Duration of RR interval from telemetry studies and for different types of general anesthesia according to sex and dependence on the light–dark cycle.
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IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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Nevertheless, liposomes, due to their various forms and applications, require further investigation. These structures can deliver both hydrophilic and hydrophobic drugs. The preparation of liposomes results in different properties for these systems. In addition, there are many factors and difficulties that affect the development of liposome drug delivery structures.The purpose of this book is to concentrate on recent developments in liposomes. The articles collected in this book are contributions by invited researchers with long-standing experience in different research areas. We hope that the material presented here is understandable to a broad audience, not only scientists but also people with a general background in many different biological sciences. This volume offers up-to-date, expert reviews of the fast-moving field of liposomes and is divided in two major sections: 1. Introduction; 2. Liposomes general properties",isbn:"978-1-78984-495-5",printIsbn:"978-1-78984-494-8",pdfIsbn:"978-1-83881-232-4",doi:"10.5772/intechopen.77926",price:119,priceEur:129,priceUsd:155,slug:"liposomes-advances-and-perspectives",numberOfPages:102,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"02b0d76190d551561ad19af0c80f98f2",bookSignature:"Angel Catala",publishedDate:"September 4th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8095.jpg",numberOfDownloads:7083,numberOfWosCitations:40,numberOfCrossrefCitations:26,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:56,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:122,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 25th 2018",dateEndSecondStepPublish:"December 10th 2018",dateEndThirdStepPublish:"February 8th 2019",dateEndFourthStepPublish:"April 29th 2019",dateEndFifthStepPublish:"June 28th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"380",title:"Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology-biochemistry-molecular-biology"}],chapters:[{id:"66574",title:"Introductory Chapter: Liposomes - Advances and Perspectives - My Point of View",doi:"10.5772/intechopen.85663",slug:"introductory-chapter-liposomes-advances-and-perspectives-my-point-of-view",totalDownloads:582,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Angel Catala",downloadPdfUrl:"/chapter/pdf-download/66574",previewPdfUrl:"/chapter/pdf-preview/66574",authors:[{id:"196544",title:"Prof.",name:"Angel",surname:"Catala",slug:"angel-catala",fullName:"Angel Catala"}],corrections:null},{id:"66763",title:"The Role of Water in the Responsive Properties in Lipid Interphase of Biomimetic Systems",doi:"10.5772/intechopen.85811",slug:"the-role-of-water-in-the-responsive-properties-in-lipid-interphase-of-biomimetic-systems",totalDownloads:1129,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The lack of details in the hydration properties of lipid bilayers hinders the design of biomimetic systems that, as liposomes and vesicles, may be used for biotechnological and medical purposes. In this chapter, studies indicate water as a membrane dynamic component determining the affinity and response of lipid membranes to amino acids, peptides and others stimuli. Based on thermodynamic analysis in lipid monolayers and its comparison with swelling shrinkage processes in liposomes and vesicles, it is concluded that: (1) the interphase of a lipid bilayer in a bidimensional solution of hydrated polar groups imbibed in labile water can be exchanged with the media by osmosis and or expansion-compression. (2) Excess water beyond the hydration shell (confined water) has solvent properties for additives in the bulk water phase and confers free energy that is in excess for binding of amino acids and peptides. (3) Dissolution in the water membrane phase changes the water activity (aw) and affects the surface pressure. (4) Defects may be formed by the compression of bilayers in which carbonyl groups organized water differently. These studies indicate that a deeper understanding of the role of lipid bilayers in cellular biology and support the development of future lipid-based biotechnology that should necessarily include the role of water as a membrane dynamic component.",signatures:"Anibal Disalvo and Maria de los Angeles Frias",downloadPdfUrl:"/chapter/pdf-download/66763",previewPdfUrl:"/chapter/pdf-preview/66763",authors:[{id:"285313",title:"Ph.D.",name:"Anibal",surname:"Disalvo",slug:"anibal-disalvo",fullName:"Anibal Disalvo"},{id:"298166",title:"Dr.",name:"Maria",surname:"Frias",slug:"maria-frias",fullName:"Maria Frias"}],corrections:null},{id:"66369",title:"General Perception of Liposomes: Formation, Manufacturing and Applications",doi:"10.5772/intechopen.84255",slug:"general-perception-of-liposomes-formation-manufacturing-and-applications",totalDownloads:3285,totalCrossrefCites:16,totalDimensionsCites:39,hasAltmetrics:0,abstract:"Liposomes