR concentrations (⩾20 μM) shows induced apoptosis in a concentration-dependent manner. The shrinkage of apoptotic cells is linked to the shortening and loss of actin filaments and microtubule depolymerization. No necrosis is observed over the concentration range tested. Piyathilaka et al. [61] evaluates the MC-LR cytotoxic and apoptotic effects on different human kidney cell lines—normal embryotic (HEK-293) and adenocarcinoma cell line (ACHN). The MTT and sulforhodamine B (SRB) cell viability assays establish that MC-LR is more cytotoxic to embryonic kidney cells compared to kidney adenocarcinoma cells after treatment with MC-LR for 24 h. In addition, morphological studies also reveal higher MC-LR toxicity to kidney cancer cells than to normal kidney cells. MC-LR does not promote cell division of human kidney adenocarcinoma cells, indicating that it cannot be a promoter of kidney cancer [61].
NODs and MCs are among the most common natural cyanotoxins. Their toxicity is mainly due to the ability to inhibit the eukaryotic protein serine/threonine phosphatase families 1 and 2A (PP1 and PP2A), which are essential for many signal transduction pathways of eukaryotic cells. This inhibition is linked to protein hyperphosphorylation, thus leading to modification of cytoskeleton and disturbances of many cellular processes: loss of cell-cell adhesion at the desmosomes [62], disruption of actin filaments [63], and altered cell signaling pathways, for example MAPKs signaling pathways that regulate cellular proliferation [55]. As potent inhibitors of protein serine/threonine phosphatase, MCs and NODs have a profound effect on cell signaling leading to the affected cell’s death. Both MC-LR and NOD have inhibitory effect on protein phosphatases, independently that MC-LR binds covalently to them and NOD does not [64].
Cell signaling pathways involving MAPKs regulate cellular proliferation through phosphorylation cascades. Several types of phosphatases including the protein serine/threonine phosphatases 2A regulate the Ras-Raf-MEK-ERK cascade (PP2A). The phosphatase PP2A inhibits these pathways by dephosphorylation. The activated (phosphorylated) forms of the transcription factor ERK1/2 are translocated to the cell nucleus, thus leading to the transcription of certain proto-oncogenes [65]. Junttila et al. [66] speculate that by inhibiting PP2A, MC-LR could deregulate the ERK1/2 pathway, thus promoting cell proliferation and tumorigenesis.
NODs and MCs also play a role as potential oxidants, which could induce reactive oxygen species production, hence causing cell oxidative stress damages [67]. Many studies demonstrate that oxidative stress is involved in the liver cell toxicity due to MCs [68] and NODs [67]. Increased production of reactive oxygen species (ROS) and lipid peroxides in mouse liver because of treatment with NODs is observed [69].
MCs may increase the production of ROS by depletion of GSH due to a high rate of conjugation [8, 67]. These observations are confirmed in zebrafish [70], where MC administration leads to lipid peroxidation and a change in the antioxidant enzyme activity [71]. A study explicates MC-RR influence on gene expression of nuclear factor—erythroid 2 related factor 2 (Nrf2), a master regulator of inducible antioxidant responses, in human hepatocytes, causing mitochondria dysfunction [72]. The transcription factor Nrf2 has been identified as a key factor in the cell protection from oxidative stress and electrophilic insults [73, 74]. Many of Nrf2 target genes play essential role in maintaining cellular antioxidant responses and xenobiotic metabolism. Its constitutive activation may contribute to a malignant phenotype [75], and its elevated expression and activity have been observed in different cancer cells [76]. Nrf2 promotes the survival of tumor cells under a deleterious environment and elevates resistance to antitumor drugs [77]. These observations suggest that Nrf2 plays contrasting roles in different tumorigenesis stages and is subject to MCs’ toxicity with predictable effect on further tumorigenesis.
Gan et al. have shown that MC-LR is able to enhance the stability of the Nrf2 transcription factor in the cytoplasm and its translocation to the nucleus via binding to the cytosolic regulator protein Keap1. Knockdown of Nrf2 mediated by siRNA can inhibit cell proliferation and cell cycle progression induced by MC-LR [78]. Therefore, upregulation of Nrf2 induced by MC-LR in tumor cells favors liver cancer cell growth. This study gives additional information supporting Nrf2 role in cancer tumorigenesis [78], respectively, of MC-LR. Moreover, a higher level of Nrf2 in toxin-treated rat primary hepatocytes after 48 h has been observed [79]. It is assumed that inhibition of protein phosphatases by MCs may affect the activity of DNA-dependent protein kinase (DNA-PK), an enzyme with key role in the nonhomologous terminal binding of DNA loops in the G0-phase of the cell cycle observed in human lymphocytes [80].
Another important mechanism of genotoxicity is the impairment of DNA repair. Experimental animals exposed to sublethal low doses of MC have shown to develop tumorigenesis in coordination with the presence of dysfunctional p53 [81]. The increased formation of reactive oxygen species leads to oxidative DNA damage. A study shows that after 4 h of exposure to 0.01, 0.1, and 1 mg/mL of MC-LR DNA strand breaks were induced in dose dependent manner in human liver carcinoma cell line (HepG2 cells) [82]. Oxidized pyrimidines are repaired within a short time of exposure to MCs (8 h), while oxidized purines (mainly 8-hydroxyguanine) remain unrepaired in the DNA and accumulate [83] leading to GC-TA transversion mutations [84]. This statement has been verified in vivo with demonstrated elevation of 8-hydroxyguanine in male rat hepatocytes 24 h after treatment with 50 mg/kg body weight of MC-LR [85]. In primary cultured rat liver cells exposed to NOD, the highest level of 8-oxo-2′-deoxyguanosine adducts is observed after 3 h exposure and its level decreased to control cells’ levels after 24 h of exposure [85].
Many studies on MC-LR adverse effects establish its ability to change gene expression, and by these means contribute to a better understanding of MC-LR mechanisms linked to toxicity, genotoxicity, and carcinogenicity potential. Sueoka et al. [86] give the first evidence that MC-LR modulates the expression of tumor suppressor genes and oncogenes. They demonstrate that primary rat liver cells exposed to MC-LR (1 mM) for 6 h remarkably elevated the tumor necrosis factor α (TNF-α) expression, which could play the role of an endogenous tumor promoter [87]. The same study shows upregulation of early-response genes from the jun and fos gene families, proto-oncogenes, which are involved in gene regulation in response to different stimuli such as growth factors, cytokines, and viral and bacterial infections (Table 1).
Experimental model
Time/dose of exposure/method of administration
Main findings
Reference
Male Wistar rats
Single intravenous administration of МС-LR extract; 80 μg/kg body weight
The maximum MC-LR content (2.9% of the injected dose) detected 2 h after injection. Highest concentration found in kidney (0.034–0.295 μg/g dry weight); concentration in liver (0.003–0.052 μg/g dry weight).
Oral administration of MC-LR in two treatment groups:
0.04 μg MC-LR/kg body weight for 13 weeks
2 μg toxin/kg body weight for 5 weeks
MC-LR not detected in serum; free MC-LR found in the large intestine (1.4 μg/kg dry weight) and kidney (1.9 μg/kg dry weight). The higher dosed animals accumulated MC-LR-conjugate in liver (26.4 μg/kg dry weight).
Intraperitoneal injection of MC-LR, 40 μg/kg body weight for 4, 24 h, and 4, 14, and 28 days
Increased proliferative response in liver after 28 days exposure time as detected by increased nuclear Ki-67 immunoreactivity and phosphohistone H3 expression.
In summary, one pathway of MC genotoxic activity is mediated by induction of ROS generation, thus leading to DNA strand breaks and at the same time significantly decreasing DNA repair system activity. The impairment of DNA repair together with DNA damage is an important factor involved in tumorigenesis. Chronic exposure to low concentrations of these cyanotoxins may increase the risk for carcinogenesis due to their potential long-term adverse effects (carcinogenic and genotoxic). For this reason, the International Agency for Research on Cancer classifies MC-LR as a possible human carcinogen [88]. Figure 1 summarizes possible mechanisms of MR-LR genotoxicity with contribution to carcinogenesis.
Figure 1.
Mechanisms of microcystin genotoxicity.
3.2 Cyclic peptides—potential sources of anticancer drugs
Essential for candidate molecules to be developed into useful anticancer therapeutics is their cancer selectivity. It is known that specific types of cancer can be targeted by redox-based therapies when cancer cells are assailable by increased ROS production induced by exogenous agents [89]. Thus, microcystin analogues are assumed to be selective anticancer drugs for certain types of cancer cells, specifically for those that express OATP, without causing significant toxicity to normal cells because of the differences of redox status between normal and cancer cells [90]. The development of OATP-targeting compounds based on the chemical structure of MC-LR, with unique physicochemical properties such as high water solubility, resistance to chemical hydrolysis or oxidation at near-neutral pH, and stability in pH shifts, appears to be a feasible and promising option in this direction [91]. There are studies focused on developing analogues of microcystin cyanotoxins for efficiently targeting the OATP-expressing metastatic cancers, which are resistant to conventional chemotherapy treatment [90] and many known cyanotoxins have been studied for their anticancer properties in human cell lines.
Currently, neither optimal nor targeted therapy has been developed for pancreatic cancer [92]. Overexpression of OATPs in pancreatic cancer offers an opportunity to develop effective novel cancer-targeted agents. A study demonstrates that MC-LR targeting OATP1B1 and OATP 1B3 can cause inhibition of proliferation of pancreatic cancer cells in a dose-response mode [92]. Study findings point that antiproliferative and pro-apoptotic effects are proportionally related to the expression of these transporters, thus suggesting an essential role for OATP expression in the process of MC-LR–induced cancer cell damage. Moreover, direct comparison of the inhibitory effect of MC-LR and the drug gemcitabine manifests a noticeable advantage of the toxin [92].
Monks et al. [93] have transfected cervical cancer cell line HeLa with the known OATP1B1 and OATP1B3 transporters seeking through appropriate in vitro models how MCs are uptaken into the cells and testing the activity of MCs against cells that express OATPs. Authors elucidate that transfected HeLa cells were 1000-fold more sensitive to MC-LR compared to the vector-transfected control cells, pointing that the expression of transporters imparts marked selectivity for MC cytotoxicity [93]. These observations suggest that MC cytotoxicity in OATP1B1- and OATP1B3-expressing HeLa cells is linked to cell-specific inhibition of PP2A and not to protein phosphatase inhibition in general.
These findings endorse the anticancer potential of MCs and raise hopes that cyanotoxins may have a promising future in cancer therapy. Challenges of potential organ-specific MC toxicity remain to be resolved by proper chemical modifications in the process of drug modulation.
4. Cylindrospermopsin—molecular mechanisms of toxicity and biotransformation
Humans are more susceptible to the exposure to cylindrospermopsin in comparison to other cyanotoxins because up to 90% of the total CYN is found outside the cyanobacterial cells [94]. Humpage et al. [95] recommend a maximum concentration of CYN in drinking water to be 1 μg/L based on tolerated daily intake, 0.03 μg/kg body weight.
CYN is generated by different freshwater cyanobacteria species, which are common worldwide, nowadays [96]. Many cyanotoxins are generally sequestered inside cyanobacteria until death, while cylindrospermopsin can be liberated in water during blooms [97].