are currently part of the most reputed carriers for various molecular species, from small and simple to large and complex molecules. Since their discovery, liposomes have been subject to extensive evolution, in terms of composition, manufacturing and applications, which led to several openings in both basic and applied life sciences. However, most of the advances in liposome research have been more devoted to launching new developments than improving the existing technology for potential implementation. For instance, the evolution of the conventional lipid hydration methods to novel microfluidic technologies has permitted upscale production, but with increase in manufacturing cost and persistent use of organic solvents. This chapter intends to present general concepts in liposome technology, highlighting some longstanding bottlenecks that remain challenging to the preparation, characterization and applications of liposomal systems. This would enhance the understanding of the gaps in the field and, hence, provide directions for future research and developments.",signatures:"Christian Isalomboto Nkanga, Alain Murhimalika Bapolisi, Nnamdi Ikemefuna Okafor and Rui Werner Maçedo Krause",downloadPdfUrl:"/chapter/pdf-download/66369",previewPdfUrl:"/chapter/pdf-preview/66369",authors:[{id:"284670",title:"Prof.",name:"Rui",surname:"Krause",slug:"rui-krause",fullName:"Rui Krause"},{id:"284672",title:"Mr.",name:"Alain",surname:"Bapolisi",slug:"alain-bapolisi",fullName:"Alain Bapolisi"},{id:"284673",title:"MSc.",name:"Christian",surname:"Nkanga",slug:"christian-nkanga",fullName:"Christian Nkanga"},{id:"284675",title:"Mr.",name:"Okafor",surname:"Nnamdi",slug:"okafor-nnamdi",fullName:"Okafor Nnamdi"}],corrections:null},{id:"67005",title:"Dissipative Particle Dynamics Simulations of Self-Assemblies of Liposomes for Drug Delivery Applications",doi:"10.5772/intechopen.85812",slug:"dissipative-particle-dynamics-simulations-of-self-assemblies-of-liposomes-for-drug-delivery-applicat",totalDownloads:874,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Liposomes are essential components in the development of functional materials for drug delivery; this is mainly due to its ability to self-associate spontaneously and form bilayer vesicles. In these potential applications, knowing the size of self-assembled liposomes is essential for optimal performance; however, this process still has many unanswered questions. Conventional experimental techniques to study self-assemblies of liposome nanoparticles still have a great challenge. Computational simulations emerge as an alternative to understand the role of thermodynamic properties responsible for the self-assembly, particularly when they are unreachable experimentally because of limited time and length resolutions. In this chapter, we present the advantages and disadvantages of dissipative particle dynamic method to explore the functioning of liposome self-assembly in the transport of drugs.",signatures:"Ketzasmin Armando Terrón-Mejía, Inocencio Higuera-Ciapara, Evelin Martínez-Benavidez, Javier Hernández and Roberto López-Rendón",downloadPdfUrl:"/chapter/pdf-download/67005",previewPdfUrl:"/chapter/pdf-preview/67005",authors:[{id:"186353",title:"Dr.",name:"Javier",surname:"Hernandez",slug:"javier-hernandez",fullName:"Javier Hernandez"},{id:"286139",title:"Dr.",name:"Roberto",surname:"López-Rendón",slug:"roberto-lopez-rendon",fullName:"Roberto López-Rendón"},{id:"286252",title:"Dr.",name:"Ketzasmin A.",surname:"Terrón-Mejía",slug:"ketzasmin-a.-terron-mejia",fullName:"Ketzasmin A. Terrón-Mejía"},{id:"286253",title:"Dr.",name:"Inocencio",surname:"Higuera-Ciapara",slug:"inocencio-higuera-ciapara",fullName:"Inocencio Higuera-Ciapara"},{id:"286254",title:"MSc.",name:"Evelin",surname:"Martínez-Benavidez",slug:"evelin-martinez-benavidez",fullName:"Evelin Martínez-Benavidez"}],corrections:null},{id:"66325",title:"Pharmaceutical Development of Liposomes Using the QbD Approach",doi:"10.5772/intechopen.85374",slug:"pharmaceutical-development-of-liposomes-using-the-qbd-approach",totalDownloads:1213,totalCrossrefCites:9,totalDimensionsCites:13,hasAltmetrics:0,abstract:"Quality by Design (QbD) is a systematic, risk-based approach to pharmaceutical product and manufacturing development, which uses quality-improving scientific methods upstream in the research, development, and design phases, in order to assure that quality and safety are designed into product at as early stage as possible. This work focuses on the state-of-the-art applications of the QbD principles in the development of liposomes. The QbD approach has recently been proposed as a useful tool to obtain higher-quality liposomal products, as their development is a challenging task, involving intricate formulation and manufacturing processes. Thus, the current strategies to define the relationship between the critical material attributes or process parameters and product critical quality attributes and to establish the design space are overviewed. 