CYN is a polycyclic uracil derivative containing guanidino and sulfate groups. The cyanobacterial toxin CYN is a tricyclic alkaloid that consists of a tricyclic guanidine moiety combined with hydroxymethyluracil. CYN has been recognized to induce cytotoxicity in vitro in human cell lines from liver and intestine [98]. The toxin primarily attacks the liver, but it is also a general cyanobacterial toxin that targets the spleen, kidney, heart, lungs, thymus, eyes, etc. [99].
The mechanisms of CYN toxicity and genotoxicity are not fully clarified. It is assumed that there are two types of toxic responses. It is established that CYN is more toxic in short-term (1–2 weeks) compared to long-term exposure in cell culture experiments [100]. Rapid toxicity is due to CYP450-generated metabolites [95]. The longer-term toxicity of CYN includes an irreversible inhibition of eukaryotic protein synthesis in in vitro experiments [98].
Many studies explore the cytotoxic effect of cylindrospermopsin and they are summarized in Table 2. These studies vary in type of cell culture used, time of exposure, concentrations of the CYN, and even the type of cytotoxicity test used.
Experimental model
Method applied
Experimental conditions
Results
Reference
Primary rat hepatocytes
MTT assay
0–10,000 ng/mL for 24, 48, 72 h exposure
The LC50 is 40 ng/mL; toxic effects are observed after 72 h.
There is no effect when cells are exposed up to 1 μg/mL for short time (2–6 h). Cell viability is decreasing in a concentration-dependent way for longer time (24–72 h).
Apoptosis is observed at low concentrations (1–2 μM) and short exposure (12 h). Necrosis is observed at higher concentrations (5–10 μM) and following longer exposure (24 or 48 h).
Most in vitro experiments demonstrate that the cytotoxic effect of cylindrospermopsin is observed after long-term exposure (24–72 h). Toxicity of CYN on primary and carcinoma cell line is compared: the primary rat hepatocyte cells are more sensitive to the toxic effect of CYN, compared to KB cell line [101].
Morphological studies are more informative than cytotoxicity studies as they identify the types of cell damage. By means of microscopy, in that respect, pleomorphic nuclei, nucleolar segregation with altered nuclei, depraved Golgi apparatus, and apoptosis in human endothelial cells (HUVEC) after exposure to 0.375 μg/mL, CYN is observed [15]. The same authors also report morphological changes (mitochondrial damage, lipid degeneration, and nucleated segmentation with altered nuclei) in Caco-2 cells after exposure to a higher concentration of CYN (2.5 μg/mL). Absorption of CYN in Caco-2 cells is very limited, which explains the result [105]. Authors report that after cells being exposed to concentration of CYN 1–10 μM for 3, 10, and 24 h, the passage of CYN across the intestinal monolayer is about 2.5% after 3 h and increases slightly up to 20.5% after 24 h.
In search for possible mechanisms of CYN toxicity, it is observed that CYN significantly reduces GSH levels in rats’ primary hepatocytes; a decline in the synthesis of GSH is the predominant mechanism, rather than an increased glutathione consumption [106], which could lead to increased oxidative stress. Other authors observe different and contradictory effects of CYN on the activity of gamma-glutamylcysteine synthetase (GCS)—the regulatory enzyme in GSH synthesis. In any case, reduction of GSH levels does not contribute significantly for the acute CYN toxicity in vivo as presumed, because no changes in the oxidative stress markers after exposure to CYN are evidenced [95].
The role of biotransformation of CYN is an important factor for understanding its toxic effect in cell lines, respectively, in various tissues. Scientific data show that toxicity and genotoxicity of CYN depend on cytochrome P450 (CYP)-mediated metabolism, as various CYP inhibitors can protect cells against toxicity, but it is not yet clear which isoforms are involved [95]. The higher activity of CYP450 in hepatocytes involved in bioactivation events is found to be important for CYN toxicity in liver cell cultures [107]. Many in vitro and in vivo studies on the toxic mechanisms of CYN prove that metabolites of the toxin produced by CYP450 are mainly responsible for its toxicity, including its genotoxicity. Thus, the activity of the cytochrome P450 enzyme system has been investigated [102], demonstrating that the inhibition of CYP450 activity by proadifen or ketoconazole in mouse hepatocytes reduces the toxicity of CYN but does not alter its effect on protein synthesis. These observations may explain lower CYN toxicity in cell lines such as human cervix carcinoma (KB cells) [101], HeLa cell types [100], and CHO-K1 cells [108] compared to primary rat hepatocytes. Another study reveals that CYP1A1 and CYP1A2 are upregulated in human peripheral blood lymphocytes after CYN exposure [109].
Due to the simultaneous presence of different cyanobacterial toxins in aquatic environment, Hercog et al. [110] investigated the genotoxic potential of MC-LR and CYN mixtures, applied on HepG2 cells. Cells are treated with different doses of CYN, a single dose of MC-LR, and several combinations. A mixture of MC-LR and CYN provokes genotoxic damages, but to a lesser extent in case of strand breaks, compared to CYN itself. Data manifest that MC-LR provoke DNA strand breaks after short-term exposure, while CYN induces DNA damage after prolonged exposure in metabolically active cells [95, 111]. These data point that CYN exhibits higher genotoxic effects compared to MC-LR in the mixture of CYN and MC-LR. The same authors disclose mRNA expression levels of certain genes after 4 and 24 h of exposition to CYN or to MC-LRs, or to a combination of both cyanotoxins. Changes in the expression levels of genes involved in the metabolism of xenobiotic, genes involved in immediate-early response/signaling, and genes involved in response to DNA damage, upon exposure to CYN/MC-LR mixture, are not different to those induced by CYN itself [110], indicating higher genotoxicity of CYN.
In summary, the main target of CYN toxic activity is the liver, and CYN metabolism plays an important part for understanding the mechanisms of its toxicity. Therefore, the activity of CYP450 enzyme system is considered a key mechanism for CYN toxicity development in hepatocyte cultures, including genotoxicity. The higher sensitivity of liver cells exposed to CYN is due to bioactivation-dependent events, research indicates [105]. One of the CYN-known mechanisms is the irreversible inhibition of protein synthesis after long-term exposure [98]. Another mechanism is via oxidative stress induced by inhibiting the regulatory enzyme in GSH synthesis [106]. CYN induces DNA damage after longer exposure in metabolically active cells [95].
4.1 Anticancer properties of cylindrospermopsin
Caco-2 cells and HepG2 are often used human cell lines for cyanotoxin effects research. A study showed that CYN is linked to a variable effect in HepG2 cell line. Cyanotoxin diminishes lipid peroxidation in cells that have not been previously induced by phenobarbital exposure for 12 h and elevates it in phenobarbital-induced cells exposed to the highest CYN concentration (10 μg/L). Lipid peroxidation increases in both cell types after 24 h exposure, only at 10 μg/L CYN [112], demonstrating that the toxicity of low concentrations of CYN (<10 μg/L) is limited in human hepatoma cells. HepG2 cells are more sensitive compared to intestinal cells, while Caco-2 cells are even less sensitive. The observation is associated with the limited CYN uptake in colon cells as described by several authors [105, 113].
Oral intake is the major route of human exposure to CYN, which makes intestine a target organ. Huguet et al. [114] examined the cellular and molecular mechanisms of cylindrospermopsin toxicity on differentiated cell line of human intestinal Caco-2 cells. This cellular monolayer provides in vitro model performing functional and morphological characteristics similar to those of enterocytes. Results reveal that differentiated Caco-2 cells exposed for 24 h to a subtoxic cylindrospermopsin concentration overexpress the gene products linked to DNA damage repair, including nucleosomal histone modifications [114]. Bain et al. examined the potential role of p53 tumor suppressor protein in CYN-induced gene expression in human hepatocellular carcinoma cell line [111]. Authors report that after 6 h of exposure to CYN, concentration-dependent increases in mRNA levels are observed for the p53 target genes CDKN1A, MDM2, GADD45alpha (all involved in the response to DNA damage), and BAX (involved in the apoptosis), indicating an early activation of p53 by CYN. The respective levels of mRNA for these genes remain elevated after 24 h. Data suggest that CYN can induce stress responses resulting in activation of the p53 transcription factor [111] and subsequent upregulation of DNA repair processes and activation of apoptosis.
That being said, a 72 h exposure of HepG2 cell line to CYN provokes DNA double strand breaks, providing evidence that CYN can perform as a direct genotoxin [115].
Obviously, available scientific data indicate controversial roles of CYN and its toxicity. CYN can cause severe cell damages, and it has the potential to activate DNA repair processes, which, concerning concentration and time-of-exposure–dependent activities, makes it another promising potential anticancer drug source.
5. Clinical toxicology and pharmacological aspects
Scientific paper analysis reveals some mechanisms linked to exposure to cyanotoxins and their effect on human health. Many episodes of severe poisonings have been registered after acute exposure, associated with adverse effects. Epidemiological studies reveal correlation between cyanotoxins and their toxic effects on human health [20].
Symptoms of poisoning by drinking water are much like those of gastrointestinal disturbances caused by a number of pathogenic bacteria, thus hampering differentiation of poisoning with cyanotoxins. Data for chronic exposure to low cyanobacterial toxin levels are still not well investigated.
Concerning the chemical diversity of cyanotoxins, the pathobiochemical mechanisms for cyanotoxin-associated diseases are variable [116] and the mechanism of toxicity is different. Thus, there is no universal antidote for treatment of cases of cyanobacteria intoxications. One treatment strategy is to apply chemoprotectants, especially for treatment of microcystin intoxications. However, there is less research available on cylindrospermopsin-induced toxicity treatment [99]. Commonly discussed is the application of antioxidants with vitamin E having the strongest protective effect, as oxidative stress is one of the most common pathobiochemical mechanisms of cyanobacteria intoxications. In reference to available knowledge about cellular uptake of cyanotoxins, especially microcystins, transport inhibitors are considered for potential administration in cases of cyanobacteria-related intoxications and in combination with other therapies. The antibiotic rifampin is reported as an example of such a drug approved for clinical use [117].
Due to nondefinitive manifestation of cyanotoxin poisoning, symptomatic treatment is applied, including oxygen application, aiming at respiratory distress amelioration, activated charcoal gastric lavage, forced diuresis for toxin elimination by glomerular filtration, alkalization, and hepatoprotective medication administration [118].
6. Discussion
Cyanobacterial blooms have been registered worldwide for centuries, and a correlation to associated human and animal illness has been suspected. Subsequently, it has been documented that blue-green algae produce various bioactive compounds with the common name cyanotoxins. Taking into account the wide variety of cyanobacteria, their effect on all aquatic ecosystems, and the various manifestation of cyanotoxin poisoning, it is essential to elucidate their toxicity mechanisms, as well as adequate treatment.
Most common and well-examined cyanotoxins are the ones of the microcystin family. Epidemiological studies do not provide definitive confirmation of linkage of acute or chronic exposure to cyanotoxins and human cancer development. Some animal studies demonstrate cyanotoxins’ carcinogenic potential. Intraperitoneal injection of MC-LR in sublethal dose causes neoplastic nodules in mouse liver [119]. MC-LR application causes liver cancer in dose-dependent manner in rat model where protein phosphatase type 1 and type 2A activities’ inhibition has been established [120]. Inhibition of serine/threonine phosphatase activity is a possible link between toxic and suspected carcinogenic potential of microcystins. Supporting evidences for this hypothesis, for example, are the findings that PP2A phosphatase inhibition by microcystins leads to disruption of MAPK signal transduction pathway [55]. This can be a possible explanation for increased proto-oncogene transcription observed [65] and promoted cell proliferation and tumorigenesis [66] in experiments with this kind of toxins. Considering research limitations of microcystin effects on humans, further investigations and evidence collection are needed to provide more robust correlation between cyanotoxin poisoning and cancer development.