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Dr. Santana de Oliveira co-directs doctoral and master\'s students at the Postgraduate Programs PPGBOT and BIONORTE in partnership with Dr. Eloisa Helena de Aguiar Andrade and Dr. Ely Simome Cashew Gurgel.',coeditorOneBiosketch:"A researcher in Organic Chemistry, Food Chemistry, and Botany, with over 500 publications, three books edited, 297 works indexed in WOS and SCOPUS, and 3380 total citations.\r\nDr. Andrade is an associated researcher for the Paraense Museum Emilio Goeldi and Adjunta, Teacher of the Postgraduate Programs in Chemistry, UFPA, PPG- in C. 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From 2010 to 2014, he worked on the chemistry of natural products at the Empresa Brasileira de Pesquisa Agropecuária (Embrapa), and from 2014 to 2018, he worked in the Postgraduate Program in Food Science and Technology at the Federal University of Pará, specifically with essential oils. Since 2020, he has been a researcher for the Institutional Training Program - PCI, at the institution Museu Paraense Emilio Goeldi, linked to the Ministério da Ciência, Tecnologia e Inovações of Brazil (MCTI), with studies focused on extraction, characterization chemistry, and applications of essential oils in several industrial segments, among them the food industry. Specifically, Dr. Oliveira has experience in engineering, food science and technology, pharmacology and drug discovery, medicinal chemistry, ethnopharmacology and ethnobotany, phytochemistry, methods of extraction of bioactive compounds, biotechnology of natural products, and allelopathy to find new natural herbicides to control invasive plants. He also has experience in the area of essential oil extraction using supercritical technology and conventional methods. Since 2020, he has supervised and co-supervised master’s and Ph.D. students in several graduate programs. Dr. Oliveira serves as a reviewer for thirty-one international scientific journals and is the academic editor of the journals Evidence-based Complementary and Alternative Medicine, Journal of Food Quality, Molecules, and Open Chemistry.",institutionString:"Museu Paraense Emílio Goeldi",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Museu Paraense Emílio Goeldi",institutionURL:null,country:{name:"Brazil"}}}],coeditorOne:{id:"314369",title:"Dr.",name:"Eloisa",middleName:null,surname:"Helena De Aguiar Andrade",slug:"eloisa-helena-de-aguiar-andrade",fullName:"Eloisa Helena De Aguiar Andrade",profilePictureURL:"https://mts.intechopen.com/storage/users/314369/images/system/314369.jpg",biography:"Eloisa Helena de Aguiar Andrade holds a degree in Pharmacy (1980), a qualification in Biochemistry (1982), a master\\'s degree in Chemistry of Natural Products (1992), and a Ph.D. in Chemistry (2008) from the Federal University of Pará, Brazil. For. She is currently Associate Researcher II at the Botany Coordination of the Museu Paraense Emílio Goeldi and Adjunct Professor III at the Faculty of Chemistry at the Federal University of Pará. Professor of the Graduate Programs in Chemistry, UFPA, PPG- in Biological C. - Tropical Botany, UFRA/MPEG and Graduate in Biodiversity Biotechnology - Bionorte Network. She is the coordinator of the Pole of the State of Pará, Graduate Program in Biodiversity and Biotechnology (PPG-BIONORTE/PA) of the Bionorte Network (2016-2020). Dr. Andrade is the author of more than 500 scientific contributions, including articles, event communications, book chapters, and books. 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Analysis of heart rate variability (HRV) is a popular tool for the assessment of autonomic cardiac control. Small periodic fluctuations in heart rate are well known to physicians and scientific investigators. Because these fluctuations are caused by the varying activity of the ANS, an examination of HRV is needed to obtain information about the functional status of the ANS. Heart rate and changes in heart rate are sensitive indicators of ANS function; therefore, cardiovascular autonomic regulation is considered to be the most reliable indicator of ANS activity.
HRV describes the beat-to-beat variation in heart rate and is used to quantify the interplay between the sympathetic and parasympathetic divisions of the ANS. Although patterns of HRV demonstrate considerable promise for clarifying issues in clinical applications, the inappropriate quantification and interpretation of these patterns may obscure critical issues or relationships, and may impede—rather than foster—the development of clinical applications [1].
HRV analysis, which supports the evaluation of successive RR intervals using electrocardiographic (ECG) methods, has been a powerful tool in the assessment of autonomic cardiac control [2]. For example, in humans, reduced HRV is associated with an increased risk for ventricular arrhythmia and has been shown to be an independent prognostic factor for mortality in patients with cardiac disease(s) [3, 4]. On the other hand, some studies have demonstrated that analysis of HRV spectral performance in rats is an ineffective method for detecting heart-related autonomic control disorders in some experimental models of myocardial infarction or diabetic neuropathy [5, 6, 7].
The ANS is an important control system that affects the function of many organs, and its activity is affected by various factors, including age [8], sex, and internal processes, such as circadian rhythm and hormonal fluctuations that slowly rise and fall over the course of 24 h. Circadian fluctuations in HRV parameters in rats were confirmed in a study by Hashimoto et al. [9], who reported that sympathetic nerve activity predominates in the dark phase. The ratio of low frequency (LF) to high frequency (HF) demonstrated a nocturnal pattern, and the value in the dark phase was significantly higher than in the light phase. In 2001, Hashimoto et al. [10] extended the monitoring of circadian rhythmicity in HRV to diabetic rats. Although diabetic autonomic neuropathy modifies circadian rhythms in HRV in diabetic WBN/Kob rats, in healthy nondiabetic Wistar rats, significant light–dark (LD) differences were detected in some of the monitored HRV parameters. In both age-different and pre-diabetic Wistar and diabetic WBN/Kob rats, no LD differences were found in the LF parameter of HRV; however, significant LD differences in the HF parameter were detected, except in older diabetic rats. Significant LD differences were found in the LF/HF ratio, but only in prediabetic Wistar rats.
In a telemetry study, Mamalyga [11] described fluctuations in ANS activity during a 24 h period, in which the control groups of male rats exhibited the greatest predominance of sympathetic activity between 12:00 h and 24:00 h. Similarly, in this time range, the LF parameter and LF/HF ratio exhibited higher values, and the HF parameter of HRV exhibited lower values. Analysis of multiday ECG recordings demonstrated the predominance of different mechanisms of heart rhythm regulation in experimental and control rats over a 24 h period. More severe dysfunction of neuroautonomical mechanisms of regulation in experimental rats was reflected in circadian dynamics. Further evidence supporting the existence of circadian rhythms in ANS activity was obtained in a study by Hsieh et al. [12], who monitored various physiological signals after implantation of sensors into the abdomen of rats and were recorded without interruption for >10 days. There was no difference in sleep/wakefulness patterns, physical activity, body weight, and autonomic functioning assessed according to HRV among control, sham, and experimental rats. Continuous recording further revealed circadian rhythms in HRV parameters, namely a 24 h cycle in RR intervals, the total power of HRV, and HF and LF powers of the RR spectrum. As such, we believe that this information may be useful in future biobehavioral studies.
In common practice, experiments are performed during “regular” working hours, even after the synchronization of rats to the LD cycle (12 h:12 h). Although this synchronization is often described in the methods section of these studies, the time of day when the experiments are performed is not reported. Therefore, it is assumed that the experiments are performed during the day (i.e., during the light) and, thus, on “sleeping” rats in their inactive period of the regimen day. However, the question is, what are the reactions of animals in their active period if there are fluctuations in the functions of individual systems in both sexes? Is there alternative reactivity of these systems, or is there a uniform reaction in both sexes? Therefore, if sex differences in the results of various experimental studies are documented, it is necessary to respect this fact. As such, future studies should decode these questions and try to include females in experiments whenever possible.
In the planning stages and design of
However, approaches based on ECG recordings of animals in an anesthetic state are not ideal nor valid for HRV analysis due to significant heart rate fluctuations associated with impaired autonomic modulation of the heart [13, 14]. In addition, anesthesia may contribute an important additional risk for animal mortality under some pathological conditions such as myocardial infarction and diabetes mellitus [15, 16, 17]. General anesthesia weakens autonomic function and baroreflex control. This side effect should be avoided as much as possible because it limits the ability of the subject to respond to physiological challenges during surgery [18]. Therefore, any research intervention that could affect aspects of the ANS and its impact(s) on internal organs should take into account the anesthetic used. Intravenous anesthetics may have different qualitative and quantitative effects on the peripheral ANS and, thus, may alter the activity of the sympathetic or parasympathetic divisions of the ANS.
In the vast majority of experimental studies, only male rats are used; however, there is also the other sex (i.e., female), in which differences may already exist in the very essence of the monitored functional system and exhibit a different response to interventions. At the same time, the study of sex differences is a driving force for development and, in many cases, the basis of health and medicine. However, there are opinions that the investigation of sex differences is ineffectual and does not merit extensive research [19].