CYN cancer potential has been less studied and not fully explained. It is assumed rather indirect. CYN metabolism and biotransformation with the participation of CYPs generate reactive metabolites and exhaust cellular glutathione. Thus, its toxicity and/or carcinogenic potential may be attributed to generated (geno)toxic metabolites and compromised antioxidant cellular defense.
Cellular penetration of MCs is mediated by tissue-specific OATPs. Overexpression of these transporters in certain cancer cells [92] provides an opportunity for the development of effective novel cancer-targeted agents. In support of this hypothesis, transfection of HeLa cancer cells with OATPs has been established to increase their susceptibility to MC treatment as compared to vector-transfected control cells [93]. More studies in this field are necessary to provide valuable data about MCs’ application as anticancer remedies.
7. Conclusions
Cyanobacteria are proved in various habitats, such as drinking water reservoirs and recreational waters, at the basis of food chains, and thus, with a substantial impact on ecosystems and human health. Centurial observations of a correlation between water blooms and health issues in animals and humans are extended in numerous epidemiological, in vivo and in vitro, studies. Various bioactive compounds under the common name cyanotoxins are established as the reason for blooming water toxicity. Some of the toxic molecular mechanisms for certain cyanotoxins are clarified. Their bioavailability, metabolism, and biotransformation are proved as well. A possible link between cyanotoxin exposure and cancer development has been suspected and there is experimental research data in support of this hypothesis. Yet, cyanobacteria produce natural compounds with promising potential for the discovery of novel anticancer drugs. Improved alertness about cyanotoxin poisoning, its relation to water blooms, poisoning symptoms, and specific treatment is needed in view of adequate human and animal health promotion and health care. Cyanobacteria have already been in the focus of food and pharmaceutical industry and cosmetics for a long time, incorporated in different preparations and food supplements. This requires raised awareness of the population and responsible institutions about the hazards of cyanotoxin contamination regarding food, water, and health remedies.
Acknowledgments
This study was supported by the Bulgarian National Science Fund, Grant No DN13/9, 15.12.2017; project “Cyanoprokaryotes—a new potential risk factor for cancer in Bulgaria?”.
\n',keywords:"cyanotoxins, microcystins, nodularins, cylindrospermopsin, toxicity mechanisms",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68132.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68132.xml",downloadPdfUrl:"/chapter/pdf-download/68132",previewPdfUrl:"/chapter/pdf-preview/68132",totalDownloads:843,totalViews:0,totalCrossrefCites:2,dateSubmitted:"April 24th 2019",dateReviewed:"June 12th 2019",datePrePublished:"July 16th 2019",datePublished:"February 3rd 2021",dateFinished:"July 16th 2019",readingETA:"0",abstract:"Cyanoprokaryotes are distributed worldwide and they produce various bioactive compounds, including cyanotoxins. The major route of human exposure to cyanotoxins is the oral intake by using contaminated drinking water, by incidental intake of contaminated water during recreational and professional activities, and by consuming contaminated food or dietary supplements prepared from cyanobacteria. The prolonged chronic exposure to low concentrations of cyanotoxins provokes cell damage and may increase the risk for cancer development. Due to the variety of cyanotoxin chemical structures, different mechanisms of their toxic effects are known. At the same time, some of the natural compounds produced by cyanoprokaryotes have anticancer potential and are promising sources for the development of novel drugs. This chapter is dedicated to the target mechanisms behind the effects of the widely distributed cyanotoxins with an impact on human health, microcystins, nodularins, and cylindrospermopsin.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68132",risUrl:"/chapter/ris/68132",signatures:"Deyana Georgieva Vankova, Milena Gincheva Pasheva, Yoana Dimitrova Kiselova-Kaneva, Dobri Lazarov Ivanov and Diana Georgieva Ivanova",book:{id:"7847",type:"book",title:"Medical Toxicology",subtitle:null,fullTitle:"Medical Toxicology",slug:"medical-toxicology",publishedDate:"February 3rd 2021",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-278-3",printIsbn:"978-1-83880-277-6",pdfIsbn:"978-1-83969-155-3",isAvailableForWebshopOrdering:!0,editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"294616",title:"Prof.",name:"Diana Georgieva",middleName:null,surname:"Ivanova",fullName:"Diana Georgieva Ivanova",slug:"diana-georgieva-ivanova",email:"divanova@mu-varna.bg",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Varna",institutionURL:null,country:{name:"Bulgaria"}}},{id:"302964",title:"Ph.D.",name:"Deyana Georgieva",middleName:null,surname:"Vankova",fullName:"Deyana Georgieva