Although there are several reasons why female animals are omitted, the primary rationale is simple—males and females are biologically different. Among other reasons, some scientists consider males to be representative of humans and differences from male norms are considered to be atypical or abnormal. Others attempt to “protect” females from the adverse effects of various interventions [20]. Still, others generalize findings from males and females, regardless of differences and, generally speaking, most scientists use male rats because they want to avoid accounting for hormonal cycles in females, which may reduce the homogeneity of the study population and affect the impact of experimental interventions [21]. When females are included in experiments, two problems arise—the sample size is effectively halved—the economic aspect; and the dispersion of results increases. One explanation for the increased variance is the simple fact that males and females are different and these differences increase the range of variability. However, if males and females are mixed, scientists may find a beneficial effect of a tested drug, for example, that lowers blood pressure, in both sexes [19]. On the other hand, on obtaining results from
As such, whether to acknowledge sex differences in
These data support the concept that sex-based variations should also be taken into account, given that females in human and animal studies exhibit different mechanisms of cardiovascular regulation [29]. Although these data suggest that if there are sex differences in individual cardiovascular parameters, they are predominantly regulated by the ANS. Logically, therefore, if sex differences exist in cardiovascular activities, sex differences in the circadian oscillations of individual divisions of the ANS must also exist in parallel.
The aim of the present study was not to downplay or critique the excellent and valid results of experimental
The present study conformed to the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (publication number 85–23, revised 1996). The study protocol was approved by the Ethics Committee of the Medical Faculty of Safarik University (Kosice, Slovak Republic; permission number 2/05 and permission number ŠVPS SR: Ro4234/15–221).
The experiments were performed using Wistar albino rats (weight, 340 ± 40 g, 3–4 months of age) acquired from a breeding and vendor company (VELAZ, Koleč, Czech Republic, certificate number 70029/2013-MZE-17214), with veterinary registration number CZ 21760118.
The animals were quarantined for 2 weeks in the Laboratory of Research Biomodels of the Medical Faculty of Safarik’s University in Košice (official number SK UCH 08018) and adapted to an LD cycle (12 h light:12 h dark [intensity of constant artificial illumination during the light period, 80 Lux]); 40–60% humidity; cage temperature 24°C; two animals/plastic cage for 4 weeks. The rats were fed a standard pellet diet, with
Anesthesia (zoletil, 30 mg/kg, Virbac, France) was administered in prescribed doses in the adaptation room by intraperitoneal injection based on the weight of the animal. After testing the effect of anesthesia (loss of uprighting reflexes, reaction to painful stimulus), the animals were transferred to the operating room, where they were fixed to an experimental table on which subcutaneous electrodes were used to record ECG and HRV. Again, the depth of anesthesia was assessed depending on whether the painful stimulus caused noticeable motor movements (minimal limb movement and muscle tension change) or cardiovascular responses such as changes in heart rate or onset of heart rhythm disorders.
The effect of the light period on the monitored parameters was examined after adaptation to an LD cycle, with the light period from 06:00 h to 18:00 h. The effect of the dark period was monitored after adaptation to the inverse setting of the LD cycle (i.e., with the light period from 18:00 h to 06:00 h). The animals were randomly divided into four experimental groups (n = 20 each) according to sex and light conditions—group 1, female (light period); group 2, female (dark period); group 3, male (light period); and group 4, male (dark period). In
HRV was analyzed using the ID Instruments computer system for biopotential recording from an average of 220 heart cycles, 20 minutes after administration of anesthesia at 09:00 h—12:00 h using separate animals. In analyzing HRV parameters, the focus was on the evaluation of RR interval duration spectral power at very-low-frequency (VLF, 0.003–0.04 Hz), low-frequency (LF, 0.04–0.15 Hz), and high-frequency (HF, 0.15–0.4 Hz), total spectral power of HRV, and the LF/HF ratio. The experiments were performed throughout the year and the results were averaged independently of the season and, in females, independently of the estral cycle. All animals (i.e., 20/20) were included in the statistical analysis. Before and after administration of the anesthetic, as well as during measurement, there were no adverse events or unexpected changes in HRV or ECG parameters, although considerable variability was observed. On completion of the measurement, the animals were transferred to the animal facility.
Data are expressed as mean ± standard deviation (SD). Data were analyzed using InStat (GraphPad, San Diego, CA, USA). The Tukey–Kramer test was used to compare data from the groups, and differences with p < 0.05 were considered to be statistically significant.
Evaluation of the RR interval can sometimes be problematic because different effect(s) of the anesthetic on this parameter has been described. The data reported in Table 1 indicate values of the duration of the RR interval from telemetry studies and under different types of general anesthesia according to sex and dependence on the LD cycle (Figure 1).
Light period | Dark period | |||
---|---|---|---|---|
Anesthesia | Female | Male | Female | Male |
Telemetry studies | 168.7 (167.3–170.1) (n = 1) | 163.2 (157–168.5) (n = 2) | 140.2 (139.5–141) (n = 1) | 145.9 (142.6–149.2) (n = 2) |
Pentobarbital | 177 (174–180) (n = 1) | — | 165 (163–167) (n = 1) | — |
Ketamine | 271.1 (231.5–310.7) (n = 2) | — | 213.1 (194.1–232.1) (n = 2) | — |
Tribromoethanol | — | — | — | — |
Thiopental | — | — | — | — |
Urethane | — | — | — | — |
Zoletil (Present study) | 142.30 (117.1–167.5) | 145.05 (136.5–153.6) | 134.97 (125.9–144.1) | 124.68 (119.5–129.8) |
Duration of RR interval from telemetry studies and for different types of general anesthesia according to sex and dependence on the light–dark cycle.
Data presented as the average RR interval duration (ms) (range); (n, number of experiments from which RR interval was evaluated).
Distribution of average values and ranges of RR intervals from telemetry studies and under different types of general anesthesia in male rats, without specification of synchronization to the light–dark cycle or the time of day when the experiments were performed. Tel – Telemetry studies (168.5(165.6–171.5), n = 3) [
Baseline RR interval analysis from telemetry studies [9, 7, 27, 30, 31] involving male Wistar rats, in which a chronobiological approach was applied, indicates that there is a circadian rhythm in the duration of RR intervals in rats, with a lower RR interval duration during the active (i.e., dark) period of the regimen day. Although adaptation of animals to the LD cycle was described in these articles, exactly what time of day the measurements were performed was not reported, nor whether they were average values from the entire 24 h period or only from certain time intervals the measurements were performed and recorded. The averaged results of baseline RR interval duration indicate that sex differences are exhibited in both the light and dark period of the rat regimen day; however, more experimental studies are needed to confirm this conclusion.
When comparing the duration of the RR interval in male rats from telemetry studies, it is clear that the shorter duration occurred during the dark period, which corresponds to a higher heart rate. Under zoletil anesthesia, a shorter RR interval was found in both light phases of the rat regimen day compared with values from telemetry studies, indicating a tachycardic effect of this anesthetic. The shortened duration of the RR interval corresponded to increased heart rate in both sexes in both lighted periods of the regimen day. Among females, LD differences were not observed in the duration of the RR interval (light, 142.30 ± 25.19 ms vs. dark, 134.97 ± 9.09 ms), in contrast to males, in which a significantly (p < 0.001) longer RR interval was recorded during the light part of the day (light, 145.05 ± 8.51 ms vs. dark, 124.68 ± 5.14 ms). Sex differences were found only in the dark (i.e., active) part of the day, with significantly shorter RR intervals in males. On the other hand, significant LD differences were maintained in males but eliminated in females. Addtitionally, compared to values reported in telemetry studies (Table 1), the RR interval was shorter, indicating a higher heart rate.
Our results, therefore, indicate that in zoletil-anesthetized rats, LD differences were maintained only in males but not in females. Considering the results of telemetry studies by Molcan et al. [50, 51], heart rate exhibits a significant circadian rhythm in non-anesthetized rats, in which the heart rate in the dark period fluctuated from 347 beats/min to 363 beats/min, and from 309 beats/min to 321 beats/min in the light period. Thus, it appears that although zoletil exerts a tachycardic effect, it can eliminate―or, at least modify―the circadian rhythm of heart rate, but only in females.
Such elimination or modification of LD differences in heart rate among females may also be partly explained by the greater sensitivity of females to acidosis, hypoxia, and hypercapnia under general anesthesia [52]. Previous studies have described the effect of hypoxia on the modulation of daily rhythmicity [53, 54, 55, 56, 57]. The fact that hypoxia modifies circadian oscillations of important variables, such as body temperature and metabolism, can lead to the expectation that the rhythms of many functions are interrupted by hypoxia on the basis of their relationship with the primary variables. Such a relationship likely contributes to a greater parasympathetic effect(s) on the heart [58]. Additionally, the effect of anesthetics can contribute to the loss or modification of rhythmicity. For example, in female rats under pentobarbital anesthesia, parasympathetic activity increases and sympathetic and baroreflex activity decreases; however, LD differences in heart rate are eliminated. Under ketamine/xylazine anesthesia, a preference toward parasympathetic activity was increased and sympathetic and baroreflex activity was depressed, resulting in significant bradycardia but with the maintenance of LD differences [59].