Vankova",slug:"deyana-georgieva-vankova",email:"deyana.vankova@mu-varna.bg",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Varna",institutionURL:null,country:{name:"Bulgaria"}}},{id:"302969",title:"Dr.",name:"Milena Gincheva",middleName:null,surname:"Pasheva",fullName:"Milena Gincheva Pasheva",slug:"milena-gincheva-pasheva",email:"milena.pasheva@mu-varna.bg",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Varna",institutionURL:null,country:{name:"Bulgaria"}}},{id:"302970",title:"Dr.",name:"Yoana Dimitrova",middleName:null,surname:"Kiselova-Kaneva",fullName:"Yoana Dimitrova Kiselova-Kaneva",slug:"yoana-dimitrova-kiselova-kaneva",email:"yoana.kiselova@mu-varna.bg",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Varna",institutionURL:null,country:{name:"Bulgaria"}}},{id:"302972",title:"Prof.",name:"Dobri Lazarov",middleName:null,surname:"Ivanov",fullName:"Dobri Lazarov Ivanov",slug:"dobri-lazarov-ivanov",email:"d.ivanov@mu-varna.bg",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Medical University of Varna",institutionURL:null,country:{name:"Bulgaria"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Water blooms, human and animal health",level:"1"},{id:"sec_3",title:"3. Cyclic peptides—toxicity and biotransformations",level:"1"},{id:"sec_3_2",title:"3.1 Cyclic peptides—molecular toxicity mechanism in relation to carcinogenicity",level:"2"},{id:"sec_4_2",title:"3.2 Cyclic peptides—potential sources of anticancer drugs",level:"2"},{id:"sec_6",title:"4. Cylindrospermopsin—molecular mechanisms of toxicity and biotransformation",level:"1"},{id:"sec_6_2",title:"4.1 Anticancer properties of cylindrospermopsin",level:"2"},{id:"sec_8",title:"5. Clinical toxicology and pharmacological aspects",level:"1"},{id:"sec_9",title:"6. Discussion",level:"1"},{id:"sec_10",title:"7. Conclusions",level:"1"},{id:"sec_11",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Awramik SM. The oldest records of photosynthesis. 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No induction of structural chromosomal aberrations in cylindrospermopsin-treated CHO-K1 cells without and with metabolic activation. Toxicon. 2007;50:1105-1115'},{id:"B109",body:'Straser A, Filipic M, Zegura B. Cylindrospermopsin induced transcriptional responses in human hepatoma HepG2 cells. Toxicology In Vitro : An International Journal Published in Association with BIBRA. 2013;27:1809-1819'},{id:"B110",body:'Hercog K, Maisanaba S, Filipic M, Jos A, Cameánn AM, Zegura B. Genotoxic potential of the binary mixture of cyanotoxins microcystin—LR and cylindrospermopsin. Chemosphere. 2017;189:319-329'},{id:"B111",body:'Bain P, Shae G, Patel B. Induction of P53-regulated gene expression in human cell lines exposed to the cyanobacterial toxin cylindrospermopsin. Journal of Toxicology and Environmental Health Part A: Current Issues. 2007;70:1687-1693'},{id:"B112",body:'Liebel S, Oliveira Ribeiro CA, Magalhaes VF, Silva C, Ramsdorf WA, Rossi SC, et al. Low concentrations of cylindrospermopsin induce increases of reactive oxygen species levels, metabolism and proliferation in human hepatoma cells (HepG2). Toxicology In Vitro. 2015;29:479-488'},{id:"B113",body:'Pichardo S, Cameán AM, Jos A. In vitro toxicological assessment of cylindrospermopsin: A review. Toxins. 2017;9(402):1-29'},{id:"B114",body:'Huguet A, Hatton A, Villot R, Quenault H, Blanchard Y, Fessard V. Modulation of chromatin remodelling induced by the freshwater cyanotoxin cylindrospermopsin in human intestinal Caco-2 cells. PLoS One. 2014;9(6):99-121'},{id:"B115",body:'Alja Š, Filipič M, Novak M, Žegura B. Double strand breaks and cell-cycle arrest induced by the cyanobacterial toxin cylindrospermopsin in HepG2 cells. Marine Drugs. 2013;11(8):3077-3090'},{id:"B116",body:'Facciponte DN, Bough MW, Seidler D, Carroll JL, Ashare A, Andrew AS, et al. Identifying aerosolized cyanobacteria in the human respiratory tract: A proposed mechanism for cyanotoxin-associated diseases. Science of the Total Environment. 2018;645:1003-1013'},{id:"B117",body:'Dawson RM. The toxicology of microcystins. Toxicon. 1998;36(7):953-962'},{id:"B118",body:'Zlateva S. Poisoning with molluscs and crustaceans. In: Kanev K, Stavrev D, editors. Handbook of Marine Toxicology. Poisoning with Sea Food and Marine Animals Incidence. 1st ed. Medical University Varna: Publishing Steno; 2018. p. 26. ISBN 978-619-221-163-0. IBSN 978-954-449-977-8'},{id:"B119",body:'Ito E, Kondo F, Terao K, Harada KI. Neoplastic nodular formation in mouse liver induced by repeated intraperitoneal injections of microcystin-LR. Toxicon. 1997;35(9):1453-1457'},{id:"B120",body:'Nishiwaki-Matsushima R, Oht T, Nishiwaki S, et al. Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR. Journal of Cancer Research and Clinical Oncology. 1992;118(6):420-424'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Deyana Georgieva Vankova",address:"deyana.vankova@mu-varna.bg",affiliation:'
Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University of Varna, Bulgaria
Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University of Varna, Bulgaria
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IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
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Does your institution already have a budget for covering Open Access publication costs?
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Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
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Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at funders@intechopen.com
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From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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The goal is to provide the required quality and safety of water from the standpoint of heavy metal contamination. The basic and most important characteristics of biosensors are high sensitivity, short response time, specificity, and relatively low production cost. Biosensors can detect the presence and measure the content of various toxic substances (pesticides, heavy metals, etc.) not only in water but also in food. Detection of contaminants, primarily heavy metals in water used in food production processes, is a potential area of biosensor application in the food industry. Biosensors can be adapted for direct and continuous (online) monitoring by measuring certain analytes that can affect the quality and safety of water. This chapter will give an overview of the development and application of biosensors in order to control the quality and safety of water from the standpoint of the presence of heavy metals.",book:{id:"7007",slug:"biosensors-for-environmental-monitoring",title:"Biosensors for Environmental Monitoring",fullTitle:"Biosensors for Environmental Monitoring"},signatures:"Amra Odobašić, Indira Šestan and Sabina Begić",authors:null},{id:"16446",doi:"10.5772/22350",title:"Advances in Aptamer-Based Biosensors for Food Safety",slug:"advances-in-aptamer-based-biosensors-for-food-safety",totalDownloads:9643,totalCrossrefCites:11,totalDimensionsCites:26,abstract:null,book:{id:"413",slug:"environmental-biosensors",title:"Environmental Biosensors",fullTitle:"Environmental Biosensors"},signatures:"Maureen McKeague, Amanda Giamberardino and Maria C. 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They perform the specific component detection in a sample through an appropriate analytical signal. Enzyme-based biosensors are the most prominent biosensors because of their high specificity and selectivity; besides being an alternative to the common immunosensors, they are more expensive and present a limited binding capacity with the antigen depending on assay conditions. This chapter approaches the use of enzymes modified electrodes in amperometric biosensing application to detect and quantify pesticides and phenolic compounds with pharmacological properties, as they have been a promising analytical tool in environmental monitoring. These biosensors may be prepared from pure enzymes or their crude extracts. Pure enzyme-based biosensors present advantages as higher substrate specificity and selectivity when compared to crude extract enzymatic biosensors; nevertheless, the enzyme high costs are their drawbacks. Enzymatic crude extract biosensors show lower specificity due to the fact that they may contain more than one type of enzyme, but they may be obtained from low-cost fabrication methods. In addition, they can contain enzyme cofactors besides using the enzyme in its natural conformation.",book:{id:"7007",slug:"biosensors-for-environmental-monitoring",title:"Biosensors for Environmental Monitoring",fullTitle:"Biosensors for Environmental Monitoring"},signatures:"Flavio Colmati, Lívia Flório Sgobbi, Guilhermina Ferreira Teixeira, Ramon Silva Vilela, Tatiana Duque Martins and Giovanna Oliveira Figueiredo",authors:null},{id:"16449",doi:"10.5772/16250",title:"Biosensors Applications on Assessment of Reactive Oxygen Species and Antioxidants",slug:"biosensors-applications-on-assessment-of-reactive-oxygen-species-and-antioxidants",totalDownloads:2779,totalCrossrefCites:1,totalDimensionsCites:11,abstract:null,book:{id:"413",slug:"environmental-biosensors",title:"Environmental Biosensors",fullTitle:"Environmental Biosensors"},signatures:"Simona Carmen Litescu, Sandra A.V. 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Eremia"},{id:"24428",title:"BSc.",name:"Mirela",middleName:null,surname:"Diaconu",slug:"mirela-diaconu",fullName:"Mirela Diaconu"},{id:"24429",title:"Prof.",name:"Gabriel-Lucian",middleName:null,surname:"Radu",slug:"gabriel-lucian-radu",fullName:"Gabriel-Lucian Radu"},{id:"47095",title:"Ms",name:"Andreia",middleName:null,surname:"Tache",slug:"andreia-tache",fullName:"Andreia Tache"}]}],mostDownloadedChaptersLast30Days:[{id:"66031",title:"Biosensors for Determination of Heavy Metals in Waters",slug:"biosensors-for-determination-of-heavy-metals-in-waters",totalDownloads:2772,totalCrossrefCites:14,totalDimensionsCites:27,abstract:"Biosensors are nowadays a powerful alternative to conventional analytical techniques for controlling the quality of not only natural water but also process water used by the food industry during the production process, as well as wastewater prior to release into natural watercourses. The goal is to provide the required quality and safety of water from the standpoint of heavy metal contamination. The basic and most important characteristics of biosensors are high sensitivity, short response time, specificity, and relatively low production cost. Biosensors can detect the presence and measure the content of various toxic substances (pesticides, heavy metals, etc.) not only in water but also in food. Detection of contaminants, primarily heavy metals in water used in food production processes, is a potential area of biosensor application in the food industry. Biosensors can be adapted for direct and continuous (online) monitoring by measuring certain analytes that can affect the quality and safety of water. This chapter will give an overview of the development and application of biosensors in order to control the quality and safety of water from the standpoint of the presence of heavy metals.",book:{id:"7007",slug:"biosensors-for-environmental-monitoring",title:"Biosensors for Environmental Monitoring",fullTitle:"Biosensors for Environmental Monitoring"},signatures:"Amra Odobašić, Indira Šestan and Sabina Begić",authors:null},{id:"68700",title:"Principle and Development of Phage-Based Biosensors",slug:"principle-and-development-of-phage-based-biosensors",totalDownloads:1433,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"Detection and identification of pathogenic bacteria is important in the field of public health, medicine, food safety, environmental monitoring and security. Worldwide, the common cause of mortality and morbidity is bacterial infection often due to misdiagnosis or delay in diagnosis. Existing bacterial detection methods rely on conventional culture or microscopic techniques and molecular methods that often time consuming, laborious and expensive, or need trained users. In recent years, biosensor remained an interesting topic for bacterial detection and many biosensors involving different bio-probes have been reported. Compared to antibodies, nucleic acids and enzymes etc., based biosensors, bacteriophages can be cheaply produced and are relatively much stable to elevated temperature, extreme pH, and diverse ionic strength. Therefore, there is an urgent need for phage-based biosensor for bacterial pathogen detection. Furthermore, bearing high affinity and specificity, bacteriophages are perfect bio-recognition probes in biosensor development for bacterial detection. In this regard, active and oriented phages immobilization is the