The paradox, under ketamine/xylazine anesthesia, therefore, remains—on the one hand, there is clearly evident increased parasympathetic activity and, on the other hand, increased heart rate. This paradox has been described by several authors [60, 61, 62, 63, 64, 65], who assumed that stimulation of the vagal nerve releases catecholamines, which in turn can affect heart activity. This is also probably the case with zoletil anesthesia, which may have a similar effect on the release of catecholamines through higher parasympathetic activity, and is particularly evident in males in both light periods of the regimen day. Because sympathetic tone is significantly reduced and parasympathetic tone dominates, it is assumed that the duration of RR intervals is predominantly determined by the parasympathetic system.
Despite the large variation in HRV spectral powers under zoletil anesthesia, in terms of sex differences, parasympathetic activity dominated in both sexes and in both light periods. In terms of sex differences, female HRV was significantly lower compared to males in the light period, while in the dark part of the regimen day, it was, in contrast, significantly higher in females compared to males (Figure 2).
Representation of heart rate variability (HRV) spectral powers in a rat model under zoletil anesthesia in both sexes. VLF – Spectral power of the very low frequency of HRV; LF - spectral power of the low frequency of HRV; HF - spectral power of high frequency of HRV; TSP – Total spectral power of HRV. Yellow columns – Light period of the rat regimen day; blue columns – Dark period of the rat regimen day.
Sympathetic activity dominates the normal life cycle of rats [7, 65] and zoletil anesthesia increases parasympathetic activity in both sexes. Similar results have been reported in previous studies. Administration of the anesthetic agent tribromoethanol in male Wistar rats [66], ketamine hydrochloride and diazepam in albino Wistar rats [67], and ketamine/xylazine and pentobarbital in females [59] resulted in predominant parasympathetic activity. However, our results indicate that precisely defining changes in HRV are difficult due to significant variability, which in turn makes it difficult to attribute sex differences. Thus, we agree with the opinion described in the introduction that approaches based on ECG recording under general anesthesia are not fully valid for HRV analysis.
In males under zoletil anesthesia—spectral power of HF (parasympathetic activity, r = 0.96) during the light and dark periods of the regimen day, spectral power of LF (baroreflex activity, r = 0.95), but also spectral power of HF (parasympathetic activity, r = 0.81) significantly contributed to changes in the total spectral power of HRV. Sympathetic activity is practically not involved in the formation of the total spectral power of HRV. The participation of individual spectral powers, as well as the total spectral power of HRV in the duration of RR intervals, is minimal in both lighted periods of the rat regimen day (Table 2). After analysis of the dependence of the duration of RR intervals on the total spectral power of HRV, we came to the conclusion that the duration of RR intervals (i.e., heart rate) is not regulated by the ANS in both light periods of the rat regimen day. We assume that other mechanisms are likely involved in the regulation of heart rate and are activated by zoletil.
Variable | Sex, light cycle | |||
---|---|---|---|---|
Female, light | Female, dark | Male, light | Male, dark | |
RR-VLF | r = 0.34 | r = −0.13 | ||
RR-LF | r = 0.26 | r = −0.12 | ||
RR-HF | r = 0.37 | r = 0.20 | r = 0.06 | |
RR-TSP | r = 0.28 | r = 0.06 | ||
TSP-VLF | r = 0.05 | |||
TSP-LF | ||||
TSP-HF |
Correlation coefficients of RR interval duration between spectral powers of heart rate variability (HRV) and the share of individual spectral powers in changes in the total spectral power of HRV.
Bolded values indicate statistically significant dependence between single parameters. VLF – spectral power of the very low frequency of HRV; LF - spectral power of the low frequency of HRV; HF - spectral power of the high frequency of HRV; TSP – total spectral power of HRV.
In female rats under zoletil anesthesia, the spectral power of LF (baroreflex activity, r = 0.99) and spectral power of HF (parasympathetic activity, r = 0.92) contributed significantly to changes in the total spectral power of HRV during the light period of the day and during the dark period proportionally in all three spectral powers of HRV. Sympathetic activity in both lighted periods was involved in the formation of the total spectral power of HRV in females (Table 2). After analysis of the dependence of the duration of RR intervals on the total spectral power of HRV, we found that the duration of RR intervals (i.e., heart rate) was under the regulatory influence of the ANS in both lighted periods of the rat regimen day (light, r = 0.51; dark, r = 0.61) with proportional representation of all three spectral powers of HRV.
We conclude that there are sex differences in the total spectral power of HRV in zoletil-anesthetized Wistar rats. In the light period in females, HRV was significantly lower than in males, and vice versa in males in the dark period of the regimen day. This means that, in females, the myocardium may be more sensitive to ANS regulatory interventions in the dark versus the light period. It is generally accepted that decreased HRV is a predictor of myocardial infarction mortality and increased HRV is associated with decreased morbidity and mortality. From this point of view, in zoletil-anesthetized female Wistar rats, during the active (dark) period, there is greater electrical stability in the myocardium than during the inactive (light) period. On the contrary, in males, the heart more sensitive reacts to changes in ANS activity in the light versus the dark period of the regimen day.