key step toward phage-based biosensor development. This chapter compares different bacterial detection techniques, and introduces the basic of biosensor and different bio-probes involved in biosensor development. Further we highlight the involvement and importance of phages in biosensor and finally we briefed different phage immobilization approaches used in development of phage-based biosensors.",book:{id:"7007",slug:"biosensors-for-environmental-monitoring",title:"Biosensors for Environmental Monitoring",fullTitle:"Biosensors for Environmental Monitoring"},signatures:"Umer Farooq, Qiaoli Yang, Muhammad Wajid Ullah and Shenqi Wang",authors:null},{id:"69216",title:"Challenges and Applications of Impedance-Based Biosensors in Water Analysis",slug:"challenges-and-applications-of-impedance-based-biosensors-in-water-analysis",totalDownloads:1220,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Monitoring of the environment is a global priority due to the close connection between the environmental pollution and human health. Many analytical techniques using various methods have been developed to detect and monitor the levels of pollutants (pesticides, toxins, bacteria, drug residues, etc.) in natural water bodies. The latest trend in modern analysis is to measure pollutants in real-time in the field. For this purpose, biosensors have been employed as cost-effective and fast analytical techniques. Among biosensors, impedance biosensors have significant potential for use as simple and portable devices. These sensors involve application of a small amplitude AC voltage to the sensor electrode and measurement of the in-/out-of-phase current response as a function of frequency integrated with some biorecognition element on the sensing electrodes that can bind to the target, modifying the sensor electrical parameters. However, there are some drawbacks concerning their selectivity, stability, and reproducibility. The aim of this paper is to give a critical overview of literature published during the last decade based on the development issues of impedimetric biosensors and their applicability in water analysis.",book:{id:"7007",slug:"biosensors-for-environmental-monitoring",title:"Biosensors for Environmental Monitoring",fullTitle:"Biosensors for Environmental Monitoring"},signatures:"Kairi Kivirand, Mart Min and Toonika Rinken",authors:[{id:"24687",title:"Dr.",name:"Toonika",middleName:null,surname:"Rinken",slug:"toonika-rinken",fullName:"Toonika Rinken"},{id:"62780",title:"Prof.",name:"Mart",middleName:null,surname:"Min",slug:"mart-min",fullName:"Mart Min"},{id:"174179",title:"Dr.",name:"Kairi",middleName:null,surname:"Kivirand",slug:"kairi-kivirand",fullName:"Kairi Kivirand"}]},{id:"63693",title:"The Modeling, Design, Fabrication, and Application of Biosensor Based on Electric Cell-Substrate Impedance Sensing (ECIS) Technique in Environmental Monitoring",slug:"the-modeling-design-fabrication-and-application-of-biosensor-based-on-electric-cell-substrate-impeda",totalDownloads:1122,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"In this research, the modeling, design, fabrication, and application of ECIS sensors in environmental monitoring are studied. The ECIS sensors are able to qualify the water toxicity through measuring the cell impedance. A novel mathematical model is proposed to analyze the distribution of electric potential and current of ECIS. This mathematical model is validated by experimental data and can be used to optimize the dimension of ECIS electrodes in order to satisfy environmental monitors. The detection sensitivity of ECIS sensors is analyzed by the mathematical model and experimental data. The simulated and experimental results show that ECIS sensors with smaller radius of working electrodes yield higher impedance values, which improves signal-to-noise ratio, which is more suitable in measuring the cell morphology change influenced by environments. Several ECIS sensors are used to detect the toxicant including, phenol, ammonia, nicotine, and aldicarb, and the decreasing cell impedance indicates the toxic effect. The gradient of measured impedance qualitatively indicates the concentration of toxicants in water.",book:{id:"7007",slug:"biosensors-for-environmental-monitoring",title:"Biosensors for Environmental Monitoring",fullTitle:"Biosensors for Environmental Monitoring"},signatures:"Xudong Zhang, William Wang and Sunghoon Jang",authors:null},{id:"65873",title:"Electrochemical Biosensors Containing Pure Enzymes or Crude Extracts as Enzyme Sources for Pesticides and Phenolic Compounds with Pharmacological Property Detection and Quantification",slug:"electrochemical-biosensors-containing-pure-enzymes-or-crude-extracts-as-enzyme-sources-for-pesticide",totalDownloads:1109,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Biosensors are chemical sensors in which the recognition system is based on a biochemical mechanism. They perform the specific component detection in a sample through an appropriate analytical signal. Enzyme-based biosensors are the most prominent biosensors because of their high specificity and selectivity; besides being an alternative to the common immunosensors, they are more expensive and present a limited binding capacity with the antigen depending on assay conditions. This chapter approaches the use of enzymes modified electrodes in amperometric biosensing application to detect and quantify pesticides and phenolic compounds with pharmacological properties, as they have been a promising analytical tool in environmental monitoring. These biosensors may be prepared from pure enzymes or their crude extracts. Pure enzyme-based biosensors present advantages as higher substrate specificity and selectivity when compared to crude extract enzymatic biosensors; nevertheless, the enzyme high costs are their drawbacks. Enzymatic crude extract biosensors show lower specificity due to the fact that they may contain more than one type of enzyme, but they may be obtained from low-cost fabrication methods. In addition, they can contain enzyme cofactors besides using the enzyme in its natural conformation.",book:{id:"7007",slug:"biosensors-for-environmental-monitoring",title:"Biosensors for Environmental Monitoring",fullTitle:"Biosensors for Environmental Monitoring"},signatures:"Flavio Colmati, Lívia Flório Sgobbi, Guilhermina Ferreira Teixeira, Ramon Silva Vilela, Tatiana Duque Martins and Giovanna Oliveira Figueiredo",authors:null}],onlineFirstChaptersFilter:{topicId:"137",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:"2753-6580",scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. Aljaser",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"428600",title:"MSc.",name:"Adriana",middleName:null,surname:"García-Alarcón",slug:"adriana-garcia-alarcon",fullName:"Adriana García-Alarcón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428599",title:"MSc.",name:"Gabino",middleName:null,surname:"De La Rosa-Cruz",slug:"gabino-de-la-rosa-cruz",fullName:"Gabino De La Rosa-Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428601",title:"MSc.",name:"Juan Carlos",middleName:null,surname:"Campuzano-Caballero",slug:"juan-carlos-campuzano-caballero",fullName:"Juan Carlos Campuzano-Caballero",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}}]}},subseries:{item:{id:"7",type:"subseries",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11403,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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