In females, changes in HRV were the result of sympathetic (i.e., VLF) and baroreflex (i.e., LF) activities and, in males, parasympathetic (i.e., HF) activity dominated. Among females, changes in RR were primarily due to changes in HRV, whereas in males, changes in HRV had no effect on RR in both lighted parts of rat regimen day. The results of these studies show that not only sex—but also the time of day experiments are performed—also plays an important role [68]. However, supportive evidence of HRV changes in rats during a 24 h period is lacking.
The LF/HF ratio can be used to quantify the changing relationship between sympathetic and parasympathetic nerve activity (i.e., sympathetic-vagal balance) [69, 70, 71]. The exact interpretation of the LF/HF ratio also depends on the assumption that physiological interventions always cause mutual changes in parasympathetic and sympathetic activity.
Our results demonstrate that the LF/HF ratio depends on the light periods of the regimen day. In females in the light period, the LF/HF ratio was significantly higher and in the dark period, significantly lower than in males. These conclusions, however, should be interpreted with caution. In a study addressing the meaning of HRV examination, Billman [72] questioned the evaluation of the LF/HF ratio. The LF component of HRV does not provide a cardiac sympathetic response index, but rather reflects a complex and not a readily recognizable mixture of sympathetic, parasympathetic, and other unidentified factors with parasympathetic factors, which account for the largest part of the variability in this frequency range. As a result, it is difficult to recognize the physiological basis for LF/HF. In addition, a relatively large amount of data suggests that the spectral power of the HF component cannot be attributed solely to changes in cardiac vagal efferentation, further compromising the accurate interpretation of the LF/HF ratio [72].
In
Based on our results, we conclude that under zoletil anesthesia, sympathetic (VLF) and baroreceptor (LF) activity were decreased, and parasympathetic (HF) activity was increased in both sexes and in both light periods. LD differences were preserved mainly in the HF component; thus, the circadian rhythm in parasympathetic activity likely also exists in both sexes. In terms of sex differences based on the total spectral power of HRV, our results suggest that HRV, in the light period of the rat regimen day, was significantly lower in females versus males. In the dark period, females exhibited higher HRV than males. In terms of LD differences, in females, HRV was lower in the light versus the dark period, unlike males, in which HRV was higher in the dark versus the light period of the rat regimen day.
The authors declare no conflict of interest.
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\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Article and has the right to contact the Corresponding Author and any Co-Author until the Article is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Article,
\\n\\nIntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n"}]'},components:[{type:"htmlEditorComponent",content:"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Journal Article:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Article who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author. Co-Author: All other Authors of the Article besides the Corresponding Author. IntechOpen: IntechOpen Ltd., the Publisher of the Journal.
\n\nJournal: The publication as a collection of Articles compiled by IntechOpen .
\n\nArticle: The original literary work created by Corresponding Author and any Co Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use and make available the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works, in electronic and print editions of the Publication and in derivative works and on any platform owned and/or operated by IntechOpen, throughout the world, in all languages, and in all media and formats now known or later developed.
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Article, including the right to deposit the Article in open access digital repositories.
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works under the condition that the Corresponding Author and each Co-Author is attributed (currently this is carried out by publishing the Article under a Creative Commons 4.0 International Licence).
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Article but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Article as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world. The Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Article and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Article.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Article as a consequence of IntechOpen's changes to the Article arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Article, the Corresponding Author agrees to credit the Journal in which the Article has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Journal in which the Article has been published as the source of first publication, as well as IntechOpen, when they are distributing or re publishing the Article.
\n\n3.2 When submitting the Article, the Corresponding Author agrees to:
\n\n• Comply with all instructions and guidelines provided by IntechOpen;
\n\n• Produce the Article with all due skill, care and diligence, and in accordance with good scientific practice;
\n\n• Submit all the corrections in due time as defined during the publishing process schedule.
\n\nThe Corresponding Author will be held responsible for the payment of the Article Processing Charge.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Article worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Article does not and will not breach any applicable law or the rights of any third party and, specifically, that the Article contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Article is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Article has not been formally published in any other peer-reviewed journal or in a Journal or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication
\n\nAgreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Article to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Article was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Article on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Article attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Article and has the right to contact the Corresponding Author and any Co-Author until the Article is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Article,
\n\nIntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. 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. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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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He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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